Discontinuation of pembrolizumab for advanced urothelial carcinoma without disease progression: Nationwide cohort study.

Pembrolizumab, an anti-programmed death 1 monoclonal antibody, has revolutionized the treatment of metastatic urothelial carcinoma. However, the optimal treatment duration for treatment responders has not been established. To address this, we retrospectively assess the treatment outcomes and duration of pembrolizumab for patients whose best response was complete response (CR) or partial response (PR) in a Japanese nationwide cohort of platinum-refractory metastatic urothelial carcinoma. Of 203 patients whose best response was CR or PR, 83 patients discontinued pembrolizumab before progression. The median pembrolizumab treatment duration was 6.9 months. The 2-year relapse-free survival (RFS), treatment-free survival, and OS rates after discontinuation were 49.0%, 57.4%, and 74.5%, respectively. CR, higher hemoglobin levels, and a better Eastern Cooperative Oncology Group performance status at the time of discontinuation were associated with significantly better RFS. Pembrolizumab was re-administered to 12 patients. Pembrolizumab re-challenge resulted in CR, PR, stable disease, and progressive disease in six, three, two, and one patient, respectively. Propensity score-matched landmark analysis revealed no significant OS difference between patients who continued or discontinued pembrolizumab at 6, 12, and 18 months (p = 0.91, 0.99, and 0.25, respectively). Our findings demonstrated that patients with objective responses had favorable survival outcomes and suggested that pembrolizumab could be discontinued safely in this population. This study should drive further efforts to optimize the treatment duration for pembrolizumab responders.

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching.

BACKGROUND: We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC). METHODS: A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients <75 and ≥75 years old were compared. RESULTS: The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged <75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the <75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age <75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the <75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651). CONCLUSIONS: The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.

Pre-pembrolizumab neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of second-line pembrolizumab treatment in urothelial cancer regardless of the pre-chemo NLR.

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P < 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.

[Multi-institute survey on actual conditions of urologic management for severe bladder dysfunction after hysterectomy].

We conducted a multi-institute survey on the conditions related to urologic management of severe voiding dysfunction after hysterectomy for uterine cancer with or without postoperative irradiation. Our first study population was a group of adult female patients currently managed by urologists, using clean intermittent catheterization (CIC). Of the 287 patients in this group, 99 (34%) had suffered from uterine cancer. Of these patients, 94 underwent hysterectomy for this disease; 44 and 30 were treated with or without postoperative radiation, respectively, while postoperative irradiation status was unknown for 20. Median follow-up after surgery was 21 (0.2-52) years and median interval from operation to the introduction of CIC was 4.0 (0-49) years. CIC tended to be introduced later for patients with postoperative radiation than those without it. Seventy-four patients, who required invasive urologic interventions other than CIC for voiding dysfunction after hysterectomy, are the second study population. Most of these (82%) had received postoperative irradiation. Continuous Foley catheter placement was the most frequent procedure. Long-term follow-up and urologic management for voiding dysfunction is required for patients undergoing hysterectomy.

High throughput comparative genomic hybridization array analysis of multifocal urothelial cancers.

The purpose of this study was to examine genetic alterations occur during synchronous or metachronous multifocal development of urothelial cancers on the whole genome using a comparative genomic hybridization (CGH) array. We used 10 tumor pairs (2 tumors for each patient), in which we had previously defined a clonal relationship by microsatellite analysis. For CGH array analysis, Vysis GenoSensor Array 300 kit was used. An unsupervised hierarchical cluster analysis revealed that the tumors from one patient were clustered together independent of the tumors of all other patients. On the other hand, many genetic divergences among multifocal urothelial cancers were newly found by a CGH array analysis. The concordant genetic alteration patterns of the chromosomal arm in tumor pairs were most frequently observed in 9p, 9q, 8p, 7p, 7q and 11q, while discordant patterns were most frequently found in 15q, 20q, 2q, 10p and 11q. Investigation using a CGH array showed that genetically stable multifocal tumors were less frequent, and that a large percentage of urothelial cancers accumulate genetic alterations during multifocal development by clonal evolution. We might have to consider these genetic accumulations during multifocal development when designing strategies for prevention and detection of recurrent multifocal urothelial cancers. CGH array can be a powerful tool for genetic analysis of multifocal urothelial cancer.

Epithelial stromal tumor of the seminal vesicle.

