Impact of salvage cytotoxic chemotherapy on prognosis in patients with recurrence after radical cystectomy: a multi-institutional retrospective study.

BACKGROUND: In patients experiencing disease recurrence after radical cystectomy (RC) for bladder cancer, data about the impact of clinicopathologic factors, including salvage treatment using cytotoxic chemotherapy, on the survival are scarce. We investigated the prognostic value of clinicopathologic factors and the treatment effect of salvage cytotoxic chemotherapy (SC) in such patients. METHODS: In this retrospective study, we evaluated the clinical data for 86 patients who experienced recurrence after RC. Administration of SC or of best supportive care (BSC) was determined in consultation with the urologist in charge and in accordance with each patient's performance status, wishes for treatment, and renal function. Statistical analyses explored for prognostic factors and evaluated the treatment effect of SC compared with BSC in terms of cancer-specific survival (CSS). RESULTS: Multivariate analyses showed that liver metastasis after RC (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.17 to 3.85; P = 0.01) and locally advanced disease at RC (HR 1.92; 95% CI 1.06 to 3.46; P = 0.03) are independent risk factors for worse CSS in patients experiencing recurrence after RC. In a risk stratification model, patients were assigned to one of two groups based on liver metastasis and locally advanced stage. In the high-risk group, which included 68 patients with 1-2 risk factors, CSS was significantly better for patients receiving SC than for those receiving BSC (median survival duration: 9.4 months vs. 2.4 months, P = 0.005). The therapeutic effect of SC was not related to a history of adjuvant chemotherapy. CONCLUSIONS: The present study indicated the potential value of 1st-line SC in patients experiencing recurrence after RC even with advanced features, such as liver metastasis after RC and locally advanced disease at RC.

Oncologic Outcomes of Salvage Chemotherapy in Patients with Recurrent or Metastatic Lesions after Radical Nephroureterectomy: A Multi-Institutional Retrospective Study.

BACKGROUND: Radical nephroureterectomy (RNU) is the standard treatment for patients with upper tract urothelial carcinoma (UTUC). However, approximately 25% of patients experience recurrence or metastasis after RNU. This study evaluated the clinical outcome and efficacy of salvage chemotherapy (SC) after recurrence or metastasis. PATIENTS AND METHODS: Of the 441 nonmetastatic UTUC patients who underwent RNU, 147 patients with recurrent or metastatic lesions were analyzed; patients with bladder cancer recurrence were excluded. Time from disease recurrence or metastasis to cancer-specific survival (CSS) was estimated by the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. RESULTS: The median time from RNU to disease recurrence or metastasis was 13.2 months. In the recurrent or metastatic sites, 31 cases (21%) were liver. In multivariate analyses, pT stage (≥pT3), time to recurrence (<12 months), and liver metastasis were independently predictive factors. In the risk stratification model for CSS after recurrence, patients were categorized into 2 groups based on pT stage, time to recurrence, and liver metastasis. The low-risk group (0-1 risk factors) included 87 patients, and the high-risk group (2-3 risk factors) included 60 patients. In the high-risk group, 27 patients received SC. The probability of CSS after recurrence or metastasis was higher in patients in the SC group compared to the non-SC group (9.5 vs. 3.7 months; p < 0.001). CONCLUSION: Two or more risk factors defined the high-risk group for patients with recurrence or metastasis after RNU. SC was associated with improved survival in patients with high-risk UTUC.

Prognostic impact of preoperative renal function in patients treated with radical cystectomy: a multi-institutional retrospective study.

