scholarly journals Urothelial cancer: a narrative review of the role of novel immunotherapeutic agents with particular reference to the management of non-muscle-invasive disease

2019 ◽  
Vol 123 (6) ◽  
pp. 947-958 ◽  
Author(s):  
Emma Doyle ◽  
Jeremy Crew ◽  
Hugh Mostafid ◽  
Mark Tuthill ◽  
Vincenzo Cerundolo ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Invasive Disease ◽  
Narrative Review ◽  
Muscle Invasive

Phase II trial of gemcitabine and cisplatin plus ipilimumab as first-line treatment for metastatic urothelial carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4676-TPS4676
Author(s):  
Benjamin Adam Gartrell ◽  
Noah M. Hahn ◽  
Thomas E. Hutson ◽  
Guru Sonpavde ◽  
Ralph J. Hauke ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Tumor Antigen ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Invasive Disease ◽  
Primary Objective ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Urothelial Carcinoma ◽  
Muscle Invasive

TPS4676 Background: While metastatic urothelial carcinoma is a chemosensitive neoplasm, current therapeutic approaches are inadequate. Preclinical and clinical data suggests that bladder cancer is immunogenic. For example, CD8+ tumor infiltrating lymphocytes correlate with survival in patients with muscle-invasive disease (Sharma, PNAS, 2007). However, immunotherapeutic approaches have been rarely investigated for advanced urothelial cancer. CTLA4 blockade with ipilimumab is a novel approach to immunotherapy that interrupts T-cell pathways responsible for immune down-regulation or tolerance. In a proof of concept study, ipilimumab was administered to 12 patients with muscle-invasive disease preoperatively (Carthon, Clin Can Res, 2010). Treatment resulted in perivascular infiltration of cells positive for CD3, CD8, CD4, and granzyme and intriguing evidence of antitumor activity. In the current trial, we will explore a “phased” schedule of chemotherapy and ipilimumab with the goal of “autovaccinating” patients to tumor antigen with chemotherapy prior to introduction of immune checkpoint blockade. Methods: We have initiated a phase II clinical trial of gemcitabine (G), cisplatin (C), plus ipilimumab in chemonaive patients with unresectable and/or metastatic urothelial cancer within the Hoosier Oncology Group network. During cycles 1 and 2, G (1000 mg/m2 D day 1 + 8) and C (70 mg/m2 D 1) will be administered every 21 days without ipilimumab. During cycles 3-6, GC plus ipilimumab (10 mg/kg day 1) will be administered every 21 days. Patients without evidence of disease progression after completion cycle 6 will continue single-agent ipilimumab “maintenance” every 3 months. The primary objective is to determine the 1-year overall survival. The trial will enroll 36 patients and is powered to detect an improvement in 1-year survival from 60% to 80%. Secondary objectives include progression-free survival, disease control rate, safety, and immunologic outcomes. Correlative studies will include serial measurements of the global composition of immune cells in the blood by polychromatic flow cytometry, whole blood transcriptional profiling, and tumor-antigen specific CD8+ T cells assays.

Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4543-4543
Author(s):  
Andrea Borghese Apolo ◽  
Young H. Lee ◽  
Fabiola Cecchi ◽  
Piyush K. Agarwal ◽  
Howard L. Parnes ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cell Invasion ◽  
Urothelial Cancer ◽  
Invasive Disease ◽  
Soft Agar ◽  
Visceral Metastasis ◽  
Anchorage Independent Growth ◽  
Median Serum ◽  
Muscle Invasive

4543 Background: Mounting evidence supports Met as a therapeutic target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (P=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (P=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.

scholarly journals Evolving Immunotherapy Strategies in Urothelial Cancer

2015 ◽  
pp. e284-e290 ◽  
Author(s):  
Sam J. Brancato ◽  
Keidren Lewi ◽  
Piyush K. Agarwal
Keyword(s):  
Urothelial Carcinoma ◽  
Urothelial Cancer ◽  
Treatment Options ◽  
Invasive Disease ◽  
T Helper ◽  
Therapeutic Approaches ◽  
Cell Therapies ◽  
Muscle Invasive ◽  
Th1 Immune Responses

The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer.

Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 314-314 ◽  
Author(s):  
Andrea Borghese Apolo ◽  
Young H. Lee ◽  
Fabiola Cecchi ◽  
Piyush K. Agarwal ◽  
Howard L. Parnes ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cell Invasion ◽  
Urothelial Cancer ◽  
Invasive Disease ◽  
Soft Agar ◽  
Visceral Metastasis ◽  
Anchorage Independent Growth ◽  
Median Serum ◽  
Muscle Invasive

314 Background: Mounting evidence supports Met as a target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits both VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (p=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (p=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.

scholarly journals Prognostic role of the systemic immune–inflammation index in upper tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration

2021 ◽  
Author(s):  
Keiichiro Mori ◽  
Irene Resch ◽  
Noriyoshi Miura ◽  
Ekaterina Laukhtina ◽  
Victor M. Schuettfort ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Urothelial Carcinoma ◽  
Cox Regression ◽  
Invasive Disease ◽  
Survival Outcomes ◽  
Regression Analyses ◽  
Radical Nephroureterectomy ◽  
Prognostic Role ◽  
Muscle Invasive

Abstract Purpose To investigate the prognostic role of the preoperative systemic immune–inflammation index (SII) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). Materials and methods We retrospectively analyzed our multi-institutional database to identify 2492 patients. SII was calculated as platelet count × neutrophil/lymphocyte count and evaluated at a cutoff of 485. Logistic regression analyses were performed to investigate the association of SII with muscle-invasive and non-organ-confined (NOC) disease. Cox regression analyses were performed to investigate the association of SII with recurrence-free, cancer-specific, and overall survival (RFS/CSS/OS). Results Overall, 986 (41.6%) patients had an SII > 485. On univariable logistic regression analyses, SII > 485 was associated with a higher risk of muscle-invasive (P = 0.004) and NOC (P = 0.03) disease at RNU. On multivariable logistic regression, SII remained independently associated with muscle-invasive disease (P = 0.01). On univariable Cox regression analyses, SII > 485 was associated with shorter RFS (P = 0.002), CSS (P = 0.002) and OS (P = 0.004). On multivariable Cox regression analyses SII remained independently associated with survival outcomes (all P < 0.05). Addition of SII to the multivariable models improved their discrimination of the models for predicting muscle-invasive disease (P = 0.02). However, all area under the curve and C-indexes increased by < 0.02 and it did not improve net benefit on decision curve analysis. Conclusions Preoperative altered SII is significantly associated with higher pathologic stages and worse survival outcomes in patients treated with RNU for UTUC. However, the SII appears to have relatively limited incremental additive value in clinical use. Further study of SII in prognosticating UTUC is warranted before routine use in clinical algorithms.

The Possible Role of Polyomavirus in Urothelial Cancer

2020 ◽  
Vol 23 (10) ◽  
Author(s):  
Noora M Kareem ◽  
Dalya Basil Hanna ◽  
Asmaa B Al-Obaidi ◽  
Haider Faisel Ghazi
Keyword(s):  
Urothelial Cancer

COVID-19 and Comorbidities: is Inflammation the Underlying Condition in Children? A narrative Review

2020 ◽  
Vol 16 ◽  
Author(s):  
Giulia Pinna ◽  
Lavinia Sanfilippo ◽  
Pier Paolo Bassareo ◽  
Vassilios Fanos ◽  
Maria Antonietta Marcialis
Keyword(s):  
Risk Factor ◽  
Severe Form ◽  
Narrative Review ◽  
Underlying Condition ◽  
Pathogenic Mechanisms ◽  
Associated Diseases ◽  
Potential Link

: This paper examines the potential link between COVID-19 and the presence of comorbidities and assesses the role of inflammation in this correlation. In COVID-19 patients, the most frequently associated diseases share a pathogenic inflammatory basis and apparently act as a risk factor in the onset of a more severe form of the disease, particularly in adulthood. However, in children, the understanding of the underlying pathogenic mechanisms is often complicated by the milder symptoms presented. A series of theories have therefore been put forward with a view of providing a better understanding of the role played by inflammation in this dramatic setting. All evidence available to date on this topic is discussed in this review.

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