下尿路梗阻与男性膀胱癌发病的相关性

目的评价下尿路梗阻暴露与男性膀胱癌发生的联系。方法采用成组病例对照研究,设计调查表,收集男性膀胱癌患者104例为病例组,同期住院男性非膀胱癌患者206例为对照组,采用SPSS 17.0软件行数据资料管理和单因素、多因素非条件Logistic回归分析。结果下尿路梗阻与膀胱癌发生有一定联系,危险性可能随梗阻时间的延长而增大。结论下尿路梗阻是膀胱癌发生的危险因素,应当重视该领域的流行病学研究,以期合理预防和选择适当的手术方式。     

Selectively increased risk of cancer in men with coronary heart disease

Cancer incidence was assessed among a cohort of 10,923 male coronary patients in Israel screened for participation in a secondary prevention trial and compared with national cancer incidence rates. Higher total and age-specific incidence rates of cancer were observed among male coronary patients than among the Israeli male population, but this excess was limited to cancers of the lung, bladder, and colon.     

上海市消化系统常见恶性肿瘤发病现况和时间趋势分析

背景:目前全球消化系统常见恶性肿瘤占所有部位恶性肿瘤新发病例数的1/3左右,是一项重要的公共卫生负担。目的:描述上海市消化系统常见恶性肿瘤发病现况和时间趋势,分析其危害程度和主要特征,为探寻病因学研究线索,制定和评估预防、研究与控制的规划和措施提供依据。方法:根据上海市恶性肿瘤病例报告登记系统收集消化系统恶性肿瘤发病资料,选择食管癌、胃癌、结直肠癌、肝癌、胆囊癌和胰腺癌6种常见恶性肿瘤,统计2003～2007年上海全市的发病情况及其年龄、性别与地区分布特征,应用年度变化百分比的方法对1973～2007年上海市区的男女标化发病率进行时间趋势分析。结果:2003～2007年,上海全市共新诊断消化系统恶性肿瘤101 612例,占所有部位恶性肿瘤的43.18%。常见恶性肿瘤中食管癌、胃癌、结直肠癌、肝癌、胆囊癌、胰腺癌分别居第7位、第3位、第2位、第4位、第12位、第6位,发病率和标化发病率分别为11.26/10万和5.52/10万、41.23/10万和21.05/10万、43.35/10万和22.23/10万、29.80/10万和16.07/10万、8.02/10万和3.77/10万、12.84/10万和6.35/10万;各部位肿瘤的年龄别发病率均随年龄的增长而升高;除胆囊癌女性标化发病率高于男性,其余均为男性高于女性。1973～2007年期间,食管癌、胃癌和肝癌标化发病率均呈下降趋势,而结直肠癌、胆囊癌和胰腺癌则呈上升趋势。结论:上海市消化系统恶性肿瘤发病负担略低于全国平均水平,远高于世界平均水平,主要特征为男性肝癌年龄别发病率的特殊变化、胆囊癌标化发病率的性别差异、老年女性人群中年龄别发病率的显著升高以及标化发病率时间趋势中女性胆囊癌、男性食管癌和胃癌的特殊变化,可作为开展相关病因学研究的重要线索。     

Pioglitazone has a dubious bladder cancer risk but an undoubted cardiovascular benefit

On 8 April 2014, a US jury ordered Takeda and Eli Lilly to pay $9 bn in punitive damages after finding that they had concealed the cancer risks associated with pioglitazone. By contrast, on 28 August 2014, the long‐awaited outcome of the 10‐year Kaiser Permanente Northern California study was announced. That study was specifically designed to investigate whether patients exposed to pioglitazone were at an increased risk of bladder cancer and found no association; thus, at last, the controversial issue has been resolved. A review, in retrospect, of the story of the proposed link between pioglitazone and bladder cancer reveals flaws at every stage. In 2012, a BMJ editorial, in keeping with some other contemporary reports, stated ‘it can confidently be assumed that pioglitazone increases the risk of bladder cancer’. Examination of the information which led to such a statement shows that: 1) the pre‐clinical findings of bladder cancer in male rats is not indicative of human risk; 2) there is no association between bladder cancer and pioglitazone in randomized controlled trials, once cases that could not plausibly be related to treatment are removed; and 3) the observational studies that have suggested a link have over‐extrapolated from the data: pioglitazone‐treated patients had more risk factors for bladder cancer than those not treated with pioglitazone. Meanwhile careful study of randomized controlled trials shows evidence of cardiovascular benefit from pioglitazone in Type 2 diabetes, a condition which results, more than anything, in premature cardiovascular death and morbidity.     