BACKGROUND: Little data on the preoperative prognostic factors in radical cystectomy (RC) patients have made it difficult to choose the appropriate type of urothelial diversion (UD). This study aimed to investigate the prognostic role of UD, with a subgroup analysis of that of preoperative renal function. METHODS: From 1990 to 2015, 279 patients underwent RC for bladder cancer at six hospitals affiliated with Kitasato University in Japan. All patients were divided into three groups: cutaneous ureterostomy (CU; n = 54), ileal conduit (IC; n = 139), and orthotopic neobladder (NB; n = 86). Patients were also stratified into three groups based on preoperative estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2): normal eGFR (> 60 mL/min/1.73 m2; n = 149), moderately reduced eGFR (45-60 mL/min/1.73 m2; n = 66), and severely reduced eGFR (< 45 mL/min/1.73 m2; n = 37). Statistical analyses were performed to investigate prognostic values of UD and preoperative eGFR. RESULTS: Kaplan-Meier analyses showed that progression-free survival (PFS) and cancer-specific survival (CSS) did not differ between the three types of UD groups. With regard to renal function, the preoperative severely reduced group had significantly worse PFS and CSS than the other groups. The multivariate analysis showed that severely reduced preoperative eGFR was an independent risk factor of worse PFS and worse CSS. CONCLUSION: The present study demonstrated that preoperative severe renal function was shown as an independent risk factor of both PFS and CSS.

Histologic variants associated with biological aggressiveness and poor prognosis in patients treated with radical cystectomy.

BACKGROUND: The prognostic value of histologic variants (HV) after radical cystectomy (RC) remains controversial. We evaluated the clinicopathological features and prognosis in patients with pure urothelial carcinoma (UC) and HV following RC. METHODS: From 1990 to 2015, 286 patients with bladder cancer were treated with RC at six Kitasato University-affiliated hospitals. All patients were divided into two groups: pure UC and HV, which contained pure variants and mixed-type UC with variant pattern. A comparison of patient characteristics between the two groups was made to assess the clinicopathological features, and statistical analyses were performed to investigate prognosis in the two groups. RESULTS: Of the 286 patients, 226 (79%) had pure UC, while 60 (21%) had HV. Of all HV, pure variants accounted for 45% (n = 27). The prevalence of lymph node involvement, locally advanced stage (≥ pT3), positive soft tissue surgical margin and lymphovascular invasion were significantly higher in patients with HV than in those with pure UC. Patients with HV showed worse disease-free survival and cancer-specific survival than those with pure UC (P = 0.009 and 0.003, respectively). In multivariate analysis, HV and lymph node involvement were independent predictors of worse disease-free survival (P = 0.017 and 0.001, respectively). HV, locally advanced stage, lymph node involvement, and positive soft tissue surgical margin were also confirmed as independent predictors of worse cancer-specific survival (P = 0.011, 0.012, 0.003 and 0.010, respectively.). CONCLUSIONS: HV was associated with greater biological aggressiveness and worse prognosis than pure UC.

Impact of histologic variants on the oncological outcomes of patients with upper urinary tract cancers treated with radical surgery: a multi-institutional retrospective study.

BACKGROUND: No definitive evidence exists regarding the clinical significance of histologic variants (HV) in upper urinary tract cancer. We investigated the impact of HV on prognosis in patients with upper urinary tract cancer following radical surgery. PATIENTS AND METHODS: We retrospectively analyzed 451 patients with upper urinary tract cancer who underwent radical nephroureterectomy at six affiliated hospitals from 1990 to 2015. Patients with distant metastatic disease prior to surgery and those who received neoadjuvant chemotherapy were excluded, leaving 441 eligible patients. Patients were classified into two groups: pure urothelial carcinoma (UC) and HV. The clinicopathological variables of each group were examined using Kaplan-Meier plots and proportional Cox hazard ratios (HR) to compare the oncological outcomes between the two groups. RESULTS: HV included 37 patients (8%). Compared with the pure UC patients, HV patients had significantly worse recurrence-free survival (RFS) and cancer-specific survival (CSS; RFS p = 0.0002, CSS p = 0.0001). Multivariate analysis for RFS revealed HV were independent predictors (HR 1.92; p = 0.026), but the association did not remain significant for CSS. There was no significant difference in CSS between the adjuvant chemotherapy (AC) group and the non-AC group for all HV patients, except in patients with ≥ pT3 tumor or positive lymph node status where the AC group had significantly favorable CSS. CONCLUSIONS: HV in upper urinary tract cancer are independent predictors for RFS, but not for CSS. AC improved CSS for HV patients with ≥ pT3 tumor or positive lymph node status.

