Cytochrome P4501A2 phenotype and bladder cancer risk: The Shanghai bladder cancer study

Cytochrome P450 1A2 (CYP1A2) is hypothesized to catalyze the activation of arylamines, known human bladder carcinogens present in cigarette smoke. The relationship between CYP1A2 phenotype and bladder cancer risk was examined in a case-control study involving 519 patients and 514 controls in Shanghai, China. Both CYP1A2 and N-acetyltransferase 2 (NAT2) phenotypic status were determined by a caffeine-based urinary assay. Our study showed that among smokers at urine collection, patients with bladder cancer had statistically significantly higher CYP1A2 phenotype scores compared to control subjects (p = 0.001). The odds ratios (95% confidence intervals) of bladder cancer for the second, third and fourth quartiles of the CYP1A2 score were 1.31 (0.53-3.28), 2.04 (0.90-4.60) and 2.82 (1.32-6.05), respectively, relative to the lowest quartile (p for trend = 0.003). NAT2 slow acetylation phenotype was associated with a statistically significant 40% increased risk of bladder cancer, and the relationship was independent of subjects' smoking status. Subjects possessing the NAT2 slow acetylation phenotype and the highest tertile of CYP1A2 scores showed the highest risk for bladder cancer. Their odds ratios (95% confidence intervals) was 2.13 (1.24-3.68) relative to their counterparts possessing the NAT2 rapid acetylation phenotype and the lowest tertile of CYP1A2 scores. The findings of our study demonstrate that CYP1A2 phenotype may be an important contributing factor in the development of smoking-related bladder cancer in humans.     

The evolving treatment paradigm of locally advanced rectal cancer: a narrative review

Background and ObjectiveSurgery is still considered the mainstay of treatment of locally advanced rectal cancer (LARC). Nevertheless, “curable” disease may still pose a great risk for both local and distant relapses. Since the early eighties of the past century, we have witnessed mounting evidence supporting the multi-modality approach to tackle this disease effectively. The multi-modality approach is variable between different positive trials. In this review, we discuss the treatment evolution of LARC, highlighting the key differences between the different contemporary strategies utilized. Based on current evidence, we sought to define distinct patient subgroups and to propose a treatment algorithm that best fits patient’s risk.MethodsWe conducted a literature search through PubMed and Google scholar. Eligible papers were phase 2/3 trials [in organ preservation (OP), observational and retrospective studies were also acceptable] published in English. We used keywords such as “locally advanced rectal cancer”, “perioperative therapy in rectal cancer”, “short course radiotherapy”, “chemoradiation in rectal cancer”, “interval to surgery”, “Neoadjuvant therapy”, “Organ preservation” and “Total neoadjuvant treatment [TNT]”.Key Content and FindingsVarious trials consistently demonstrated the benefit of preoperative radiotherapy in LARC, the role of adjuvant chemotherapy is controversial based on published studies, TNT was associated with a risk reduction in distant metastasis, and more reassuring evidence is accumulating regarding OP.ConclusionsThe treatment landscape of LARC is rapidly changing. Clinicians should carefully tailor treatment strategy based on patient’s risk.     

Massage modalities and symptoms reported by cancer patients: narrative review

The results of several studies on the use of massage therapies for cancer patients have been published in the peer-reviewed literature over the past 20 years. The current article provides a summary and critique of published studies in which patient-reported symptom ratings were assessed in relation to massage. Twenty-two studies are discussed. Most studies were on Swedish massage, followed by aromatherapy massage, foot reflexology, and acupressure. Symptoms assessed as outcomes included pain, fatigue, anxiety, nausea, and depression. Study designs included uncontrolled observational studies, crossover designs, and quasiexperimental and randomized controlled studies. Several studies included methodologic limitations such as small sample sizes, lack of blinded assessment, lack of accounting for subject attrition in statistical analyses, and other limitations. The results of the studies reviewed are mixed and vary as a function of several study characteristics. The most consistent symptom reduction was anxiety reduction. Additional well-designed studies are needed. Several recommendations are offered for future studies.     

