Taketo Kawai

Pretreatment neutrophil‐to‐lymphocyte ratio as an independent predictor of survival in patients with metastatic urothelial carcinoma: A multi‐institutional study

To evaluate the prognostic significance of the pretreatment neutrophil‐to‐lymphocyte ratio in patients with metastatic urothelial carcinoma who underwent salvage chemotherapy.

Prognostic Factors for Metastatic Urothelial Carcinoma Undergoing Cisplatin-based Salvage Chemotherapy

OBJECTIVE To assess the clinicopathologic factors influencing survival in patients with metastatic urothelial carcinoma undergoing salvage chemotherapy. METHODS A retrospective review was conducted on cases of metastatic urothelial carcinoma who underwent cisplatin-based salvage chemotherapy at our institution between April 2003 and July 2011. The association of various clinicopathologic factors with survival was assessed. Survival curves were constructed by the Kaplan-Meier method. A log-rank test for univariate analysis and a Cox proportional hazards model for multivariate analysis were used. RESULTS Eighty-three cases were identified in the study. Among them, 64 patients were dead during the follow-up. The median survival was 14.6 months. Multivariate analysis evaluating variables at the start of chemotherapy demonstrated that liver metastasis, performance status score ≥ 2 and leukocyte counts ≥ 8000/µl were significant predictive factors for poor outcome. Based on these three pre-induction variables, a risk model predicting the overall survival from the initiation of chemotherapy was constructed, which classified patients into three groups with significantly different overall survival (P < 0.0001). Additionally, factors after induction of chemotherapy were studied, and poor response for chemotherapy and absence of focal treatment for metastatic lesions were also significantly associated with poorer survival. CONCLUSIONS Liver metastasis, poor performance status and higher leukocyte counts were independent poor prognostic indicators for metastatic urothelial carcinoma. Our risk classification enables an accurate prediction of survival that can be useful in deciding which patients are likely to benefit from salvage chemotherapy.

MAGE-A expression, immune microenvironment, and prognosis in upper urinary tract carcinoma

The melanoma-associated antigen A (MAGE-A) family comprises cancer-testis antigens that represent promising prognostic biomarkers and immunotherapy targets in several cancer types. The aim of this study was to investigate the significance of MAGE-A expression in upper urinary tract urothelial carcinoma in relation to clinicopathological features, lymphocytic infiltration, and clinical outcome. We immunohistochemically examined the expression of MAGE-A in 171 patients with upper urinary tract urothelial carcinoma. High (≥ 50% positive) and low MAGE-A expression levels were observed in 33 (19%) and 49 (29%) cases, respectively. MAGE-A was negative in 89 cases (52%). MAGE-A expression was positively correlated with high histologic grade; concomitant carcinoma in situ; higher Ki-67 proliferation index; and infiltration of CD3-, CD8-, and CD45RO-positive T lymphocytes, but not with CD20-positive B lymphocytes. High MAGE-A expression was significantly associated with shorter metastasis-free survival after nephroureterectomy (log-rank P = .019; multivariate hazard ratio, 1.98; 95% confidence interval, 1.00-3.92). MAGE-A expression in metastatic lymph nodes was highly correlated with its expression in primary lesions. MAGE-A expression was retained in chemotherapy-resistant metachronous metastatic lesions of urothelial carcinoma. MAGE-A may be a promising prognostic biomarker and potential immunotherapeutic target for patients with upper urinary tract urothelial carcinoma.

Nomogram for predicting survival of postcystectomy recurrent urothelial carcinoma of the bladder