Chronic Indwelling Urinary Catheter Increase the Risk of Bladder Cancer,Even in Patients Without Spinal Cord Injury

Chronic indwelling urinary catheters (CIDCs) are known as a risk factor for bladder cancer in patients with spinal cord injury (SCI). This study examined the potential risk of bladder cancer from CIDCs in patients without SCI.The National Health Insurance Research Database in Taiwan was used to identify SCI patients (N = 1816). This group was compared against a control CIDC cohort without SCI (N = 1816) and a reference cohort with normal individuals without SCI and a record of CIDC (N = 7264). Comparisons were made based on age and gender matching over a maximum of 11 follow-up years. The incidence risk and hazard ratio (HR) of bladder cancer were estimated in all 3 groups.During the follow-up period, the bladder cancer incidence rates were 68.90 and 102.53 per 100,000 person-years in the SCI and CIDC-non-SCI groups, respectively. These values were both higher than that of the reference cohort (12.00 per 100,000 person-years). Patients who had history of SCI (HR: 6.51; 95% CI, 2.56–16.52) or CIDC without SCI (HR: 9.11; 95% CI, 3.9–21.29) had a higher risk of bladder cancer compared with the reference cohort.Patients with CIDCs may have an increased risk of bladder cancer development, especially in older aged and male patients compared with general population.     

Impact of schistosomiasis on urinary bladder cancer in the southern province of Saudi Arabia: review of 60 cases.

The histopathologic findings reported in 254 consecutive urinary bladder biopsies were reviewed. Evidence of urinary schistosomiasis was identified in 88 biopsies (35%) and malignant neoplasms were diagnosed in 60 cases (24%). Nine out of 60 (15%) cases of bladder cancer had urinary bladder schistosomiasis and the remaining 51 cases (85%) had no clinical evidence of schistosomiasis. Transitional cell carcinoma was the commonest type of urinary bladder cancer (70%) followed by squamous cell carcinoma (20%) adenocarcinoma (8%) and rhabdomyosarcoma (2%). The mean age of the patients included was 60 +/- 15 years and the male:female ratio was 9:1. Comparison of our findings to those reported from other provinces of Saudi Arabia and from other countries, including those with known high incidence of schistosomiasis, is included.     

Clinical utility of urodynamics for postprostatectomy incontinence

Understanding the role of urodynamics in postprostatectomy incontinence helps urologic clinicians determine optimal treatment choices. The most common urodynamic diagnosis in men with leakage after prostatectomy is urodynamic stress incontinence usually due to intrinsic sphincter deficiency. Findings of detrusor overactivity and bladder outlet obstruction often coexist. Only urodynamics with pressure-flow study allow accurate diagnosis of physiologic bladder outlet obstruction. Simultaneous fluoroscopy may be useful in further defining or diagnosing clinically significant obstruction. By employing specific urodynamic techniques, one avoids misdiagnosis of incontinence and overdiagnosis of obstruction. Decreased bladder compliance is rare in recent urodynamic studies. With the advent of new surgical techniques for postprostatectomy incontinence such as male perineal and transobturator slings, it is imperative to understand bladder, sphincter, and bladder outlet function. Underlying pathologic conditions may be caused by the treatment of prostate cancer, as well as the treatment of incontinence itself.     

Bladder cancer in Africa

Accurate epidemiological data about the incidence and mortality of bladder cancer are unavailable for most African countries. Transitional cell carcinoma (TCC) of the bladder is probably less common in rural African regions than in industrialized countries, due to lower levels of exposure to carcinogenic chemicals. In areas with endemic schistosomiasis (bilharzia) caused by parasitic schistosomes (blood flukes), most bladder cancer cases are comprised of squamous cell carcinoma (SCC). However, with increased urbanization, industrialization, and cigarette smoking in many African countries, there is an increasing incidence of TCC relative to SCC of the bladder. SCC of the bladder presents in patients who are on average 10 to 20 years younger than those with TCC. In Egypt and other North African countries, SCC is more common in men (the male to female ratio ranges from 3:1 to 5:1), probably because boys and men performing agricultural work are more exposed to schistosomiasis-infested water. In some sub-Saharan countries, SCC of the bladder is equally common in men and women, probably due to equal schistosomiasis exposure of girls and boys, and because women obtain household water and perform most agricultural tasks. Although SCC of the bladder often presents at a locally advanced stage, the tumors are usually well differentiated, with a relatively low incidence of lymphatic and hematogenous metastases. Patients with localized SCC are ideal candidates for cystectomy and orthotopic neobladder construction, because they are relatively young and healthy, and there is no risk of urethral recurrence, unlike with TCC. Unfortunately, many patients in Africa still present with advanced and inoperable bladder cancer, and many do not have access to healthcare facilities that can provide a cure and a good quality of life by means of radical cystectomy and neobladder construction.     

Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas.

Pancreatic cancer is a leading cause of cancer-related deaths in developed countries. Gall bladder cancer is very common in South American countries, around the Mediterranean and in Japan. A majority of patients with these cancers receive only palliative therapy in spite of recent advances in investigation and surgery. Their poor prognosis and increasing incidence in India necessitate a better epidemiologic approach towards their control. This review is based on epidemiological data, publications and abstracts from India. Population-based data reveal that the incidence of gall bladder cancer is very high in northern Indian cities (5-7 per 100,000 women) and low (0-0.7 per 100,000 women) in southern India. The distribution suggests a high-incidence region comprising Uttar Pradesh, Bihar, Orissa, West Bengal and Assam. The cancer is twice more common in women and is the leading cancer among digestive cancers in women in the northern Indian cities of Delhi and Bhopal. There are few analytical data to hypothesize why this geographical predisposition. The high incidence is also observed in north Indian immigrants to the United Kingdom. The incidence of pancreatic cancer is low (0.5-2.4 per 100,000 men and 0.2-1.8 per 100,000 women) in most parts of India. Somewhat higher rates are seen in the male urban populations of western and northern India. Studies from Kerala support an association between tropical pancreatitis and pancreatic cancer. Time trends reveal an increase in the incidence of gall bladder and pancreas cancers; the increase in the former is alarming. We estimate that the approximate annual cancer burden of India in 2001 would include 17,730 cases of gallbladder cancer and 14,230 of pancreatic cancer. Multi-center studies are needed to identify potentially preventable risk factors associated with gall bladder and pancreatic cancer in India.     

Dactilitis and oligoarthritis after BCG immunotherapy in a patient affected by bladder cancer

The treatment of bladder cancer with Bacillus of Calmette-Guerin (BCG) immunotherapy can induce the appearance of a reactive disorder. The Authors describe a 55-year-old male patient with bladder cancer treated with endovesical instillation of BCG immunotherapy, followed after the fifth application by asymmetric oligoarthritis and dactilitis. The observed positivity of both HLA-B27 and HLA-B51 antigens reinforces the hypothesis of a reactive form, possibly through "molecular mimicry" mechanism. The discontinuation of BCG instillation along which a therapeutic attempt with NSAD failed to improve the rheumatic manifestation, which completely remitted after a four-month course of oral steroids. No relapses of joint and tendon involvement was observed during the following five-month period. The clinico-pathogenetic implications suggested by this case are discussed.     

CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated

Overexpression of CD24, a glycosyl phosphatidylinositol-linked sialoglycoprotein, is associated with poor outcome in urothelial carcinoma and contributes to experimental tumor growth and metastasis. However, the requirement for CD24 (Cd24a in mice) in tumorigenesis and spontaneous metastasis from the orthotopic site remains uncharacterized. Using N-butyl-N-(4-hydroxybutyl) nitrosamine induction of invasive and metastatic bladder cancer, we show that Cd24a-deficient male mice developed fewer bladder tumors than C57BL/6 control male mice. Evaluating only mice with evidence of primary tumors, we observed that Cd24a-deficient male mice also had fewer metastases than wild-type counterparts. In parallel observations, stratification of patients based on CD24 immunohistochemical expression in their tumors revealed that high levels of CD24 are associated with poor prognosis in males. In female patients and mice the above observations were not present. Given the significant role of CD24 in males, we sought to assess the relationship between androgen and CD24 regulation. We discovered that androgen receptor knockdown in UM-UC-3 and TCCSUP human urothelial carcinoma cell lines resulted in suppression of CD24 expression and cell proliferation. Androgen treatment also led to increased CD24 promoter activity, dependent on the presence of androgen receptor. In vivo, androgen deprivation resulted in reduced growth and CD24 expression of UM-UC-3 xenografts, and the latter was rescued by exogenous CD24 overexpression. These findings demonstrate an important role for CD24 in urothelial tumorigenesis and metastasis in male mice and indicate that CD24 is androgen regulated, providing the foundation for urothelial bladder cancer therapy with antiandrogens.     

Infection: is it a cause of bladder cancer?