羟基喜树碱膀胱灌注化疗预防膀胱癌术后复发

目的 探讨羟基喜树碱在膀胱癌术后膀胱灌注化疗预防肿瘤复发的效果。方法 52例膀胱恶性肿瘤患行膀胱部分切除术或羟尿道膀胱肿瘤电气化切除术后，采用羟基喜树碱20mg 生理盐水20mg膀胱灌注20次预防膀胱肿瘤复发。结果 随访1～6年，术后2年无复发，2年后复发6例，复发率11．5％。结论 膀胱癌术后羟基喜树碱膀胱灌注化疗预防肿瘤复发，疗效肯定副作用小。     

Bladder cancer: chemotherapy of advanced bladder cancer

Chemotherapy of advanced bladder cancer aims to destroy all the cancer cells in the host. For this purpose the most suitable and effective anticancer agents should be chosen. There have been many methods to select the anti-cancer drugs: sensitivity test. However, no reliable tests are available. We developed new anti-cancer sensitivity test, using the radio-active nucleic acids precursors; C14-Formate and C14-Adenine. This test revealed that Cisplatin, Adriamycin, and Mitomycin C were the most potent for the transitional cell carcinoma of the urinary bladder. Chemotherapy with a single agent was disappointing. Combined use of these agents was rather promising. Among them combination of cis-platin with Adriamycin and/or cyclophosphamide was the most effective. However, the overall response rate was reported around 50%. Multi-disciplinary treatment including surgery, irradiation, chemotherapy, and immunotherapy was disclosed to be useful for the treatment of bladder cancer. Since 1977 25 cases were treated with this mode of therapy in our clinic. Anti-tumor effect was remarkable. The categories, disappeared, and over 50% decrease of the mass, were found in 96% of the patients. Also, down-staging was demonstrated in 20% of the cases. Histologically no cancer cells were found in the surgical specimens of 3 cases and no viable cancer cells in 3 cases respectively. From these results it is now assumed that multi-disciplinary treatment is promising for the treatment of bladder cancer.     

The biology and treatment of superficial bladder cancer

Management of the superficial bladder cancer patient consists of two complementary but separate therapeutic goals: treatment of the existing tumor(s) and prevention of tumor recurrence. At present, the stage, grade, and multicentricity are the major determinants in the natural and therapeutic history of the disease. Although intravesical instillation of chemotherapeutic agents has been used for greater than 20 years, neither its exact role nor the optimal dose or schedule of administration have been established. To date, no dramatic differences in efficacy between the agents commonly used for intravesical chemotherapy, either as definitive therapy or prophylaxis, have been appreciated. These agents do appear to lower the recurrence rate as well as extend the disease-free interval. Since the most thorough experience is with thiotepa, it is the drug against which other agents should be compared in terms of both efficacy and toxicologic evaluation. Different administration schedules and methodologies need further study, such as the utility of continuous bladder irrigation, the use of sequential chemotherapeutic agents to gain cell synchronization, and the use of multiple drug regimens. Because there are multiple factors that influence the occurrence and recurrence of bladder cancer, combined modality therapy deserves testing. Modes of therapy that could be used together because they act through different mechanisms are intravesical chemotherapy, radioactive needle implants, carcinogen modifiers such as pyridoxine, chemoprotective agents such as retinoic acid, and immune stimulants such as BCG. These studies should be performed in a randomized prospective controlled fashion, which may require cooperative multi-institutional involvement to accrue adequate numbers of patients. At this time there are a number of important questions that remain to be answered concerning the treatment of superficial bladder cancer: (1) does this mode of therapy affect overall survival, (2) does prophylactic intravesical chemotherapy alter the incidence of subsequent muscle invasive disease, (3) does intravesical chemotherapy alter the sites, incidence, or responsiveness to systemic chemotherapy of subsequent metastatic disease, and (4) and what is the optimal timing and duration of prophylactic therapy from a cost-effectiveness standpoint?     

The epidemiology of bladder cancer: a second look.

