Immunoregulation of Dendritic Cell Subsets by Inhibitory Receptors in Urothelial Cancer

Blockade of inhibitory receptors (IRs) overexpressed by T cells can activate antitumor immune responses, resulting in the most promising therapeutic approaches, particularly in bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-present antigens to T cells, dendritic cells (DCs) are an immune cell population that plays a central role in the generation of effective antitumor T-cell responses. While IR function and expression have been investigated in T cells, very few data are available for DCs. Therefore, we analyzed whether DCs express IRs that can decrease their functions. To this end, we investigated several IRs (PD-1, CTLA-4, BTLA, TIM-3, and CD160) in circulating CD1c⁺ DCs, CD141⁺ DCs, and plasmacytoid DCs from healthy donors and patients with urothelial cancer (UCa). Different DC subsets expressed BTLA and TIM-3 but not other IRs. More importantly, BTLA and TIM-3 were significantly upregulated in DCs from blood of UCa patients. Locally, bladder tumor–infiltrating DCs also overexpressed BTLA and TIM-3 compared to DCs from paired nontumoral tissue. Finally, in vitro functional experiments showed that ligand-mediated engagement of BTLA and TIM-3 receptors significantly reduced the secretion of effector cytokines by DC subpopulations. Our findings demonstrate that UCa induces local and systemic overexpression of BTLA and TIM-3 by DCs that may result in their functional inhibition, highlighting these receptors as potential targets for UCa treatment.

Growth, Differentiation and Senescence of Normal Human Urothelium in an Organ-Like Culture

Objective: To examine the kinetics of growth, differentiation and senescence of normal human urothelium in an organoid-like culture model.Materials and Methods: Micro-dissected normal human urothelium explants were grown on porous membranes pretreated with various matrix components. Between 5 and 30 days of culture, cell proliferation was assessed by BrdU incorporation. Differentiation was evaluated on the basis of cytokeratin (Ck) and uroplakin (UP) expression. Epidermal growth factor family mRNA expression was monitored during explant outgrowth. Senescence was assessed by measuring endogenous β-galactosidase activity and p16^INK4a mRNA expression.Results: Collagen IV was the most efficient matrix component for urothelial cell expansion. BrdU incorporation by urothelial cells was 5% between 15 and 30 days, corresponding to steady-state urothelium in vivo. Heparin-binding EGF (HB-EGF), Amphiregulin (AR) and Transforming Growth Factor α (TGFα) expression correlated with increased cell proliferation. UPII expression was stable throughout culture. P16^INK4a mRNA expression and β-galactosidase activity increased on day 25, giving signs of senescence.Conclusions: This model retains many characteristics of the urothelium in vivo. It can be used for pharmacological studies between 15 to 25 days and to study mechanisms such as wound healing, proliferation and senescence.     

Scanning Electron Microscopy in the Study of Normal,Inflamed and Neoplastic Human Urothelium

Summary— Seventy-two samples of human urothelium have been examined by scanning electron microscopy (SEM) and the appearances compared with those of conventional light microscopy. Six main SEM cell types were recognised. None was diagnostic of malignancy; in particular, the presence of surface pleomorphic microvilli was not pathognomonic. However, the relation of the SEM appearance to malignancy and the accepted histological grades and clinical stages of malignancy was such as to warrant further examination.     

Epidemiology and Risk Factors of Urothelial Bladder Cancer

Context

Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease.

Objective

To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors.

Evidence acquisition

A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected.

Evidence synthesis

UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence.

Conclusions

UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported.     

Biomolecular Predictors of Urothelial Cancer Behavior and Treatment Outcomes

Urothelial carcinoma of the urinary bladder (UCB) is a highly heterogeneous malignancy that causes significant morbidity and mortality. Despite advances in surgical and medical treatment, there has been no change in mortality in UCB over the past decades. Standard pathological features (stage, grade, nodal status) provide only limited information regarding biological potential and clinical behavior. Molecular biomarkers may shed light on important mechanisms of pathogenesis, provide useful additional prognostic information, and serve as targets for therapy. This review summarizes recent advances and the most promising UCB tissue and blood biomarkers of the past few years. We discuss the predictive and prognostic value of biomarkers at different stages of UCB. There is no doubt that a panel of biomarkers will eventually improve our clinical decision-making with regard to treatment and follow-up.     

The Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer

Context

The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients.