[A Case of Hydrocephalus Due to Brain Metastasis from Renal Cell Carcinoma Successfully Treated with Axitinib].

We report a case of hydrocephalus due to brain metastasis from renal cell carcinoma treated with axitinib. A 65-year-old man had undergone right radical nephrectomy for renal cell carcinoma in 2010. The pathological diagnosis indicated clear cell carcinoma G3, pT1a. After adjuvant treatment with interferon-α, computed tomography, in 2011, revealed multiple lung metastases. He was administered sorafenib. Because of progressive lung metastases, sunitinib was administered. The lung metastases were progressive and bone scan revealed multiple bone metastases. The patient was administered axitinib 10 mg/day in February 2014. Brain metastases were found in both the lateral ventricles in the same month and were controlled using axitinib. The patient, however, experienced adverse events such as diarrhea and hand foot syndrome, and the axitinib dosage was titrated. Cognitive function declined rapidly in August 2015. Brain magnetic resonance imaging revealed hydrocephalus due to brain metastasis from renal cell carcinoma. Axitinib was administered again. Cognitive function improved within approximately 10 days. Furthermore, hydrocephalus improved, and the patient was discharged on the 21st day.

Noninferior oncological outcomes in adults aged 80 years or older compared with younger patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma.

AIM: Radical nephroureterectomy (RNU) is the gold standard treatment for upper tract urothelial carcinoma (UTUC), but the usefulness of this surgery for older patients is rarely discussed. The prognosis following RNU for patients ≥80 years old remains controversial. We retrospectively investigated the prognosis of UTUC in patients ≥80 years old who underwent RNU. METHODS: Between January 1990 and December 2015, 451 patients with UTUC underwent RNU at six hospitals affiliated with Kitasato University (Kanagawa, Japan), eight patients who underwent neoadjuvant chemotherapy and two patients with metastases before surgery were excluded. Patients were divided into three groups according to their age at the time of RNU: ≤64 years (n = 135), 65-79 years (n = 254), and ≥80 years (n = 52). Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) curves were estimated using Kaplan-Meier analysis for all patients and each pT stage. Independent prognostic factors for survival were examined via multivariate analysis. RESULTS: RFS and CSS did not significantly differ between the three groups, but OS was significantly poorer in patients ≥80 years old. Stratification by pT stage (≤pT1, ≥pT2, and ≥pT3) yielded the same results. In the multivariate analysis for OS, an age of ≥80 years was a significant independent risk factor (hazard ratio: 3.01, p = .01), but RFS and CSS did not significantly differ. CONCLUSION: Oncological outcomes showed the same anticancer effects in patients ≥80 years old who underwent RNU for UTUC compared with those of younger patients. Our study suggests that surgical treatment is a beneficial option for older patients who can tolerate radical surgery.

A multi-institutional retrospective study of open versus laparoscopic nephroureterectomy focused on the intravesical recurrence.

AIM: Intravesical recurrence (IVR) after nephroureterectomy for upper tract urothelial carcinoma (UTUC) is relatively frequent, occurring in about 30-50% of patients. The aim of this study was to investigate the differences of the prognosis and IVR between open and laparoscopic surgery and to elucidate the risk factor of IVR. PATIENTS AND METHODS: We retrospectively analyzed data from 403 patients with UTUC treated with laparoscopic or open nephroureterectomy at six affiliated hospitals between 1990 and 2015. The clinicopathological factors of each group were examined using Kaplan-Meier plots, and univariate and multivariate analyses. RESULTS: There was no difference in recurrence and cancer-specific mortality between open and laparoscopic surgery in univariate and multivariate analyses. There was no significant difference in IVR rate between the laparoscopic and open groups (p = .22). Among the patients with IVR, 84% of patients relapsed within 2 years. Univariate analysis of IVR showed a significant increase in patients with low-grade (p = .03, HR = 1.64) or low-stage urothelial carcinoma (pT1 or lower, p = .006, HR = 1.77) with no lymph node involvement (p = .002, HR = 10.3) or lymphovascular invasion (p = .009, HR = 1.79). Surgical modality was not an independent factor. In multivariate analysis, there was no independent predictive factor for IVR. CONCLUSIONS: There was no difference in recurrence, cancer-specific mortality, and IVR between open and laparoscopic surgery. On the other hand, our results suggested that the low malignant potential tumor may be a risk factor for IVR. This finding provides insight into IVR, which may help with the development of personalized prevention and treatment strategies.