A case-control study among 574 male and 158 female bladder cancer patients and equal numbers of matched controls was conducted between 1969 and 1974 in 17 hospitals in six United States cities. We determined that cigarette smokers of both sexes were at higher relative risk than nonsmokers. Cigarette smoking was responsible for about one-half of male and one-third of female bladder cancer. There was an excess of bladder cancer patients with some previous occupational exposure, such as rubber, chemicals, and textiles. A weak association with coffee drinking, which appeared to be independent of smoking, was found for males. Users of artificial sweeteners were not over-represented among the cases. The authors conclude that the epidemiologic pattern of bladder cancer cannot be fully accounted for by cigarette smoking and occupational exposure and suggest a series of metabolic studies to assess the role of additional factors, such as nutrition.     

Schistosomiasis and bladder cancer: similarities and differences from urothelial cancer

Through the years, schistosoma-associated bladder cancer was believed to be a unique entity of disease, different from urothelial cancer. As carcinogenesis is a highly complex process resulting from the accumulation of many genetic and epigenetic changes leading to alterations in the cell proliferation and regulation process, confirmation of their minute differences or similarities are extremely difficult. In bladder cancer, many of these carcinogenic cascades were not fully documented in spite of the efforts undertaken. The control of schistosomiasis and the subsequent decrease in the intensity of infestation showed feature changes approaching that of urothelial tumors. However, schistosoma-associated bladder cancer still presents in more advanced stages than schistosoma-non-associated urothelial cancer. Furthermore, many data were collected proving that, upon applying the same treatment protocol and management care, stage-by-stage comparison of the treatment end results were found to be similar in bladder cancer patients with the different etiologies.     

雌激素受体与膀胱癌和前列腺癌的关系

  雌激素受体（ER）属于核受体超家族成员，是一类重要的核转录因子，有雌激素受体α（estrogen receptor α，ERα）和雌激素受体β（estrogen receptor β，ERβ）两种亚型。ER在膀胱癌和前列腺癌中表达，且关系密切。文章从ER不同亚型的结构特点、组织学分布、生理功能以及与膀胱癌和前列腺癌的关系等方面进行简要综述     

Nutrition and bladder cancer

Epidemiologic evidence on the relation between nutrition and bladder cancer is reviewed. A role of diet and nutrition in bladder carcinogenisis is plausible since most substances or metabolites, including carcinogens, are excreted through the urinary tract. Ecologic studies on populations have found positive correlations between fats and oils and bladder cancer, but these are reflected only partly in the international differences in bladder cancer rates, which are systematically higher in Europe than in the United States. Ten case-control and three cohort studies of bladder cancer published in English between 1979 and 1994, and including some information on dietary factors, were reviewed. Of seven studies which considered various types and measures of fruit and vegetable consumption, six found a reduced risk with increasing consumption, which was more consistent for vegetables, with relative risk (RR) estimates between 0.5 and 0.7 for the highest cf the lowest consumption level. There is, therefore, suggestive evidence that a diet rich in fresh fruit and vegetables is a correlate-or an indicator-of reduced bladder cancer risk. No clear association emerged for other foods investigated, including meat and milk. With reference to nutrients, total fat intake was related to bladder cancer risk in three case-control studies, with relative risks between 1.4 and 1.7 for the highest cf the lowest consumption level. However, no relationship between fats and bladder cancer emerged in c cohort study on Japneese-Americans in Hawaii. No consistent association emerged between protein or carbohydrate consumption and bladder cancer risk. Among micronutrients, vitamin A, and particularly carotenoids, showed an inverse association with bladder cancer risk in four case-control studies, including one allowing for a measure of total caloric intake, but were not related consistently in two other studies. There oere only scattered and inconclusive data on vitamin C and E. Finally, two studies suggested that calcium and sodium and sodium may be related to bladder cancer risk. Thus, available data on diet and bladder cancer are still inconclusive. This is at least partly attributable to the limited number of cohort studies and the paucity of case-control studies, including satisfactorily detailed and validated dietary questionnaires. Despite these limitations, available data suggest that a diet rich in fresh fruit and vegetables, and, hence, possibly in carotenoids, is a correlate of reduced bladder cancer risk.This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project Clinical Applications of Oncological Research (Contracts No. 94.01321.PF39), and with the contributions of the Italian Association for Cancer Research and the Italian League Against Tumors, Milan.     