Primary tumors of the seminal vesicles are rare neoplasms; there have been only 69 accepted cases. The histologic features are usually adenocarcinoma; however, there are rarely reported epithelial stromal tumors of the seminal vesicles. We report a case of a 70-year-old man with an epithelial stromal tumor of the seminal vesicle who presented without symptoms of bladder outlet obstruction. The patient underwent radical cystoprostatectomy. No signs of tumor recurrence were noted within 14 months of surgery. To our knowledge, 13 cases of epithelial stromal tumors of the seminal vesicle have been previously reported.

[BK virus nephropathy in a kidney transplant recipient: a case report and literature review].

BK virus nephropathy (BKVN) has emerged as an important cause of allograft dysfunction and loss in kidney transplant recipients. We present a case in a 30-year-old female who underwent ABO-compatible living kidney transplant from her mother and was maintained with tacrolimus, mycophenolate mofetil and prednisolone. The serum creatinine level was stabilized about 0.9 mg/dl on postoperative day (POD) 35. On POD258, the serum creatinine increased to 1.8 mg/dl and the patient received methylpredonisolone pulse therapy under the diagnosis of acute rejection, which resulted in further increase in creatinine level from 1.8 to 2.6 mg/dl. Urine cytology showed decoy cells, but renal biopsy specimen showed no evidence of viral infection. Despite histopathological findings, positive urine and serum BKV-DNA suggested that allograft dysfunction was caused by BKVN. Therefore, the immunosuppession was reduced and gamma-globuline was given for 2 weeks. After the treatment, urine cytology became negative for decoy cells and serum creatinine level recovered to 2.0 mg/dl. On POD456, serum creatinine level was stabilized about 1.8 mg/dl and decoy cells remained negative.

Biweekly paclitaxel and gemcitabine for patients with advanced urothelial cancer ineligible for cisplatin-based regimen.

BACKGROUND: To avoid cisplatin-related gastrointestinal, renal and other toxicity while maintaining efficacy in the palliative setting or second line chemotherapeutic regimen for cisplatin-resistant urothelial cancer, chemotherapeutic regimens have been investigated that do not include cisplatin. The current study was designed to evaluate efficacy, clinical feasibility and safety of gemcitabine and paclitaxel (GP) regimen in patients with metastatic urothelial cancer who were ineligible for standard cisplatin-based combination chemotherapy. METHODS: Gemcitabine 2500 mg/m(2) and paclitaxel 150 mg/m(2) were administered intravenously every 2 weeks for 23 patients (17 males and 6 females) with advanced urothelial cancer who were ineligible for cisplatin-based chemotherapy; metastatic disease being resistant to cisplatin-based chemotherapy regimen in 14, heavy toxicity in prior cisplatin-based chemotherapy in three, poor ECOG performance in two and impaired renal function in four. Average age was 67 (53-77). Performance status was 0 in 18 patients, 1 in three patients and 2 in two patients. RESULTS: The overall response rate was 30% (95% CI 15.6-50.8%). Of the 23 patients, no patient attained CR and 7 patients had PR. In the cisplatin-resistant group, the response rate was 14.2% (2/14; 95% CI 4.0-39.9%). In the remaining patients ineligible for cisplatin, the response rate was 55.5% (5/9; 95% CI 26.6-81.1%). The median duration of response was 4 months (range 3-8). The median duration of survival for all patients was 12.1 months (95% CI 8.6-15.5). Myelosuppression, predominantly neutropenia, was the most common serious toxicity and toxicity of Grade 3 or greater was observed in six patients (26%). Among non-hematological toxicity, neuralgia was the most commonly observed and occurred in nine patients (39%) although no patient had toxicity of Grade 3 or greater. Three patients had interstitial pneumonitis possibly attributed to gemcitabine. One patient developed severe bilateral disease after two cycles of the regimen, which was partially resolved with corticosteroid therapy. CONCLUSION: GP regimen is effective in some patients with cisplatin-resistant urothelial cancer and promising as second line chemotherapy. GP regimen is more effective and well tolerated as first line chemotherapy in patients ineligible for cisplatin-based chemotherapy. Toxicity is generally mild but care must be taken for patients with risk of interstitial pneumonitis. A further larger scale study is required to confirm the efficacy of the GP regimen.

Monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer.

