Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

An unusual case of Aß2M amyloid deposition in bladder cancer in a non-dialysis patient.

ß2-microglobulin-related (Aß2M) amyloidosis (dialysis-associated amyloidosis) is a common complication in long-term dialysis patients. An increased concentration of ß2-microgloblin (ß2-m) in the serum appears to be a prerequisite for Aß2M amyloidosis, in turn causing Aß2M amyloid deposition predominantly in the osteoarticular tissue. There are few reports, however, of Aß2M amyloid deposition in non-dialysis patients. We describe an atypical case of a non-dialysis patient with Aß2M amyloid deposition in bladder cancer. A Japanese man in his 80s with no history of dialysis was admitted for transurethral resection of bladder cancer. Histopathological analysis revealed a small amount of amyloid deposition in the small-vessel wall of both the peripheral urothelial carcinoma and necrotic area. Amyloid typing by immunohistochemistry was strongly positive for anti-ß2-m antibody, and ß2-m was most frequently detected in laser microdissection-liquid chromatography tandem mass spectrometry. Although Aß2M amyloidosis was expected, contrary to this, the patient's serum ß2-m was only 4 mg/L, although his urine ß2-m level was increased at 1340 mg/L. The unique findings observed in our patient may contribute to the elucidation of the novel pathogenesis of Aß2M amyloid fibril formation that is distinct from conventional Aß2M amyloidosis.

Identification of curable high-risk prostate cancer using radical prostatectomy alone: who are the good candidates for undergoing radical prostatectomy among patients with high-risk prostate cancer?

BACKGROUND: Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with high-risk PCa who are treatable by RP alone. METHODS: We retrospectively reviewed data on 315 patients with D'Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors. RESULTS: At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92, p < 0.05) and % positive core (≥ 30%, HR 2.85, p < 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03; p < 0.0001). CONCLUSION: The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).

Use of preoperative performance status and hemoglobin concentration to predict overall survival for patients aged ≥ 75 years after radical cystectomy for treatment of bladder cancer.

BACKGROUND: The standard of care for treatment of localized muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC). The patient's condition may affect management of MIBC, especially for elderly patients with more comorbid conditions and lower performance status. We retrospectively evaluated the association between clinicopathological data and outcomes for patients with bladder cancer (BCa) treated by RC. We particularly focused on elderly patients (age ≥75 years) with BCa. METHODS: We enrolled 254 patients with BCa who underwent RC and urinary diversion with or without pelvic lymph node dissection. We assessed perioperative complications and clinicopathological data affecting overall survival (OS) after RC. RESULTS: The incidence of complications was 34.3 %, and that of severe complications (Grade 3-5) was 16.5 %. The elderly group experienced more severe complications (P = 0.042). Median follow-up was 43.0 months (range 1.0-155.6). Five-year OS after RC was 62.7 %. OS after RC was no different for patients aged ≥75 and <75 years (P = 0.983). Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) and hemoglobin (Hb) concentration were associated with all-cause mortality. Hb concentration of <12.6 g/dl was an independent predictor of a poor prognosis among elderly patients after RC for BCa. ECOG PS >1 tended to affect OS after RC in this group. CONCLUSION: ECOG PS and preoperative Hb concentration were useful for prediction of clinical outcome after RC for elderly patients. This information may aid decision-making in the treatment of elderly patients with MIBC.

Angiotensin-II combined intra-arterial chemotherapy for locally advanced bladder cancer: a case series study at a single institution.

Patients with locally advanced bladder cancer are at significant risk for metastases. We aimed to evaluate the usefulness of intra-arterial chemotherapy (IAC) combined with angiotensin-II (AT-II) in such patients. The possibility of bladder preservation is also discussed. Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4NxM0). Cisplatin, pirarubicin, and AT-II were infused through the tumor-feeding arteries. Cause-specific survival was the end point. We enrolled 37 patients who were treated with neoadjuvant IAC and 5 patients with adjuvant IAC. There were 7 patients (16.7%) with pathological complete remission. Overall 5-year and 10-year survival rates of the patients were 61.3% and 47.7%, respectively. The 5-year cause-specific survival rate was 100% for the clinical T2 group and 63% for the T3-4 group, and the 8-year survival rate was 33% and 63%, respectively. There was no statistically significant difference between these two groups (P=0.445). Multivariable analysis using tumor number, pattern of growth, and tumor size seemed to independently correlate with cause-specific survival, but there were no significant differences. Our results suggest that intra-arterial chemotherapy combined with AT-II is a useful treatment for patients with locally advanced bladder cancer, since this modality achieves a favorable response rate without severe toxicity or mortality.