肌层浸润性膀胱癌保留膀胱综合治疗的疗效评价研究

目的 评价髂内动脉灌注化疗+经尿道膀胱肿瘤电切术+膀胱内灌注化疗综合治疗肌层浸润性膀胱癌的临床疗效.方法 比较64例采用髂内动脉灌注化疗(吡柔比星40 mg/m2、5-FU 1000 mg/m2、羟喜树碱30 mg/m2)+经尿道膀胱肿瘤电切术+膀胱内灌注化疗(综合治疗组)和62例采用经尿道膀胱肿瘤电切术+膀胱内灌注化疗(对照组)的肌层浸润性膀胱癌(T2N0M0期)患者经治疗后的肿瘤复发/转移率、死亡率及治疗相关不良反应的发生情况.结果 至随访截至日期,综合治疗组的无复发/转移率为93.75%(60/64),明显高于对照组的45.16%(28/62),差异有统计学意义(P=0);转移死亡率为3.13%(2/64),低于对照组的16.13%(10/62),差异有统计学意义(P=0.015);非膀胱癌死亡率为10.94%(7/64),与对照组的12.90%(8/62)相比,差异无统计学意义(P﹥0.05).结论 髂内动脉灌注化疗+经尿道膀胱肿瘤电切术+膀胱内灌注化疗的综合治疗方案,能够降低肌层浸润性膀胱癌(T2N0M0)患者肿瘤复发率和死亡率,不增加非癌性死亡风险,值得进一步探讨.     

The association between physical activity and bladder cancer: systematic review and meta-analysis

Background:

Physical activity may protect against bladder cancer through several biologic pathways, such as enhanced immune function and decreased chronic inflammation. Physical activity may also indirectly prevent bladder cancer by reducing obesity. A sizeable number of epidemiologic studies have examined the association between physical activity and bladder cancer, but the available evidence has not yet been formally summarised using meta-analysis.

Methods:

We performed a systematic literature review and meta-analysis of English-language studies published from January 1975 through November 2013. We followed the PRISMA guidelines and used a random effects model to estimate the summary risk estimates for the association between physical activity and bladder cancer.

Results:

A total of 15 studies with 5 402 369 subjects and 27 784 bladder cancer cases were included. High vs low levels of physical activity were related to decreased bladder cancer risk (summary relative risk (RR)=0.85, 95% confidence interval (CI)=0.74–0.98; I²=83% P-value for heterogeneity across all studies<0.001). Results were similar for cohort studies (RR=0.89, 95% CI=0.80–1.00; I²=64%) and case–control studies (RR=0.71, 95% CI=0.43–1.16; I²=87% P-value for difference=0.108) and they were comparable for women (RR=0.83, 95% CI=0.73–0.94; I²=0%) and men (RR=0.92, 95% CI=0.82–1.05; I²=67; P-value for difference=0.657). Findings were also comparable for recreational (RR=0.81, 95% CI=0.66–0.99; I²=77%) and occupational physical activity (RR=0.90, 95% CI=0.76–1.0; I²=76% P-value for difference=0.374), and they were largely consistent for moderate (RR=0.85, 95% CI=0.75–0.98; I²=76%) and vigorous activity (RR=0.80, 95% CI=0.64–1.00;I²=87% P-value for difference=0.535).

Conclusions:

Physical activity is associated with decreased risk of bladder cancer. Further studies are required to assess the relations of intensity, frequency, duration, and timing in life of physical activity to bladder cancer risk.     

