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Joaquim Bellmunt - One of the best experts on this subject based on the ideXlab platform.
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health related quality of life analysis from keynote 045 a phase iii study of pembrolizumab versus chemotherapy for previously treated advanced Urothelial Cancer
Journal of Clinical Oncology, 2018Co-Authors: David J Vaughn, Joaquim Bellmunt, Toni K Choueiri, Daniel P Petrylak, Yves Fradet, Jaelyun Lee, Lawrence Fong, Nicholas J Vogelzang, Miguel Angel Climent, A NecchiAbstract:Purpose In the phase III KEYNOTE-045 study ( ClinicalTrials.gov identifier: NCT02256436), pembrolizumab significantly prolonged overall survival compared with investigator's choice of chemotherapy in patients with previously treated advanced Urothelial Cancer. Here, we report the results of health-related quality-of-life (HRQoL) analyses from the KEYNOTE-045 trial. Patients and Methods Patients were randomly assigned 1:1 to pembrolizumab 200 mg or investigator's choice of docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 administered intravenously every 3 weeks. Key prespecified HRQoL analyses were time to deterioration (TTD) and mean change from baseline to week 15 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 global health status/quality-of-life score. Results Of 542 patients who were randomly assigned, 519 were included in HRQoL analyses (pembrolizumab, n = 266; chemotherapy, n = 253). HRQoL compliance was > 95% at baseline and approximately 88% at week 15 for both groups. Pembrolizumab prolonged TTD in global health status/quality-of-life score compared with chemotherapy (median, 3.5 months v 2.3 months; hazard ratio, 0.72; nominal one-sided P = .004). Mean (95% CI) change from baseline to week 15 in global health status/quality-of-life score was 0.69 (-2.40 to 3.77) with pembrolizumab and -8.36 (-11.84 to -4.89) with chemotherapy (mean difference, 9.05 points; 95% CI, 4.61 to 13.50; nominal two-sided P < .001). Conclusion Pembrolizumab prolonged TTD in HRQoL compared with chemotherapy. Patients who were treated with pembrolizumab had stable or improved global health status/quality of life, whereas those who were treated with investigator's choice of chemotherapy experienced declines in global health status/quality of life. Combined with efficacy and safety outcomes, these data support pembrolizumab as standard of care for patients with platinum-refractory advanced Urothelial Cancer.
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safety and activity of pembrolizumab in patients with locally advanced or metastatic Urothelial Cancer keynote 012 a non randomised open label phase 1b study
Lancet Oncology, 2017Co-Authors: Elizabeth R Plimack, Joaquim Bellmunt, Shilpa Gupta, Raanan Berger, Jonathan Juco, Jared Lunceford, Laura Quan Man Chow, Sanatan Saraf, Rodolfo F Perini, Peter H OdonnellAbstract:Summary Background PD-1 and its ligands are expressed in Urothelial Cancer, and findings have shown that inhibition of the PD-1 pathway has clinical benefit. We aimed to assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic Urothelial Cancer. Methods This study was part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket trial. We enrolled patients aged 18 years and older with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic Urothelial Cancer, including Cancers of the renal pelvis, ureter, bladder, or urethra, from eight hospitals in the USA and Israel. Patients were required to have at least 1% PD-L1 expression detected on the tumour cells or in tumour stroma, as determined by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab every 2 weeks until disease progression, unacceptable toxic effects, or the end of the study (ie, 24 months of treatment). Primary endpoints were safety and overall response (defined by Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1), as assessed by a masked, independent central review. Safety was assessed in patients who received one or more doses of pembrolizumab (all-patients-as-treated population); activity was assessed in patients who received pembrolizumab, had measurable disease at baseline, and had one or more post-baseline scans, or discontinued because of progressive disease or treatment-related adverse events (full analysis set). This study is registered with ClinicalTrials.gov, number NCT01848834, and is no longer enrolling patients; follow-up is ongoing. Findings Between May 14, 2013, and Dec 10, 2013, 115 patients were tissue pre-screened as part of a two-part consent process. 61 (53%) patients were PD-L1 positive, of whom 33 were enrolled in this study. All enrolled patients received at least one dose of pembrolizumab and were included in the safety analyses. 27 patients comprised the full analysis set and were deemed assessable for activity. Six patients were not assessable: three discontinued study drug because of a non-treatment-related adverse event before the first post-baseline scan, two withdrew before the first post-baseline scan, and one had no measurable disease at baseline. The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced five serious treatment-related adverse events. After median follow-up of 13 months (range 1–26, IQR 5–23), an overall response was achieved in seven (26% [95% CI 11–46]) of 27 assessable patients, with three (11% [2–29]) complete and four (15% [4–34]) partial responses. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related. Interpretation Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced Urothelial Cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population. Funding Merck & Co., Inc.