PURPOSE We aimed to identify prognostic clinicopathological factors and to create a nomogram able to predict overall survival (OS) in recurrent urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC). MATERIALS AND METHODS Among 1,087 patients with UCB who had undergone RC at our 11 institutions between 1990 and 2010, 306 patients who subsequently developed distant metastasis or local recurrence or both were identified. Clinical data were collected with medical record review. Univariate and multivariate Cox regression models addressed OS after recurrence. A nomogram predicting postrecurrence OS was constructed based on Cox proportional hazards model, without using postrecurrence factors (systemic chemotherapy and resection of metastasis). The performance of the nomogram was internally validated by assessing concordance index and calibration plots. RESULTS Of the 306 patients, 268 died during follow-up with a median survival of 7 months (95% CI: 5.8-8.5). Postrecurrence chemotherapy was administered in 119 patients (38.9%). Multivariable analysis identified 9 independent predictors for OS; period of time from RC to recurrence (time-to-recurrence), symptomatic recurrence, liver metastasis, hemoglobin level, serum alkaline phosphatase level, serum lactate dehydrogenase level, serum C-reactive protein level, postrecurrence chemotherapy, and resection of metastasis. A nomogram was formed with the following 5 variables to predict OS: time-to-recurrence, symptomatic recurrence, liver metastasis, albumin level, and alkaline phosphatase level. Concordance index rate was 0.75 (95% CI: 0.72-0.78) by internal validation using Bootstraps with 1,000 resamples. Calibration plots showed that the nomogram fitted well. CONCLUSIONS We identified 9 clinicopathological factors as independent OS predictors in postcystectomy recurrence of UCB. We also created a validated nomogram with 5 variables that efficiently stratified those patients regardless of eligibility for chemotherapy. The nomogram would be useful for acquiring relevant prognostic information and for stratifying patients for clinical trials.

Clinical characteristics of testicular germ cell tumors in patients aged 50 years and older: A large‐scale study from the Cancer Registration Committee of the Japanese Urological Association

To determine the characteristics of testicular germ cell tumors in older patients.

Adjuvant Chemotherapy Is Possibly Beneficial for Locally Advanced or Node-Positive Bladder Cancer

BACKGROUND This study aimed to evaluate the outcomes of cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) in non-organ-confined bladder cancer. METHODS Sixty-one patients who did not receive neoadjuvant chemotherapy (NAC) underwent RC for locally advanced (pT3-4) or node-positive (pN1-3) bladder cancer, or both, between 1990 and 2012. Of these patients, 39 (64%) received cisplatin-based AC after RC (AC group) and the remaining 22 patients (36%) did not (non-AC group). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were compared between the groups. RESULTS The AC group was significantly younger (P = .004), but no significant differences were noted between the groups for pT stage, pN stage, nuclear grade, renal function, and salvage chemotherapy rates after recurrence. During a follow-up of 29 months (median), 40 patients (67%) experienced recurrence/metastasis and 34 (56%) died of recurrent bladder cancer. The AC group showed better RFS than the non-AC group, but the difference was not statistically significant (median survival time [MST], 23.7 vs. 11.4 months, respectively; P = .154). CSS was significantly better for the AC group than for the non-AC group (MST, 57.4 vs. 17.9 months, respectively; P = .008). On multivariate analysis, AC was an independent predictive factor for both RFS (hazard ratio [HR], 0.325; P = .005) and CSS (HR, 0.186; P < .001), along with surgical margin status and lymphovascular invasion (LVI). In a subgroup analysis of 31 node-positive cases, the AC group had a significantly better CSS compared with the non-AC group (P = .029). Analysis of node-negative cases (n = 30) yielded no significant benefit for AC. CONCLUSION Our observations suggest that postoperative cisplatin-based AC improves survival in locally advanced or node-positive bladder cancer, especially in node-positive cases.

Prognostic significance of neutrophil-to-lymphocyte ratio in collecting duct carcinoma

Collecting (Bellini) duct carcinoma of the kidney is a rare lethal tumor, and its prognostic factors remain unclear. The present study investigated the prognostic significance of neutrophil-to-lymphocyte ratio, which has recently been recognized as a readily available prognostic marker in various malignancies, in patients with collecting duct carcinoma. Of 11 patients who were pathologically diagnosed with collecting duct carcinoma at our institution, nine died of collecting duct carcinoma, one died of a postoperative complication, and one was alive, with a median follow-up period of 6 (range: 0-97) months. Both univariate and multivariate analyses associated neutrophil-to-lymphocyte ratio ≥4 (median) with worse cancer-specific survival. Notably, the sole surviving patient maintained a low neutrophil-to-lymphocyte ratio (<4) both at the initial diagnosis and at the time of distant recurrence. These results suggest that neutrophil-to-lymphocyte ratio might serve as a useful biomarker for collecting duct carcinoma as well as other malignancies.