Investigation of estimated glomerular filtration rate and its perioperative change in patients with upper urinary tract urothelial carcinoma: A multi-institutional retrospective study.

AIM: To investigate the association of perioperative estimated glomerular filtration rate (eGFR) with prognosis in patients with upper urinary tract urothoelial caicinoma (UTUC). METHODS: A total of 433 patients underwent radical nephroureterectomy with excision of the bladder cuff (RNU) at six hospitals affiliated with Kitasato University in Japan. Patients were divided into three groups each in terms of preoperative eGFR: normal eGFR (>60 mL/min/1.73 m2 ; n = 172), moderately reduced eGFR (45-60 mL/min/1.73 m2 ; n = 147) and severely reduced eGFR (<45 mL/min/1.73 m2 ; n = 114), and with regard to changes between pre- and postoperative eGFR: normal change (increased or <10% decreased; n = 132), moderate change (10%-30% decreased; n = 172) and severe change (>30% decreased; n = 129). Statistical analyses were performed to investigate the association between perioperative eGFR and prognosis. RESULTS: Patients in the preoperative normal and moderately reduced eGFR group had significantly better progression-free survival (PFS) and cancer-specific survival (CSS) than those in the severely reduced eGFR group (both; P < 0.001). With regard to changes in postoperative eGFR, PFS and CSS were significantly better in patients in the severe and moderate change group than in those in the normal change group (both; P < 0.001). When adjusted for the effects of clinicopathological features, pathologic factors were associated with both PFS and CSS, but perioperative eGFR were not independent prognostic factors. CONCLUSIONS: Patients with preoperative normal and moderately reduced eGFR and those with severe and moderate change in postoperative eGFR appeared to have a significantly better prognosis.

Impact of body mass index on the oncological outcomes of patients with upper and lower urinary tract cancers treated with radical surgery: A multi-institutional retrospective study.

AIM: To evaluate the impact of body mass index (BMI) on the oncological outcomes of urothelial carcinoma (UC) patients. PATIENTS AND METHODS: We retrospectively analyzed data from 818 patients with upper tract urothelial cancer (UTUC) and bladder cancer (BC) who were treated with radical nephroureterectomy (RNU) or radical cystectomy (RC) between 1990 and 2015 at six different institutions in Japan. Patients with distant metastasis at diagnosis and those who received neoadjuvant therapies were excluded, leaving 727 eligible patients (UTUC: n = 441; BC: n = 286). Patients were classified into four groups according to World Health Organization BMI criteria: underweight (BMI <18.5  kg/m2 ), normal weight (BMI 18.5-25 kg/m2 ), overweight (BMI 25.1-30 kg/m2 ), and obese (BMI >30 kg/m2 ). RESULTS: Overweight UTUC and BC patients achieved significantly better cancer-specific survival (CSS) than the other three groups. However, obese UTUC and BC patients had significantly worse CSS than the other three groups (UTUC: P = 0.031; BC: P = 0.0019). Multivariate analysis of BC patients demonstrated that obesity was an independent predictor of unfavorable CSS (hazard ratio [HR] = 7.47; P = 0.002) and that being underweight was an independent predictor of favorable CSS (HR = 0.37; P = 0.029). However, BMI was not a prognostic factor for CSS in UTUC patients according to multivariate analysis. CONCLUSIONS: Obesity was an independent predictor of BC patients requiring RC. Conversely, being underweight was associated with a favorable prognosis for BC patients. However, BMI was not an independent prognostic factor in patients with upper urinary tract cancer.