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pembrolizumab mk 3475 for advanced Urothelial Cancer updated results and biomarker analysis from keynote 012
Journal of Clinical Oncology, 2015Co-Authors: Elizabeth R Plimack, Joaquim Bellmunt, Shilpa Gupta, Raanan Berger, Robert B Montgomery, Karl Heath, Jonathan Juco, Kenneth Emancipator, Kumudu Pathiraja, Jared LuncefordAbstract:4502 Background: Pembrolizumab, an anti–PD-1 antibody, demonstrated antitumor activity and acceptable safety in patients with recurrent or metastatic PD-L1–positive Urothelial Cancer enrolled in th...
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neoadjuvant dose dense methotrexate vinblastine doxorubicin and cisplatin with pegfilgrastim support in muscle invasive Urothelial Cancer pathologic radiologic and biomarker correlates
Journal of Clinical Oncology, 2014Co-Authors: Toni K Choueiri, Joaquim Bellmunt, Susanna Jacobus, Angela Qu, Leonard Joseph Appleman, Christopher P G Tretter, Glenn J Bubley, Edward C Stack, Sabina Signoretti, Meghara K WalshAbstract:Purpose In advanced Urothelial Cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive Urothelial Cancer (MIUC). Patients and Methods Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Results Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% ...
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neoadjuvant dose dense methotrexate vinblastine doxorubicin and cisplatin with pegfilgrastim support in muscle invasive Urothelial Cancer pathologic radiologic and biomarker correlates
Journal of Clinical Oncology, 2014Co-Authors: Toni K Choueiri, Joaquim Bellmunt, Susanna Jacobus, Leonard Joseph Appleman, Christopher P G Tretter, Glenn J Bubley, Edward C Stack, Sabina Signoretti, Meghara K Walsh, Graeme S SteeleAbstract:Purpose In advanced Urothelial Cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive Urothelial Cancer (MIUC). Patients and Methods Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Results Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% ...
Mef Nilbert - One of the best experts on this subject based on the ideXlab platform.
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urinary tract Cancer in lynch syndrome increased risk in carriers of msh2 mutations
Urology, 2015Co-Authors: Patrick Joost, Christina Therkildsen, Mev Dominguezvalentin, Mats Jonsson, Mef NilbertAbstract:To evaluate the risk of Urothelial Cancer in the upper urinary tract and the bladder, determine the contribution from the different mismatch-repair genes and define clinical characteristics of Urothelial Cancer in Lynch syndrome.
Toni K Choueiri - One of the best experts on this subject based on the ideXlab platform.