This article reviews the literature regarding the possible correlation between infection and occurrence of bladder cancer. The PubMed literature database was searched from inception to January 2008. Keywords of bladder, cancer, parasitic, bacterial, viral and infection, were used. Forty studies were included in the review. Several investigators support the idea that schistosomiasis is aetiologically related to the development of bladder cancer in individuals infected with Schistosoma haematobium. Approximately 70% of those with chronic schistosomiasis who have bladder cancer develop squamous cell rather than transitional cell carcinoma. Several investigators suggest that bacteria may play a role in inducing bladder cancer. Clinically, researchers have linked the development of infection, urinary stones and indwelling catheters with bladder cancer. Nevertheless, to date, no prospective study has examined the association between urinary tract infection and bladder cancer risk. The possibility that infection by human papilloma virus (HPV) is a risk factor contributing to bladder cancer has been investigated but no definite conclusions have been drawn. Thus, the debate remains open as to whether there is any direct link between chronic HPV infection and bladder cancer. Only 15 cases of vesical carcinoma have been reported, to date, in the setting of human immunodeficiency virus (HIV). The rare occurrence of bladder cancer during HIV infection and the lack of correlation with the laboratory markers of HIV disease progression may suggest a trivial association between two unrelated disorders. BK virus is oncogenic in newborn hamsters and can transfer to mammalian cells in vitro, but there is little consistent evidence of a link with human bladder cancer. Studies showed no correlation between herpes simplex virus (HSV) and bladder cancer, but bladder cancer becomes infected with HSV much more easily than non-neoplastic urothelium. In conclusion, with the exception of chronic infection with S. haematobium, the association between the occurrence of bladder cancer and chronic bacterial or viral infections could not be confirmed. Prospective studies with large numbers of patients and controls are required to confirm this issue.     

Elevated IL-37 Serum Levels in Patients with Transitional Cell Carcinoma of Bladder

Background: Interleukin-37 (IL-37) is a recently described cytokine that emerges as a natural inhibitor of inflammatory and immune responses. However, IL-37 has not yet been investigated in bladder cancer, and its biological role is unknown. Objective: The purpose of this study was to investigate IL-37 serum levels in patients with bladder cancer and determine whether they were linked to the patients' pathological characteristics. Methods: IL-37 serum levels were measured using a commercial ELISA kit in 60 patients with transitional cell carcinoma (TCC) of the bladder (mean age: 64.55±12.93) and 50 healthy controls (mean age: 62.94±12.69). Non-parametric tests were used for statistical comparisons, and the Cohen's d effect size was calculated to evaluate the practical and clinical significance of the results. Results: Our findings indicated an increasing trend in IL-37 serum levels in patients with TCC (42.77±3.36 pg/ml) in comparison with controls (40.51±7.32 pg/ml, p=0.09). However, IL-37 serum levels were found to be significantly higher in male patients (44.72±3.81 pg/ml) and patients aged ≥70 (46.92±6.77 pg/ml) in comparison with male controls (29.96±3.30 pg/ml, p=0.026) and controls aged ≥70 (23.62±4.43 pg/ml, p=0.009). In comparison to similar controls, Cohen's d effect size for patients aged ≥70 years was found to be 0.90. Conclusion: The findings reveal a higher serum level of IL-37 in patients with TCC, which might be clinically associated with immunosuppression and tumor growth. However, this is a preliminary study, and more research on the biological role of IL-37 and its potential therapeutic effects in bladder cancer is required.     

膀胱癌合并上尿路上皮癌的诊断与外科治疗

目的探讨膀胱癌合并上尿路上皮癌的诊治方法。方法本组膀胱癌合并输尿管癌13例,膀胱癌合并肾盂癌5例。用B超、静脉尿路造影（IVU）、CT、膀胱镜检查及输尿管镜检查进行诊断。对上尿路癌予切除患侧肾及全长输尿管或切除含肿瘤的下段输尿管后行再种术;对膀胱癌行扩大范围的管口周围膀胱切除术,或管口周围＋膀胱部分切除术,或管口周围切除＋经尿道膀胱肿瘤电切术。结果IVU诊断上尿路梗阻最好,检出率为100％;CT对上尿路癌定位诊断符合率最高（87．5％）,膀胱肿瘤诊断符合率为93．75％;膀胱镜发现膀胱癌比率为100％;输尿管镜发现输尿管癌比率为100％。采用各种手术方法均一期完成手术,无明显并发症。术后随访6—24个月,各手术方法间疗效无明显差别。结论多种检查方法相结合有利于减少膀胱癌合并上尿路上皮癌的漏诊率。对该疾病的治疗应根据具体病情采用个体化的方案。     