Selected High-Risk Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy for Adjuvant Chemotherapy: A Multi-Institutional Retrospective Study.

BACKGROUND: No definitive evidence exists regarding use of adjuvant chemotherapy (AC) for high-risk cases after radical nephroureterectomy (RNU), and the benefit of AC remains controversial. The aims of this study were to evaluate the efficacy of AC in patients with upper tract urothelial carcinoma (UTUC) and to determine those who qualified for AC. PATIENTS AND METHODS: From 1990 to 2015, 449 patients with nonmetastatic UTUC underwent RNU at 6 Kitasato University-affiliated hospitals. Eight patients who received neoadjuvant chemotherapy were excluded from this study. One hundred patients (23%) received platinum-based AC for a median of 3 courses. Disease-free survival and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. RESULTS: The median age was 69 years, and the median follow-up period was 35.7 months. In multivariate analyses, factors independently predictive of poorer survival included pT stage (≥pT3), lymph node status (pN+), tumor grade (Grade 3), lymphovascular invasion, and soft tissue surgical margin. For the risk stratification model, patients were categorized into 3 groups on the basis of these 5 risk factors. In the high-risk group (at least 3 risk factors, 83 patients), 41 patients (49%) were treated with AC, and the 5-year CSS rate was higher in the AC group compared with the non-AC group (P = .02). CONCLUSION: Having more than 3 risk factors defined the high-risk group among UTUC patients after RNU. AC was associated with improved CSS in patients with high-risk UTUC.

A Case of Urachal Carcinoma of the Abdominal Wall in a Kidney Transplant Recipient.

Urachal carcinoma is an extremely rare malignant tumor arising from the urachus in the fetus. We report a patient who developed urachal carcinoma 18 years after kidney transplantation. A 59-year-old man was admitted because of abdominal pain and massive ascites. He had undergone kidney transplantation 18 years earlier and had end-stage renal disease requiring dialysis. Abdominal CT showed massive ascites and an abdominal wall cystic mass separated from the peritoneal cavity. Hemodialysis was started, and paralytic ileus was diagnosed and treated. His ileus symptoms improved temporarily, but he died of myocardial infarction. An autopsy was performed, which revealed cystadenocarcinoma in the abdominal wall mass, leading to a diagnosis of urachal carcinoma.

Gemcitabine plus nedaplatin as salvage therapy is a favorable option for patients with progressive metastatic urothelial carcinoma after two lines of chemotherapy.

This study was conducted to evaluate the effectiveness of a combination of gemcitabine and nedaplatin therapy among patients with metastatic urothelial carcinoma previously treated with two lines of chemotherapy. Between February 2009 and August 2013, 30 patients were treated with gemcitabine and paclitaxel as a second-line chemotherapy. All had received a first-line chemotherapy consisting of methotrexate, vinblastine, doxorubicin and cisplatin. Ten patients who had measurable histologically proven advanced or metastatic urothelial carcinoma of the urinary bladder and upper urinary tract received gemcitabine 1,000 mg/m2 on days 1, 8 and 15 and nedaplatin 70 mg/m2 on day 2 as a third-line chemotherapy. Tumors were assessed by imaging every two cycles. The median number of treatment cycles was 3.5. One patient had partial response and three had stable disease. The disease-control rate was 40%, the median overall survival was 8.8 months and the median progression-free survival was 5.0 months. The median overall survival times for the first-line and second-line therapies were 29.1 and 13.9 months, respectively. Among disease-controlled patients (n=4), median overall survival was 14.2 months. Myelosuppression was the most common toxicity. There were no therapy-related deaths. Gemcitabine and nedaplatin chemotherapy is a favorable third-line chemotherapeutic option for patients with metastatic urothelial carcinoma. Given the safety and benefit profile seen in this study, further prospective trials are warranted given the implications of our results with regard to strategic chemotherapy for patients with advanced or metastatic urothelial carcinoma.