BACKGROUND: We aimed to determine the safety and efficacy of monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with prostate cancer that was progressing despite androgen ablation therapy were treated with i.v. paclitaxel, 175 mg/m2, over 3 h, followed by carboplatin (area under the curve, 5) on day 1, with oral estramustine phosphate, 280 mg twice daily, for a 28-day treatment cycle. Estramustine phosphate was precluded in those patients who had experienced adverse effects during prior chemotherapies. Patients were evaluated for response every cycle, and the treatment was continued until the cancer progressed. RESULTS: Twenty-one patients with progressive hormone-refractory disease were treated for a median of 4 cycles (range, 1 to 11 cycles). Estramustine phosphate was precluded in seven patients. Post-therapy decreases in serum prostate-specific antigen levels of 50% and 75%, respectively, were seen in 43% and 19% of the patients (95% confidence intervals, 22% to 64% and 2% to 36%). Of the nine patients with measurable disease, 1 (11%) had a complete response and 2 (22%) had a partial response. The overall median time to progression was 4 months, and the median survival time for all patients was 11 months. Major grade 3 or 4 adverse effects were anemia (29%), neutropenia (48%), and thrombocytopenia (24%). Mild peripheral neuropathy and myalgia/arthralgia were observed in 11 (52%) and 9 (43%) patients, respectively. CONCLUSION: Monthly paclitaxel and carboplatin with oral estramustine phosphate has significant antitumor activity and is well tolerated in patients with progressive HRPC.

[The influence over the long-term prognosis of BCG therapy and the surgical treatment in superficial bladder cancer treatment].

From the view point that total cystectomy is important in treatment of carcinoma in situ (CIS) of the bladder, we reviewed the cases showing resistance to bacillus Calmette-Guerin (BCG) among 42 CIS treated with intravesical BCG. Twenty-six cases were cured by BCG treatment. Twelve total cystectomies were done in 16 cases of BCG-resistant CIS of the bladder. Four died with urethral invasion or upper urinary tract recurrence. There was invasion into the prostate in 3 cases. The development of CIS to the upper urinary tract and the prostatic urethra is not rare and this has an influence on the prognosis. In bladder CIS treatment, the inspection to see extravesical progression is necessary. It is important not to delay the radical cystectomy.

[Transitional cell carcinoma in prostate after intravesical instillation of Bacillus Calmette-Guerin].

We report 3 cases of prostatic involvement of transitional cell carcinomas (TCCs). All cases presented positive urinary cytology after intravesical instillation of Bacillus Calmette-Guerin (BCG) and then random biopsy of bladder and transurethral resection (TUR)-biopsy of prostatic urethra were performed. TUR-biopsy demonstrated TCC in the prostate, although random biopsy failed to detect tumors in the bladder in all cases. Case 1 was treated with cystourethrectomy with ileal conduit, case 2 was treated with cystourethrectomy with bilateral ureterocutaneostomy and case 3 was treated with cystectomy with orthotopic ileal neobladder reconstruction. All cases are alive with no evidence of disease. TUR-biopsy of prostatic urethra should be perfomed when patients present positive urinary cytology after BCG instillation therapy, because prostatic involvement of TCC associated with bladder carcinoma in situ is not rare.

Polymorphism within the cyclin D1 gene is associated with an increased risk of carcinoma in situ in patients with superficial bladder cancer.

OBJECTIVES: To evaluate the prognostic value of CCND1 polymorphism in superficial and invasive transitional cell cancer of the bladder. METHODS: CCND1 polymorphism of blood DNA from patients with transitional cell cancer of the bladder was evaluated using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No statistically significant difference was found in the recurrence-free survival of patients with superficial (pTa-T1) transitional cell cancer after transurethral resection among different genotype groups (AA versus GG, P = 0.746; GA versus GG, P = 0.979). In patients with superficial bladder cancer, the occurrence of primary carcinoma in situ was significantly greater in patients with the AA genotype compared with those with the GA or GG genotypes (P = 0.006, chi-square test). No statistically significant difference was found in disease-specific survival after radical cystectomy among the different genotype subgroups (AA versus GG, P = 0.245; GA versus GG, P = 0.649). CONCLUSIONS: Although CCND1 polymorphism is not able to serve as a prognostic marker for bladder cancer, the CCND1 variant A allele may recessively increase the risk of carcinoma in situ incidence in patients with superficial bladder cancer.

Pathology of interstitial cystitis.