Evaluation of serum and urine clusterin as a potential tumor marker for urinary bladder cancer

Clusterin is a stress-associated cytoprotective chaperone up-regulated by various apoptotic triggers in many cancers and neurodegenerative diseases. No valid information about serum or urine clusterin concentration in patiens with bladder cancer exists. Aim of our paper was evaluation of the urine and serum clusterin concentrations in individuals with bladder cancer. Blood and urine samples were used from 43 patients with urothelial tumors of the urinary bladder and from 50 patients with benign urological diseases. Blood and urine were collected before cystoscopy. Enzyme-linked immunosorbent assays (ELISA) were performed for clusterin from serum and urine. Serum clusterin was higher in individuals with bladder cancer (means 185,812.5 vs 171,946.5 kU/l, p=0.04). Sensitivity for bladder cancer detection was 73% and specificity 55% (AUC 0.63); efficacy was not sufficient. Urine values of clusterin were higher in individuals with bladder cancer (197.2 vs 67.7, p=0.0007). Sensitivity for bladder cancer detection was 49% and specificity 92% (AUC 0.75, LR+ 6.1, PPV+ 84%); diagnostic efficacy was sufficient. In conclusion, serum and urine clusterin can differ between bladder cancer patients and the control group. Urine clusterin could be the possible laboratory marker of bladder cancer. Further research is warranted to confirm findings in larger studies of various clinical status.     

膀胱癌患者体液中血管内皮生长因子含量检测

目的 测定膀胱癌患者血液和尿液中血管内皮生长因子（VEGF）的含量.方法 采用免疫组化ELISA法检测60例膀胱癌患者及30例健康志愿者体液中VEGF的表达.结果 膀胱癌组血液和尿液中VEGF含量明显高于对照组（P＜0.001和P＜0.005）.结论 膀胱癌患者VEGF水平增高有可能成为一种新的肿瘤标志物而用于膀胱癌的早期诊断及病情进展的动态监测指标.     

膀胱移行细胞癌组织中NF-κB p65、uPA、Bcl-2的表达变化及其意义

目的观察膀胱移行细胞癌（下称膀胱癌）组织中NF—κBp65和尿激酶型纤溶酶原激活物（uPA）及Bcl-2的表达变化,并探讨其相关性。方法采用免疫组化SP法对40例膀胱癌组织和10例正常膀胱组织中NF—κBp65、uPA、Bcl-2进行测定,分析三者与膀胱癌分级、分期、侵袭转移及复发的关系及NF-κBp65表达与uPA、Bcl-2的相关性。结果NF-κBp65、uPA、Bcl-2在膀胱癌组织中的表达均明显高于正常膀胱组织（P〈0．05）;NF—κBp65和uPA与膀胱癌病理分级、分期、淋巴结转移有关（P均〈0．05）,Bcl-2与膀胱癌病理分级、分期有关（P〈0．05）,与淋巴结转移无关（P〉0．05）;膀胱癌组织中,NF—κBp65表达与uPA、Bcl-2表达呈正相关（r分别为0．388、0．462,P均〈0．05）。结论在膀胱癌组织中NF-κBp65、uPA、Bcl-2均呈高表达,并与膀胱癌的临床病理学特征有关;NF—κBp65可能通过调控uPA、Bcl-2的表达促进膀胱癌的进展;NF—κBp65、uPA、Bcl-2可以作为判断膀胱癌侵袭性、转移及预后的生物学标志物。     

Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells

Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44⁺CK5⁺CK20⁻). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% β-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.     

Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide

OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.     

Current bladder cancer tests: unnecessary or beneficial?

Bladder cancer is currently diagnosed using cystoscopy and cytology in patients with suspicious signs and symptoms. These same tests are used to monitor patients with a history of bladder cancer for recurrence. The recurrence rate for bladder cancer is high, thus necessitating long-term follow-up. Urine cytology requires an experienced cytopathologist and is costly. It has high specificity, but low sensitivity for low-grade bladder tumors. Recently many non-invasive bladder cancer tests, utilizing markers found in the urine, have been developed. The FDA has approved several of these for the use is bladder cancer diagnosis, and many others are undergoing development and investigation. An ideal bladder cancer test would be non-invasive, highly sensitive and specific, inexpensive, easy to perform, and yield highly reproducible results. Many of the tests reviewed meet some, but not all, of these criteria.