Steroid Receptors and Cell Cycle in Normal Mammary Epithelium

The ovarian steroids estrogen and progesterone (E(2) and P) are essential for normal mammary gland growth and development; however, the mechanisms by which they influence the proliferative activity of the mammary epithelium remain unclear. Mammary epithelial cells cells expressing the receptors for E(2) and P (ER and PR respectively) are separate from, although often adjacent to, those capable of proliferating, implying that the ovarian steroids act indirectly via paracrine or juxtacrine growth factors to stimulate entry into the cell cycle. A large number of candidate factors have been identified in a variety of different experimental systems, and it appears that transforming growth factor beta may play a role in preventing proliferation of steroid receptor-containing cells. Dysregulation of the strict inverse relationship between ERalpha expression and proliferation is detectable in premalignant human breast lesions, indicating that it might be essential to the tumorigenic process. Challenges for the future include determining which of the candidates identified as being mediators of the effects of E(2) are physiologically and clinically relevant as well as finding out how ERalpha-containing cells become proliferative during tumorigenesis. Answering these questions could greatly increase our understanding of the factors controlling mammary gland development and the processes leading to cancer formation.     

Estrogen and Progesterone Receptors in Primary Breast Cancer

Abstract: The purpose of this study was to determine biological variable profiles and survival experiences associated with different combinations of estrogen receptor (ER) and progesterone receptor (PR) status (ER+PR+, ER+PR-, ER-PR+, ER-PR-). Data were collected and provided by the State Health Registry (SHR) of Iowa, part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Significant associations were determined for individual prognostic variables with each ER/PR categories, and overall survival was compared between each ER/PR category. Multiple logistic regression analyses were conducted to determine all significant prognostic variables associated with each ER/ PR category. All women diagnosed with primary breast cancer in Iowa from 1990 through 1992 were included in this study (N = 6, 178). In unadjusted analyses, Caucasian woman and older women were significantly more likely to be ER + PR+, while African American women and younger women were significantly more likely to be ER-PR-. In multivariate analyses, each ER/PR category was associated with distinct profile of age, menopausal status, histologic grade, and histology. Survival was best for women in the ER+PR+ group, followed, in decreasing order, by ER+PR-, ER-PR+, and ER-PR-. In this population-based study of primary breast cancer, combined hormone receptor status was a significant prognostic determinant for primary breast cancer, and was associated with distinct biological variables and survival experiences. In combination with other variables such as age, menopausal status, tumor histologic grade, and tumor histology, combined hormone receptor status can provide important prognostic information to the clinician.?     

Indications and Oncologic Outcome of Radical Cystectomy for Urothelial Bladder Cancer

ContextRadical cystectomy (RC) offers the best opportunity for ultimate cure of high-grade and high-risk invasive bladder cancer (BCa).ObjectiveTo review the available literature on indications for and oncologic outcomes of RC for urothelial carcinoma of the bladder.Evidence acquisitionA database search of the US National Library of Medicine (PubMed) was performed for relevant medical articles using the Medical Subject Headings invasive bladder cancer and radical cystectomy with restrictions to English-language publications.Evidence synthesisImmediate or early RC should be offered as a treatment of choice to all patients with recurrent or multifocal high-grade T1 tumours, T1 tumours at high risk of progression, failures of bacillus Calmette-Guérin treatment, and muscle-invasive bladder tumours. RC offers excellent recurrence-free survival (RFS) and disease-specific survival rates as well as local tumour control in patients with organ-confined and node-negative disease. Tumour control in non–organ-confined tumours is still satisfactory, with long-term RFS rates of about 50%. For node-positive disease, surgery may only be curative in approximately one-fourth of patients.ConclusionsEvidence from the literature supports early, aggressive surgical management for invasive BCa. Risk stratification of patients with BCa based on pathologic features at initial transurethral resection or at recurrence can select those patients most appropriate for RC early. In patients with organ-confined, lymph node–negative urothelial bladder carcinoma, excellent long-term survival rates can be achieved.     