The prognostic value of PD-L1 expression in upper tract urothelial carcinoma varies according to platelet count

Programmed cell death ligand‐1 (PD‐L1) is a ligand for programmed cell death‐1 (PD‐1) that negatively regulates T‐cell activation and plays a crucial role in suppressing anti‐tumor host immunity. Although PD‐L1 is a promising immunotherapy target in various cancers, including urothelial carcinoma (UC), the prognostic significance of PD‐L1 in UC is unclear. As platelets help protect tumor cells from immune elimination in the circulatory system, we hypothesized that tumor PD‐L1 and circulating platelets might synergistically promote tumor metastasis, and that the prognostic significance of PD‐L1 might vary according to platelet count. We immunohistochemically examined tumor PD‐L1 expression in 271 patients with upper tract UC, which revealed PD‐L1 positivity in 31 of 271 cases (11%). The associations of tumor PD‐L1 expression with outcomes varied among patients with high or low platelet counts (Pinteraction < 0.004). Among patients with high platelet counts (N = 136), PD‐L1 positivity (N = 15) was significantly associated with shorter metastasis‐free survival (univariate hazard ratio [HR]: 6.23, 95% confidence interval [CI]: 2.95‐13.1; multivariate HR: 2.68, 95% CI: 1.27‐5.64) and shorter overall survival (univariate HR: 4.92, 95% CI: 2.14‐11.3, multivariate HR: 2.78, 95% CI: 1.19‐6.51). In contrast, among patients with low platelet counts (N = 135), PD‐L1 positivity (N = 16) was not significantly associated with these outcomes. Our results suggest that tumor PD‐L1 expression and platelet count might interact and help regulate tumor progression. Although a larger prospective study is needed to validate our findings, this relationship is important to consider, as immunotherapies targeting the PD‐1/PD‐L1 axis have gained significant attention as promising therapies for UC.

Loss of Stromal Antigen 2 (STAG2) Expression in Upper Urinary Tract Carcinoma: Differential Prognostic Effect According to the Ki-67 Proliferating Index

BackgroundInactivating mutation and consequent expression loss of stromal antigen 2 (STAG2, also known as SA2), a component of the cohesion complex, is one of the most common genetic aberrations in urothelial carcinoma. However, the clinicopathologic or prognostic significance of STAG2 alterations in upper tract urothelial carcinoma (UTUC) is largely unknown.MethodsThis study immunohistochemically examined the expression of STAG2 in 171 patients with UTUC. The correlations of STAG2 loss with clinicopathologic features and patients’ prognoses were examined.ResultsLoss of STAG2 expression was observed in 28 cases (16%). Loss of STAG2 was significantly correlated with histological low grade, papillary architecture, noninvasive tumors, absence of concomitant carcinoma in situ, and lower Ki-67 expression. Loss of STAG2 alone was not significantly associated with patients’ prognoses in either the uni- or multivariate analysis. However, STAG2 loss was significantly associated with worse clinical outcome in UTUC with high Ki-67 proliferation indexes, but not in UTUC with low Ki-67 expression.ConclusionsLoss of STAG2 was generally associated with less aggressive features in UTUC. However, the STAG2 loss was an ominous sign in the subpopulation with higher Ki-67 proliferation indexes. Examining both STAG2 and Ki-67 status may be useful for identifying aggressive clinical behavior of UTUC.

Lower ureteral lesion is an independent predictor of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma

OBJECTIVE To elucidate whether the lower ureteral lesion can predict subsequent intravesical recurrence (IVR) in patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). PATIENTS AND METHODS We retrospectively reviewed 186 consecutive patients with UTUC who underwent RNU at our institution between 1996 and 2013. Associations of various clinicopathological factors with subsequent IVR were assessed. Lower ureteral lesion was defined as the pathologically confirmed lowest carcinoma component within 5 cm from the lower end of the ureter. The log-rank test and Cox proportional hazards model were used for univariable and multivariable analysis, respectively. RESULTS Overall, 86 patients (46%) developed IVR during the follow-up, with a median follow-up period of 43 months (interquartile range: 17-79 mo). In all, 53 patients (28%) had lower ureteral lesions, and 34 (64%) of them developed IVR. Univariable analysis demonstrated that lower ureteral lesion was significantly associated with IVR, as well as tumor multifocality, lymphatic invasion, and history of bladder cancer. Multivariable analysis identified the lower ureteral lesion as a sole independent predictor of IVR (P = 0.0304, hazard ratio = 1.74). CONCLUSIONS Lower ureteral lesion was an independent predictor of IVR in patients with UTUC treated with RNU. Such patients may deserve prophylactic treatment and intensive follow-up.