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health related quality of life analysis from keynote 045 a phase iii study of pembrolizumab versus chemotherapy for previously treated advanced Urothelial Cancer
Journal of Clinical Oncology, 2018Co-Authors: David J Vaughn, Joaquim Bellmunt, Toni K Choueiri, Daniel P Petrylak, Yves Fradet, Jaelyun Lee, Lawrence Fong, Nicholas J Vogelzang, Miguel Angel Climent, A NecchiAbstract:Purpose In the phase III KEYNOTE-045 study ( ClinicalTrials.gov identifier: NCT02256436), pembrolizumab significantly prolonged overall survival compared with investigator's choice of chemotherapy in patients with previously treated advanced Urothelial Cancer. Here, we report the results of health-related quality-of-life (HRQoL) analyses from the KEYNOTE-045 trial. Patients and Methods Patients were randomly assigned 1:1 to pembrolizumab 200 mg or investigator's choice of docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 administered intravenously every 3 weeks. Key prespecified HRQoL analyses were time to deterioration (TTD) and mean change from baseline to week 15 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 global health status/quality-of-life score. Results Of 542 patients who were randomly assigned, 519 were included in HRQoL analyses (pembrolizumab, n = 266; chemotherapy, n = 253). HRQoL compliance was > 95% at baseline and approximately 88% at week 15 for both groups. Pembrolizumab prolonged TTD in global health status/quality-of-life score compared with chemotherapy (median, 3.5 months v 2.3 months; hazard ratio, 0.72; nominal one-sided P = .004). Mean (95% CI) change from baseline to week 15 in global health status/quality-of-life score was 0.69 (-2.40 to 3.77) with pembrolizumab and -8.36 (-11.84 to -4.89) with chemotherapy (mean difference, 9.05 points; 95% CI, 4.61 to 13.50; nominal two-sided P < .001). Conclusion Pembrolizumab prolonged TTD in HRQoL compared with chemotherapy. Patients who were treated with pembrolizumab had stable or improved global health status/quality of life, whereas those who were treated with investigator's choice of chemotherapy experienced declines in global health status/quality of life. Combined with efficacy and safety outcomes, these data support pembrolizumab as standard of care for patients with platinum-refractory advanced Urothelial Cancer.
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neoadjuvant dose dense methotrexate vinblastine doxorubicin and cisplatin with pegfilgrastim support in muscle invasive Urothelial Cancer pathologic radiologic and biomarker correlates
Journal of Clinical Oncology, 2014Co-Authors: Toni K Choueiri, Joaquim Bellmunt, Susanna Jacobus, Angela Qu, Leonard Joseph Appleman, Christopher P G Tretter, Glenn J Bubley, Edward C Stack, Sabina Signoretti, Meghara K WalshAbstract:Purpose In advanced Urothelial Cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive Urothelial Cancer (MIUC). Patients and Methods Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Results Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% ...
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neoadjuvant dose dense methotrexate vinblastine doxorubicin and cisplatin with pegfilgrastim support in muscle invasive Urothelial Cancer pathologic radiologic and biomarker correlates
Journal of Clinical Oncology, 2014Co-Authors: Toni K Choueiri, Joaquim Bellmunt, Susanna Jacobus, Leonard Joseph Appleman, Christopher P G Tretter, Glenn J Bubley, Edward C Stack, Sabina Signoretti, Meghara K Walsh, Graeme S SteeleAbstract:Purpose In advanced Urothelial Cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive Urothelial Cancer (MIUC). Patients and Methods Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Results Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% ...
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double blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum pretreated metastatic Urothelial Cancer
Journal of Clinical Oncology, 2012Co-Authors: Toni K Choueiri, Susanna Jacobus, Guru Sonpavde, David I Quinn, Robert W Ross, Ulka N Vaishampayan, Noah M Hahn, Thomas E Hutson, Stephanie Morrissey, Geoffrey BuckleAbstract:Purpose Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced Urothelial Cancer (UC) who progressed on prior platinum-based chemotherapy.
Randall E Millikan - One of the best experts on this subject based on the ideXlab platform.
