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In a trial comparing enfortumab vedotin and a PD-1 inhibitor with chemotherapy in patients with untreated advanced or metastatic urothelial cancer, progression-free and overall survival nearly doubled with the experimental treatment.

The aim of this study is to examine the incidence and risk factors of upper urinary tract recurrence (UUTR) following radical cystectomy (RC) in bladder cancer and to evaluate its relationship with neobladder (Neo) or ileal conduit (IC). All clinicopathologic parameters and perioperative parameters of 311 patients who underwent RC with either Neo or IC by a single surgeon from 1999 to 2012 were retrospectively included in this study. Patients with a history of renal surgery, concomitant UUTR, or a histopathology of non-transitional cell carcinoma were excluded. For statistical analyses of predictive risk factors of UUTR, a multivariate analysis was performed with known risk factors of UUTR, including type of urinary diversion with significance defined as P < 0.05. During the median follow-up period of 53 months, 143 (46.0%) IC and 168 (54.0%) Neo were performed, resulting in 11 (3.5%) cases of UUTR (Neo 7 and IC 4) after RC and all patients then underwent nephroureterectomy. No significant differences in incidence and overall survival in UUTR were observed according different types of urinary diversion (p = 483), and the prognosis for survival of Neo was insignificantly better than that of IC (5-year overall survival 78% vs 74%, respectively, p>0.05). Higher number of positive lymph nodes (HR 9.03) and the presence of pelvic local recurrence (HR 7286.08) were significant predictive factors of UUTR (p<0.05). This study reports a UUTR rate of 3.5%, and positive lymph nodes and presence of local recurrence at the pelvis as important risk factors. No significant differences in incidence and survival were observed between Neo and IC.

The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation and survival and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF-1 des in prostate epithelial cells. This encodes a mature isoform of IGF-1 with decreased affinity for IGF binding proteins (IGFBP) due to a 3-amino acid deletion in the N terminus. Expression of IGF-1 des was sufficient to cause hyperplastic lesions in all mice, however the well-differentiated lesions did not progress to adenocarcinoma within a year. Remarkably, crossing the PB-Des mice to an established model of prostate cancer delayed progression of organ-confined tumors and emergence of metastatic lesions in young mice. While dissemination of metastatic lesions was widespread in old bigenic mice we did not detect IGF-1 des in poorly differentiated primary tumors or metastatic lesions. Expression of endogenous IGF-1 and levels of P-Akt and P-Erk were reduced independent of age. These data suggest that increased physiologic levels of IGF-1 facilitate the emergence of hyperplastic lesions while imposing a strong IGF-1-dependent differentiation block. Selection against IGF-1 action appears requisite for progression of localized disease and metastogenesis.

To determine whether a limited immunohistochemical panel can help differentiate metastatic colonic adenocarcinoma from primary enteric-type adenocarcinoma of the urinary tract and urothelial (transitional cell) carcinoma with glandular differentiation, which appear morphologically similar but most often necessitate different treatment protocols. We examined lower urinary tract tumors (5 urinary bladder, 2 urethral) from 7 patients with a history of colonic adenocarcinoma. The differential diagnoses in these cases included metastatic colonic adenocarcinoma, primary enteric-type adenocarcinoma of the urinary tract, and urothelial carcinoma with glandular differentiation. An immunohistochemical panel consisting of cytokeratin 7 (CK-7), cytokeratin 20 (CK-20), and villin was evaluated in all cases. Four primary enteric-type adenocarcinomas of the urinary tract and 5 conventional urothelial carcinomas were also studied to compare morphologic features and immunohistochemical staining patterns. Of the 7 cases, 6 were determined to be metastatic colonic adenocarcinoma and 1 was diagnosed as a primary urothelial carcinoma with glandular differentiation. All 6 metastatic colonic adenocarcinomas, 6 of the 7 primary colonic adenocarcinomas, and all 4 primary enteric-type adenocarcinomas of the urinary tract were CK-20 positive (1 was CK-20 negative), villin positive, and CK-7 negative. The single urothelial carcinoma with glandular differentiation and all 5 control cases of urothelial carcinoma were CK-7 and CK-20 positive, and villin negative. We conclude that (1) villin is expressed in primary enteric-type adenocarcinoma of the urinary tract; (2) in difficult cases, urothelial carcinoma with glandular differentiation can be distinguished from colonic adenocarcinoma because the former is CK-7 positive, CK-20 positive, and villin negative, whereas the latter is CK-20 positive, villin positive, and CK-7 negative; (3) clinical information is essential when evaluating lower urinary tract tumors that are clinically and morphologically similar to enteric-type adenocarcinoma of the urinary tract; and (4) the similar immunohistochemical profiles of metastatic colonic adenocarcinoma and primary enteric-type adenocarcinoma of the urinary tract may be in keeping with the hypothesis that the latter arise from intestinal metaplasia.