In this workshop the participants were asked to consider the role of pathology in the diagnosis and management of interstitial cystitis (IC). Currently, the NIDDK definition of IC is made on clinical criteria; bladder biopsy is not required for the clinical work-up and histology is not used as a diagnostic criterion. The literature review described the most common pathological findings to be epithelial denudation or ulceration, mononuclear inflammation, edema, congestion, hemorrhage, and mast cell activation. These pathological changes were not universal or specific with 55% of IC subjects in one study having histology that was normal and indistinguishable from control subjects. Presentations were made which generally confirmed an association between abnormal pathology and more severe disease as determined by symptoms, cystoscopic capacity, and prognosis. During the workshop it was clear that whether or not a biopsy was performed depended on a number of factors, for example, country of origin, the research interest of the unit, and the desire to exclude malignancy on histological grounds. The consensus, which was not unanimous, was that bladder biopsy was a-non-mandatory test in the clinical work-up of the patient with IC but that urine cytology should be performed. It was discussed that bladder biopsy be an optional test and particularly relevant when one was suspicious of other conditions and in IC research. It was hoped that bladder biopsy pathology will give clues to contributory pathogenic processes such as epithelial dysfunction and inflammation; and in the future, with the help of molecular biology, may help determine etiology.

[Vesical actinomycosis: a case report].

A 55-year-old woman had complained of lower abdominal pain for 5 years. A computed tomographic CT scan and magnetic resonance imaging revealed a heterogeneous density mass on the left side of the bladder. CT-guided needle biopsy showed only inflammatory cell infiltration without histological diagnosis. To confirm the diagnosis, the mass was resected together with part of the bladder and peritoneum. On the cut surface, the mass was centrally pale yellow and adherent to the thickened hard wall of the bladder and peritoneum. Pathological diagnosis was chronic granulomatous inflammation with actinomycosis. This is, to our knowledge, the 12th case report of vesical actinomycosis in Japan. Although actinomycosis is very rare in urological field, abdominal actinomycosis should be considered as the differential diagnosis of any inflammatory abdominal mass.

[Adult sacrococcygeal teratoma: a case report].

We report a case of adult sacrococcygeal teratoma resected by an abdominosacral approach. A cystic mass 13 cm in diameter in the pelvic cavity and left hydronephrosis were detected incidentally by abdominal computed tomographic (CT) scan in a 55-year-old man. The pelvic tumor extending from the presacral area to the coccyx was resected via a combined abdominal and transsacral approach. The resected specimen weighed 700 g and the pathological diagnosis was mature teratoma. While the sacrococcygeal area is the most frequent site of teratoma in infants, it is a rare site in adults. This is to our knowledge, the 30th case report of adult sacrococcygeal teratoma in Japan. At one month after the operation the patient had no bowel dysfunction and no dysbasia, but he had mild bladder dysfunction requiring self-catheterization twice a day at twelve months. The patient had no evidence of disease at twenty months after the operation.

Resistance of DRH strain rats to chemical carcinogenesis of liver: genetic analysis of later progression stage.

The inbred DRH rats are highly resistant to the induction of hepatocellular carcinoma (HCC) by feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Previously, we found that two quantitative trait loci (QTLs), Drh1 and Drh2, significantly reduced the number, size and area of glutathione S-transferase-placental form (GST-P)-positive foci and GST-P mRNA levels in (F344xDRH)F(2) rat livers induced by feeding 3'-Me-DAB for 8 weeks. It is unclear, however, whether these QTLs affecting pre-neoplastic lesions are also the determinants of the later stage hepatocarcinogenesis, and whether there are any additional QTLs affecting hepatocarcinogenesis in the progression stage. To answer these questions, we analyzed QTL parameters for liver tumors in 99 (F344xDRH)F(2) rats induced by feeding 3'-Me-DAB for 20 weeks. The QTL parameters examined were GST-P mRNA, ornithine decarboxylase activity, and the number and total area of HCC/nodules macroscopically detectable on the liver surface. In composite interval mapping, we observed two major QTL peaks overlapping on the map positions of Drh1 on rat chromosome 1 (RNO1) and Drh2 on RNO4, respectively. The newly mapped QTL on RNO1 affected the GST-P mRNA level at 20 weeks of 3'-Me-DAB feeding, but did not affect the number and size of tumors. The primary effect of Drh1 is, therefore, to inhibit GST-P induction and to prevent enzyme altered foci (EAF) formation. On the other hand, the QTLs on RNO4, co-mapped to Drh2, affected all parameters of liver tumors examined except for the level of GST-P mRNA. The latter QTLs influenced not only the induction of GST-P and formation of EAF but also the progression of tumors in the later stage of hepatocarcinogenesis. The GST-P induction is differentially controlled by stages of hepatocarcinogenesis and the DRH resistance to carcinogenesis is principally attributed to the QTLs on RNO4 out of two resistance QTLs identified in the pre-neoplastic stage.