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a prognostic gene expression signature in the molecular classification of chemotherapy naive Urothelial Cancer is predictive of clinical outcomes from neoadjuvant chemotherapy a phase 2 trial of dose dense methotrexate vinblastine doxorubicin and cis
European Urology, 2016Co-Authors: David J Mcconkey, Randall E Millikan, Yu Shen, Woonyoung Choi, Sima P Porten, Surena F Matin, Ashish M Kamat, Paul G Corn, Colin P Dinney, Bogdan CzerniakAbstract:Abstract Background Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive Urothelial Cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. Objective To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. Design, setting, and participants Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. Outcome measurements and statistical analysis Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. Results and limitations Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p =0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p =0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP. Conclusion GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease. Patient summary We can no longer think of Urothelial Cancer as a single disease. Gene expression profiling identifies subtypes of Urothelial Cancer that differ in their natural history and sensitivity to chemotherapy.
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a phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide doxorubicin and gemcitabine followed by cisplatin gemcitabine and ifosfamide in locally advanced Urothelial Cancer final results
Cancer, 2013Co-Authors: Arlene O Siefkerradtke, Dallas Williams, Yu Shen, Ashish M Kamat, Barton H Grossman, Colin P N Dinney, Randall E MillikanAbstract:BACKGROUND: Neoadjuvant chemotherapy improves the survival of patients with high-risk Urothelial Cancer. However, the lack of curative alternatives to cisplatin-based chemotherapy is limiting for patients with neuropathy or hearing loss. Sequential chemotherapy also has not been well studied in the neoadjuvant setting. The authors explored sequential neoadjuvant ifosfamide-based chemotherapy in a patient cohort at high risk of noncurative cystectomy. METHODS: Patients with muscle-invasive Cancer and lymphovascular invasion, hydronephrosis, clinical T3b and T4a (cT3b-4a) disease (defined as a 3-dimensional mass on examination under anesthetic or invasion into local organs), micropapillary tumors, or upper tract disease received 3 cycles of combined ifosfamide, doxorubicin, and gemcitabine followed by 4 cycles of combined cisplatin, gemcitabine, and ifosfamide. The primary endpoint was downstaging to pT1N0M0 disease or lower. RESULTS: At a median follow-up of 85.3 months, the 5-year overall survival (OS) and disease-specific survival (DSS) rates for all 65 patients were 63% and 68%, respectively (95% confidence interval: 5-year OS rate, 0.52%-0.76%; 5-year DSS rate, 0.58%-0.81%). Pathologic downstaging to pT1N0 disease or lower occurred in 50% of patients who underwent cystectomy and in 60% of patients who underwent nephroureterectomy and was correlated with the 5-year OS rate (pT1N0 disease or lower, 87%; pT2-pT3aN0 disease, 67%; and pT3b disease or higher or lymph node-negative disease, 27%; P ≤ .001 for pT1 or lower vs pT2 or higher). Variant histology was associated with an inferior 5-year DSS rate (50% vs 83% in pure transitional cell carcinoma; P = .02). The most frequent grade 3 toxicities were infection (38%), febrile neutropenia (22%), and mucositis (18%). There were 3 grade 4 toxicities (myocardial infarction, thrombocytopenia, and vomiting) and 1 grade 5 toxicity in a patient who refused antibiotics for pneumonia. CONCLUSIONS: Sequential therapy was active and maintained the historic expectation of achieving a cure. The current results strongly reinforced previous experience suggesting that pathologic downstaging to pT1N0 disease or less is a useful surrogate for eventual cure in patients with Urothelial Cancer. Cancer 2013. © 2012 American Cancer Society.
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phase ii clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide doxorubicin and etoposide cisplatin in small cell Urothelial Cancer
Journal of Clinical Oncology, 2009Co-Authors: Arlene O Siefkerradtke, Dallas Williams, Ashish M Kamat, Colin P Dinney, Barton H Grossman, Wei Qiao, Peter F Thall, Randall E MillikanAbstract:Purpose Currently, treatment recommendations for small-cell Urothelial Cancer (SCUC) are based on anecdotal case reports and small retrospective series. We now report results from the first phase II clinical trial developed exclusively for SCUC, to our knowledge. Patients and Methods From 2001 to 2006, 30 patients with SCUC provided consent and were treated with alternating doublet chemotherapy. Patients with surgically resectable disease (≤ cT4aN0M0) received a total of four cycles of neoadjuvant chemotherapy, whereas those with unresectable disease (≥ cT4b, N+, or M+) received two cycles beyond maximal response. Results Eighteen patients with surgically resectable SCUC received neoadjuvant treatment with a median overall survival (OS) of 58 months; 13 of these patients remain alive and Cancer free. For patients with cT2N0M0 SCUC, the 5-year OS rate is 80%; only one of four patients with cT3b-4aN0M0 remains alive (median OS, 37.8 months). For 12 patients with unresectable or metastatic SCUC, the median O...