Objective To evaluate the efficacy and toxicity of third-line gemcitabine monotherapy (Gem) in patients with platinum-resistant advanced urothelial cancer (UC). Patients and methods From July 2005 to March 2009, 13 patients were enrolled. All patients had previously received methotrexate, vinblastine, doxorubicin, and cisplatin as first-line therapy. Second-line therapy consisted of paclitaxel/carboplatin (Pca) therapy: paclitaxel (175 mg/m 2 ) followed by carboplatin (area under the curve = 5) was intravenously infused on day 1 of each 21-day cycle. Following Pca failure, Gem was given as third-line treatment: gemcitabine (1,000 mg/m 2 ) was intravenously administered on days 1, 8, and 15 of each 28-day cycle. All patients were eligible for toxicity assessment. Survival curves were produced using the Kaplan–Meier method. Results An average of 3.2 Gem cycles (range, 1–8 cycles) were given. Following Gem treatment, overall response rates were 0% CR, 7.7% PR ( n  = 1), 53.8% SD ( n  = 7), and 38.5% PD ( n  = 5). Grade 3–4 toxicities included anemia (31%), neutropenia (31%), and thrombocytopenia (31%). One case experienced grade 3–4 hepatic dysfunction during treatment with Gem. Low-grade alopecia was observed in all 13 patients (100%). Median time to progression and overall survival was 2 and 7.3 months, respectively, following Gem. The 1- and 2-year overall survival rate was 30.8% and 15.3%, respectively, for Gem. Conclusion Gem as third-line therapy was performed safely with good tolerability in platinum-resistant advanced UC, even though the efficacy was very limited.

This study investigated morbidity, mortality, and long-term survival after multimodality management of locally recurrent rectal carcinoma involving the urinary tract. A total of 82 patients (63 males) were identified during 1987 to 2000. Data sources were a prospectively collected database of intraoperative radiotherapy, institutional tumor registry, and chart review. The median follow-up was 3.3 years and lasted until death or for at least 2 years on all patients. A total of 20 (24%) of 82 patients had resection of urogenital tract structures without reconstruction. Sixty-two patients (76%) underwent reconstruction with ileal conduit (43%), ureteroneocystostomy (15%), or miscellaneous (18%). The mean number of fixation sites was 2.8 (SD, 1.5), and the mean number of organs at least partially resected was 2.6 (SD, 1.3). Eighty percent of patients underwent intraoperative radiotherapy among adjuvant treatments. Postoperative mortality was 2% (2 of 82), and morbidity was 39% (32 of 82), most frequently consisting of neuropathy and urinary leak (6% each). The overall 1-, 3-, and 5-year survival rates were 82%, 45%, and 19%, respectively. The median survival was 2.6 years. The number of sites involved was the only survival predictor at multivariate analysis (P < .001). A multimodality approach for locally recurrent rectal carcinoma involving the urinary tract carries acceptable morbidity, mortality, and potential for long-term survival. The number of fixation sites correlates with a poorer prognosis.

Conventional frontline cisplatin-based combination chemotherapy with gemcitabine and cisplatin, or traditional or dose-dense methotrexate, vinblastine, doxorubicin and cisplatin, yields high response rates but few durable remissions for advanced urothelial cancer. Salvage therapy is generally disappointing with few responses. A significant proportion of patients exhibit renal dysfunction, entailing carboplatin-based regimens that appear inferior to cisplatin-based regimens, which warrants a special focus In this population. The profusion of novel biologic agents offers the promise of improved outcomes. A multidisciplinary approach is necessary to make therapeutic advances.

The median survival of patients with metastatic bladder cancer treated with M-VAC is approximately 1 year and long-term survival occurs in a small proportion of patients. Recent efforts to improve the outcome of patients with metastatic transitional cell carcinoma have focused on identifying new drugs with single agent activity and on their incorporation into platinum-based combination regimens. Paclitaxel, docetaxel, ifosfamide and gemcitabine are among the most active new agents. A large number of phase I-II trials have evaluated these agents in two- and three-drug combination regimens. The response proportion observed with these combinations varies considerably and median survival times range from 8 to 20 months. A better understanding of the molecular biology of bladder cancer will undoubtedly influence the selection of new therapeutic modalities. Molecular targeted small molecule therapy and monoclonal antibodies have begun to dominate contemporary studies. Whether or not this approach to therapy will lead to better results must still be determined.