Tumor markers of bladder cancer: the schistosomal bladder tumors versus non-schistosomal bladder tumors

Recent data have redefined the concept of inflammation as a critical component of tumor progression. However, there has been little development on cases where inflammation on or near a wound and a tumor exist simultaneously. Therefore, this pilot study aims to observe the impact of a wound on a tumor, to build a new mouse tumor model with a manufactured surgical wound representing acute inflammation, and to evaluate the relationship between acute inflammation or wound healing and the process of tumor growth. We focus on the two phases that are present when acute inflammation influences tumor. In the early phase, inhibitory effects are present. The process that produces these effects is the functional reaction of IFN-γ secretions from a wound inflammation. In the latter phase, the inhibited tumor is made resistant to IFN-γ through the release of TGF-β to balance the inflammatory factor effect on the tumor cells. A pair of cytokines IFN-γ/TGF-β established a new balance to protect the tumor from the interference effect of the inflammation. The tumor was made resistant to IFN-γ through the release of TGF-β to balance the inflammatory effect on the tumor cells. This balance mechanism that occurred in the tumor cells increased proliferation and invasion. In vitro and in vivo experiments have confirmed a new view of clinical surgery that will provide more detailed information on the evaluation of tumors after surgery. This study also provides a better understanding of the relationship between tumor and inflammation, as well as tumor cell attacks on inflammatory factors.     

Radical cystectomy in non-metastatic sarcomatoid bladder cancer: A direct comparison vs urothelial bladder cancer

IntroductionThe effect of radical cystectomy (RC) on cancer-specific mortality (CSM) is unclear in non-metastatic sarcomatoid bladder cancer (SBC) patients. We aimed to test the benefit of RC in SBC, and to perform a direct comparison vs urothelial bladder cancer (UCB).Materials and methodsWithin the Surveillance, Epidemiology, and End Results database (SEER 2001–2018) all non-metastatic SBC and UBC patients were identified. Endpoint of interest was CSM. Propensity score matching (PSM), cumulative incidence plots, competing risks regression (CRR) analyses, three-months landmark analyses, and sensitivity analyses were performed. All results were stratified according to organ-confined (OC: T₂N₀M₀) vs non-organ-confined (NOC: T_3-4N₀M₀ or T_anyN_1-3M₀) stages.ResultsOf 554 SBC patients, 49 vs 51% harbored OC vs NOC stages. Of 47,741 UBC patients, 62 vs 38% harbored OC vs NOC stages. RC rates were 33 vs 67% in OC vs NOC-SBC patients, and 40 vs 60% in OC vs NOC-UBC patients. After 1:1 PSM, comparison between RC vs no-RC was performed in OC-SBC (67 patients per group), OC-UBC (7611 patients per group), NOC-SBC (63 patients per group), and NOC-UBC patients (4644 patients per group). CRR hazard ratios associated with RC vs no-RC were 0.37 (p < 0.001) in OC-SBC vs 0.45 (p < 0.001) in OC-UBC, and 0.56 (p = 0.01) in NOC-SBC vs 0.68 (p < 0.001) in NOC-UBC. These results were replicated in sensitivity and landmark analyses.ConclusionsThe protective effect of RC vs no-RC is stronger in SBC than UBC patients, regardless of OC vs NOC stages.     

Molecular profiling of bladder cancer: involvement of the TGF-beta pathway in bladder cancer progression

A human bladder cancer model of nine cell sublines derived from the BL17/2 cell line was used to evaluate genes related to disease progression. Molecular profiling of sublines that were non-tumorigenic and invasive in nude mice was performed and identified 1367 differentially-expressed genes. Quantitative real-time PCR analysis of six transforming growth factor-beta (TGF-beta) pathway genes using the entire panel of nine cell lines was performed. Bone morphogenetic protein-2 expression was significantly associated with in vivo tumorigenicity of the cell lines (p=0.0228, Mann-Whitney); inhibin-betaB was related to their invasiveness (p=0.0468, Mann-Whitney). Analysis of conditioned medium showed TGF-beta1 production to be significantly associated with the phenotype of the cell line. The study shows the possible involvement of the TGF-beta pathway in bladder cancer progression.