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is there a role for surgery in the management of metastatic Urothelial Cancer the m d anderson experience
The Journal of Urology, 2004Co-Authors: Arlene O Siefkerradtke, Christopher J Logothetis, Garrett L Walsh, Louis L Pisters, Yu Shen, David A Swanson, Randall E MillikanAbstract:ABSTRACTPurpose: Although rarely curative, chemotherapy remains the mainstay of treatment for metastatic Urothelial Cancer. The role of surgery for metastatic disease is not well established for Urothelial Cancer, but is sometimes undertaken in the face of persistent or recurrent disease that can be surgically resected.Materials and Methods: We identified 31 patients with metastatic Urothelial Cancer undergoing metastasectomy with the intent of rendering them free of disease. All gross disease was completely resected in 30 patients (97%). The most frequently resected location was lung in 24 cases (77%), followed by distant lymph nodes in 4 (13%), brain in 2 (7%) and a subcutaneous metastasis in 1 (3%).Results: Median survival from diagnosis of metastases and from time of metastasectomy was 31 and 23 months, respectively. The 5-year survival from metastasectomy was 33%. Median time to progression following metastasectomy was 7 months. Five patients were alive and free of disease for more than 3 years after...
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phase iii trial of fluorouracil interferon alfa 2b and cisplatin versus methotrexate vinblastine doxorubicin and cisplatin in metastatic or unresectable Urothelial Cancer
Journal of Clinical Oncology, 2002Co-Authors: Arlene O Siefkerradtke, Randall E Millikan, Dennis F Moore, Terry L Smith, Dallas Williams, Christopher J LogothetisAbstract:PURPOSE: Previously, we developed a novel biochemotherapy regimen combining interferon alfa-2b with fluorouracil and cisplatin (FAP). We now report the results of a prospective randomized trial comparing FAP with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), the standard chemotherapy regimen for locally advanced and metastatic Urothelial Cancer. The purpose of this study was to compare the response rates and overall survival of patients with metastatic or unresectable Urothelial Cancer treated with these two chemotherapy regimens. PATIENTS AND METHODS: Between October 1992 and September 1999, 172 previously untreated patients were registered and randomly assigned to treatment with either FAP or M-VAC. Patients were followed until their death. RESULTS: The pretreatment clinical characteristics of the groups were similar except for sex (P < .01). Sex did not affect prognosis or survival. The objective response rate for patients assigned to FAP was 42% (35 of 83 patients), with complete resp...
Takahiko Katoh - One of the best experts on this subject based on the ideXlab platform.