前列腺癌中内皮素及其受体的研究进展

内皮素是一种主要由血管内皮细胞产生的肽类物质,不仅具有强大的血管收缩功能,而且还有一些重要的生理学作用,如组织分化、细胞增殖及激素分泌等。近年来的研究发现内皮素还参与体内多种肿瘤的生长过程,如前列腺癌、宫颈癌、乳腺癌等,其生物学效应的实现可能与促有丝分裂、抑制凋亡、诱导肿瘤生长过程中的血管生成、原癌基因的激活等有关。晚期前列腺癌患者骨转移、成骨作用及疼痛等均与其有关。     

p-mTOR、P-p70S6K蛋白在膀胱尿路上皮癌中的表达

目的：探讨哺乳动物雷帕霉素靶蛋白（mTOR）通路蛋白（p-mTOR）、核糖体蛋白s6激酶（p-p70S6K）在膀胱尿路上皮癌中的表达情况及与预后的关系。方法：利用免疫组化染色检测mTOR通路蛋白p-mTOR、P-p70S6K在膀胱尿路上皮癌中的表达情况,分析p-mTOR、P-p70S6K在不同膀胱组织中的表达差异,与膀胱癌临床病理参数的关系及与膀胱尿路上皮癌预后的关系。结果：p-mTOR在膀胱尿路上皮癌中的阳性表达率（43.3％）高于正常黏膜（17．5％）,p-mTOR表达阳性率随着肿瘤分级分期的增加相应增加,多发性膀胱尿路上皮癌p-mTOR表达阳性率（70．5％）高于单发组（31．4％）,复发组（70．5％）高于未复发组（31.4％,P〈0．01）;P-p70S6K在膀胱尿路上皮癌阳性率（25．9％）高于正常膀胱黏膜（7．5％,P〈0．05）,p-p70S6K表达阳性率随着肿瘤分级分期的增加相应增加,多发性膀胱尿路上皮癌p-p70S6K表达阳性率（45．9％）高于单发组（17．1％）,复发组（30．3％）高于未复发组（17．4％,P〈0．01）;肿瘤分级、分期、数目及p-mTOR表达分别是膀胱肿瘤无瘤生存的独立预后因子。结论：mTOR／p-mTOR／p-p70S6K通路的激活与膀胱尿路上皮癌的发生发展有关,p-mTOR可以作为预测膀胱尿路上皮癌复发的预后因子。     

The Role of Systemic Chemotherapy in Management of Upper Tract Urothelial Cancer

Upper tract urothelial cancer (UTUC) accounts for roughly 5 % of all urothelial cancers. At presentation, 30 % of patients demonstrate invasive and/or locally advanced disease, 30–40 % have regional lymph node involvement, and 20 % harbor metastatic disease. Systemic recurrence and progression rates after surgery for patients with advanced disease range between 45–60 %. Five-year cancer specific survival rates for pT2 and pT3 tumors are 73 % and 40 %, respectively. Median survival for patients with pT4 disease is approximately 6 months. Nonetheless, there is a lack of improvement in the rates of systemic recurrence and progression in patients with advanced UTUC. Extrapolating evidence obtained from experience with multi-modal therapy of patients with urothelial bladder cancer, additional improvements in oncological outcomes for patients with UTUC can be achieved through integration of effective systemic chemotherapy with local tumor control. We provide an overview of the rationale and utilization strategies of peri-operative systemic chemotherapy in patients with UTUC.     

荧光原位杂交(FISH)技术对尿路上皮癌诊断价值的Meta分析

目的对国内已发表的应用荧光原位杂交(FISH)技术对尿路上皮癌患者的临床试验进行综合评价,对FISH技术与传统尿脱落细胞学检查进行比较,评价其对尿路上皮癌的诊断价值方法检索相关文献,根据纳入标准筛选文献,利用Meta-DiSc软件分别计算FISH检测组和尿脱落细胞学检查组敏感性、特异性、似然比和诊断性比数比,绘制总受试者工作特征(SROC)曲线,计算曲线下面积,并比较。结果有8篇文献被纳入,FISH检测尿路上皮癌的总敏感性为0.83(95%CI 0.79～0.86),特异性为0.90(95%CI 0.85～0.93),SROC曲线下面积为0.9278。尿脱落细胞学检查的总敏感性为0.51(95%CI0.47～0.56),特异性为0.93(95%CI 0.90～0.96),SROC曲线下面积为0.8501。FISH检查在总体诊断效能上较尿脱落细胞学检查更高,且具有统计学意义(P0.05)。结论就本次Meta分析的结果而言,可以认为FISH检测较尿脱落细胞学检查在尿路上皮癌的诊断中具有更高的价值。