In vitro antitumor activity of bropirimine against urinary bladder tumor cells.

BACKGROUND: Bropirimine is an orally-active immunostimulant that has an antitumor effect on superficial transitional cell carcinoma of the bladder. The mechanism of its antitumor effect has not yet been clarified. MATERIALS AND METHODS: The cytokine-mediated antiproliferative activity of bropirimine was tested against cultured KK-47 and 724 cells using a modified human clonogenic tumor assay. Perpheral blood mononuclear cells (PBMCs) obtained from five healthy volunteers were co-cultured with bropirimine and the levels of various cytokines, including IFN-alpha, gamma, IL-1beta and TNF-alpha in the supernatants, were quantified. RESULTS: Colony formation by both cell lines was directly inhibited by bropirimine in a dose-dependent manner. In co-cultures of bropirimine and PBMCs, the inhibition of colony formation by both cell lines was not enhanced compared with the effect of bropirimine alone. No significant elevation of cytokines was detected in the presence of PBMCs. CONCLUSION: The results obtained suggest that bropirimine is like to have direct antitumor activity rather than a cytokine-mediated antitumor effect.

Granulocyte colony-stimulating factor may promote proliferation of human bladder cancer cells mediated by basic fibroblast growth factor.

OBJECTIVES: To investigate whether granulocyte colony-stimulating factor (G-CSF) promotes the proliferation of two bladder cancer cell lines, and to assess the mechanism of tumor proliferation in terms of cytokine expression. MATERIAL AND METHODS: The proliferation of two bladder cancer cell lines derived from transitional cell carcinoma (KK-47 and T-24) was assessed by using the double-layer soft agarose colony assay in combination with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Seven cytokines were measured in the culture supernatant. Expression of granulocyte colony-stimulating factor (G-CSF) receptor and fibroblast growth factor (FGF) receptor mRNA was studied by means of reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Recombinant human G-CSF (rhG-CSF) caused greater induction of the proliferation of KK-47 cells in the presence than in the absence of peripheral blood mononuclear cells (PBMCs) and its effect was dose-dependent. In contrast, rhG-CSF did not stimulate the proliferation of T-24 cells. Among several cytokines measured, only basic FGF was elevated in cultures of KK-47 cells with or without PBMCs. The basic FGF level was significantly increased by rhG-CSF stimulation in a dose-dependent manner. Specific PCR products for the G-CSF and FGF receptors were observed in KK-47 cells as well as PBMC, while no G-CSF receptor was detected in T-24 cells. CONCLUSION: rhG-CSF may promote the proliferation of KK-47 cells, probably via an increase in basic FGF production.

Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guérin immunotherapy for carcinoma in situ of the bladder.

PURPOSE: The mechanism by which bacillus Calmette-Guérin (BCG) mediates antitumor activity has not been clearly established. Specific cytokines in the urine after BCG intravesical instillation therapy may serve as a prognostic factor of treatment response. In this study, various urinary cytokines such as interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8. IL-10, IL-12, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were measured. MATERIALS AND METHODS: In total 20 patients were treated with BCG intravesical instillation therapy for carcinoma in situ of the bladder. At the completion of the first and eighth instillations, spontaneously voided urine specimens were collected before BCG instillation, every 2 h until 12 h, and thereafter until 24 h. All specimens were ultrafiltrated using an ADVANTEC UK-10 membrane. The cytokines were measured using ELISA and RIA techniques. RESULTS: Significantly higher levels of IL-2, IL-6, IL-8, IL-10, IFN-gamma, and TNF-alpha were detected in the eighth instillation as compared to the first instillation ( p<0.001). After BCG intravesical instillation therapy, treatment failure occurred in 6 of the 20 patients (30%), including primary failure (persistence of CIS) in 3, and de novo failure (tumor recurrence) in 3 with a median follow-up of 46.9 months. Significantly higher production of IL-2, IL-6, IL-8, IL-10, and TNF-alpha was observed in the responder group than in the non-responder group ( p<0.05). Multivariate analysis revealed IL-2 as an independent prognostic cytokine of responder status. CONCLUSIONS: This study indicates that urinary IL-2 at the eighth instillation of BCG may serve as a valuable prognostic factor of treatment efficacy as well as tumor recurrence after treatment.