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association of genotypes of carcinogen activating enzymes phenol sulfotransferase sult1a1 st1a3 and arylamine n acetyltransferase nat2 with Urothelial Cancer in a japanese population
International Journal of Cancer, 2002Co-Authors: Shogo Ozawa, Takahiko Katoh, Hisato Inatomi, Hirohisa Imai, Yoshiki Kuroda, Masayoshi Ichiba, Yasuo OhnoAbstract:Carcinogenic aromatic amines such as 4-aminobiphenyl, which is contained in tobacco smoke, are one of the causal factors of Urothelial epithelial Cancers. 4-Aminobiphenyl has been shown to be bioactivated through N-hydroxylation by hepatic cytochrome (CYP) 1A2 and subsequently through O-sulfation and O-acetylation by phenol sulfating sulfotransferase, ST1A3 (SULT1A1), and arylamine N-acetyltransferase, NAT2, respectively. In a case-control study for Urothelial epithelial Cancers, low activity alleles of NAT2 are overall high-risk alleles (OR 2.11; 95% CI 1.08-4.26). Wild-type ST1A3*1 ((213)Arg) alleles were slightly overrepresented in nonsmoking Urothelial Cancer patients (82.6% vs. 69.7%) and in smoking Cancer patients (76.7% and 74.3%) compared to a variant ST1A3*2 ((213)His) allele. In combination of ST1A3 and NAT2 genotypes for analyses of Urothelial Cancer risk, the highest OR of 2.45 (95% CI 1.04-5.98) was obtained with ST1A3*1 and NAT2 slow genotype among the 4 combinations. Recombinant ST1A3*1 enzyme showed a tendency of catalyzing higher in vitro 3'-phosphoadenosine 5'-phosphosulfate-dependent DNA adduct formation than ST1A3*2 (2.84 +/- 0.49 and 2.22 +/- 0.11 adducts/10(8) nucleotides). Combined analyses of different alleles of carcinogenic aromatic amine-activating phase II enzymes were applied to Urothelial Cancer risk for the first time and showed the highest risk combination of ST1A3 and NAT2 alleles.
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effects of glutathione s transferase gst m1 and gstt1 genotypes on Urothelial Cancer risk
Cancer Letters, 1998Co-Authors: Takahiko Katoh, Hisato Inatomi, Heon Kim, Mihi Yang, Tetsuro Matsumoto, Toshihiro KawamotoAbstract:Abstract The M1 member of the mu class of the glutathione S-transferase (GSTM1) gene is present in about 50% of individuals. GSTT1, a member of the theta class, which has been recently shown to be polymorphic, is expressed in 35–90% of individuals. In this study, 145 Japanese patients with Urothelial transitional cell carcinoma and 145 healthy controls, frequency-matched for age and gender, were compared for frequencies of GSTM1 and GSTT1 genotypes. The Urothelial Cancer risk increased due to the GSTM1 null genotype (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.05–2.79). On the other hand, the OR tended to decrease due to the GSTT1 null genotype, although not significantly. Among individuals of the GSTM1 null genotype, those of the GSTT1-positive genotype had a two-fold risk (OR 2.62, 95% CI 1.36–5.05) compared with the GSTT1 null genotype (OR 1.25, 95% CI 0.62–2.51). A significant interaction between the GSTM1 genotype and smoking status was found; the GSTM1 null genotype was associated with an increased risk of Urothelial Cancer among smokers (OR 1.98, 95%CI 1.10–3.57).
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cytochrome p4501a1 gene polymorphism and homozygous deletion of the glutathione s transferase m1 gene in Urothelial Cancer patients
Carcinogenesis, 1995Co-Authors: Takahiko Katoh, Hisato Inatomi, Akira Nagaoka, Atsuo SugitaAbstract:Japanese Urothelial (bladder, renal pelvis and ureter) Cancer patients (n = 83) and community controls (n = 101) were compared for rates of polymorphism in exon 7 of the cytochrome P4501A1 (CYP1A1) gene or homozygous deletion of the glutathione S-transferase class mu (GSTM1) gene. A CYP1A1 polymorphism was detected in a HinCII polymorphism assay utilizing a primer with a single base pair mismatch. The frequency distribution of the CYP1A1 genotypes in Urothelial Cancer patients showed no significant difference from that in healthy controls. The increased frequency of homozygous deletions of GSTM1 gene loci in patients with Urothelial Cancer was statistically significant compared with the controls, 51 of 83 (61%) and 43 of 101 (43%) (odds ratio = .2.15, 95% confidence interval = 1.18-3.86). These results lead us to conclude that homozygous deletion of the GSTM1 gene may be associated with susceptibility to Urothelial Cancer.