Protein expression profile related to cisplatin resistance in bladder cancer cell lines detected by two-dimensional gel electrophoresis.

We used a proteomic approach to compare the differentially regulated protein expression profiles of cisplatin-naïve and cisplatin-resistant bladder cancer cell lines to screen candidate molecules related to cisplatin resistance. The cisplatin-resistant cell line T24 was established by the stepwise exposure of T24 cells to up to 40 µM of cisplatin. We performed a comprehensive study of protein expression in bladder cancer cell lines that included cisplatin-naïve (T24) and cisplatin-resistant cells (T24CDDPR) by means of agarose two-dimensional gel electrophoresis followed by analysis of liquid chromatography tandem mass spectroscopy. We identified 25 obviously different spots for T24 and T24 CDDPR. Seven spots had increased expression and 18 spots had decreased expression in T24CDDPR compared to those in T24. Cytoskeletal proteins and enzyme modulators were prominent among differential proteins. Of the 25 proteins, we selected HNRNPA3, PCK2, PPL, PGK1, TKT, SERPINB2, GOT2, and EIF3A for further validation by Western blot. HNRNPA3, PGK1, TKT, and SERPINB2 had more than 1.5-times incremental expression in T24CDDPR compared to that in T24. PCK2 and PPL expressions were decreased less than 20% in T24CDDPR compared to that in T24. The results of 25 new proteins in this study could be valuable and could lead to the development of a new molecular marker.

Prostatic stromal sarcoma with neuroectodermal differentiation.

Prostatic stromal sarcoma is a fairly rare tumor that constitutes approximately 0.1-0.2% of all prostatic cancers. Detailed characteristics of the tumor are still unclear due to its rarity.We describe a case of prostatic stromal sarcoma in a 63 year-old man who suffered from urinary obstructive symptoms. Palliative transuterine resection was performed and the preliminary histopathological diagnosis was neuroendocrine carcinoma. After chemotherapy, total pelvic exenteration was performed. Histopathologically, the tumor was composed of monotonously proliferating small to medium-sized round cells, which existed in compact islands with loose or dense fibrovascular networks. Immunohistochemically, the tumor cells were widely positive for vimentin, CD56, CD99 and focally positive for synaptophysin, CD10, progesterone receptor, desmin and CD34, but negative for EMA, cytokeratin, estrogen receptor, S-100 and myoglobin. Most of the previously reported tumors exhibited positive stainability for CD10 and progesterone receptor. In addition to these markers, expressions of CD56, CD99 and synaptophysin were characteristically detected in our case. To the best of our knowledge, we present the first case of prostatic stromal sarcoma with characteristic immunohistochemical staining properties. Although the biological characteristics of this rare tumor have not yet been elucidated, these findings suggest prostatic stromal sarcoma can potentially show neuroectodermal differentiation. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7291874028051262.

Laparoscopic radical cystectomy and bilateral ureteric ligation for muscle-invasive bladder cancer in a patient on hemodialysis.

Laparoscopic cystectomy and bilateral ureteric ligation were performed on a 52-year-old woman with end-stage renal disease on hemodialysis (HD) for muscle-invasive bladder cancer. Her volume of urine production was approximately 100 mL/day. Excisions of the bladder and uterus with ligation of the bilateral ureter were conducted completely laparoscopically. Total operative time was 280 min and the amount of blood loss was 60 mL. No complications were seen perioperatively and no adverse events regarding ureteric ligation arose. HD was performed on the second postoperative day. At a 12-month follow-up, the patient showed no evidence of disease.

Immediate improvement of a persistent cough after tumor embolization for renal cell carcinoma--a rare manifestation of paraneoplastic syndrome.

We report an interesting case of a patient with renal cell carcinoma who developed a refractory cough, which immediately resolved after tumor embolization. Patient's symptoms including low-grade fever, weight loss, and abnormal laboratory results also improved shortly after subsequent nephrectomy. The clinical manifestations of the patient are most likely representing paraneoplastic syndrome secondary to renal cell carcinoma.