肌层浸润性膀胱癌亚型的生物信息学分析

目的通过生物信息学分析研究两种膀胱癌亚型(基底样膀胱癌和管腔型膀胱癌)之间不同的分子调控机制和分子特性,为更准确地区分膀胱癌亚型和探索潜在的治疗靶点提供帮助。方法利用稳健的多芯片平均算法将由22个基底样膀胱癌和132管腔型膀胱癌样本组成的数据集进行标准化,并选择其中前1000个具有最高标准差的基因进行两种亚型的差异表达基因分析。将得到的差异表达基因进行GO功能注释和KEGG通路富集分析。此外,选择前100个差异表达基因构建蛋白质互作网络。结果得到基底样和管腔型膀胱癌差异表达基因共742,其中基底样亚型上调的基因405个,下调的基因337个。GO富集分析显示差异表达基因显著富集在细胞外区基质、趋化性、炎症等功能上,KEGG通路富集显示差异表达基因显著富集在细胞外基质受体相互作用的通路上。构建的蛋白质互作网络显示重要的hub蛋白质为LNX1、MSN和PPARG。结论本研究得到的基底样和管腔型膀胱癌亚型分子机制的区别主要体现在细胞外区域的分子作用机制、细胞趋化性和炎症反应等,基因LNX1、MSN和PPARG为区别两种膀胱癌亚型的特征基因。     

Single institutional experience of bladder-preserving trimodality treatment for muscle-invasive bladder cancer

The authors designed this study to determine the clinical effectiveness of trimodality treatment, i.e., transurethral resection of a bladder tumor (TURBT) and concurrent chemoradiotherapy (CRT). Twenty patients with a muscle-invasive bladder cancer were treated by TURBT followed by concurrent cisplatin (75 mg/m(2) day), administered on weeks 1 and 4 of radiotherapy. According to residual tumor status after TURBT, patients were classified into patients with a complete TURBT group and incomplete TURBT group. Response to treatment was evaluated by restaging TURBT at 4 weeks after completing CRT (post-CRT). Fifteen patients (75%) achieved complete remission (CR) at restaging; 10 patients (50%) remained continuously free of tumor recurrence. Disease-specific and overall survivals were 51.1% and 38.6% at 5 yr post-CRT, respectively. Of 16 patients in the complete TURBT group, 14 patients (87.5%) achieved CR, which was significantly different from that observed in the incomplete TURBT group, in which only 1 (25%) of 4 patients achieved CR (p=0.032). Five- year disease-specific and overall survivals were 71.6% and 53.5%, respectively. Ten patients (90.9%) maintained their own bladder among the 11 surviving patients. Trimodality treatment was found to be an effective treatment in patients who underwent complete TURBT for a muscle-invasive bladder cancer.     

Relationship between serum cholinesterase level and urinary bladder activity in patients with or without overactive bladder and/or neurogenic bladder

We compared the serum cholinesterase (ChE) level and various parameters between patients with or without overactive bladder (OAB) and/or neurogenic bladder (NB). A total of 258 patients who met the following criteria were enrolled: the presence/absence of OAB and/or NB was documented, laboratory data were available, and liver and renal functions were normal. Patients were divided into the 3 groups: 1) a NB+/OAB+ group who had both NB and OAB, 2) a NB-/OAB+ group who had OAB alone, and 3) an OAB- group who did not have OAB. The relationship between the presence of OAB and various biochemical parameters were examined, as well as the therapeutic outcome in relation to the same biochemical parameters. Forty-three patients had both NB and OAB (NB+/OAB+), 66 patients had OAB without NB (NB-/OAB+), and 149 patients had no OAB (OAB-). Serum ChE, total protein, and albumin levels were lower in the NB-/OAB+ group than the NB+/OAB+ group or the OAB- group. In the NB-/OAB+ group, a higher serum albumin or ChE level was associated with a better therapeutic outcome. These results suggest that a decrease of serum ChE level is related to the occurrence of OAB and the poor response to treatment in OAB patients without NB.     

Association between DNA repair gene polymorphisms and p53 alterations in Japanese patients with muscle-invasive bladder cancer.

OBJECTIVE: DNA repair enzymes play a vital role in protecting the genome from carcinogens, several of which can cause mutations in the TP53 gene in bladder cancer. Some single nucleotide polymorphisms (SNPs) in DNA repair genes reportedly modulate the repair capacity. This study aimed to clarify the effect of these functional SNPs on the alteration of p53 in muscle-invasive bladder cancer. METHODS: We investigated the association between SNPs in xeroderma pigmentosum complementation groups C (XPC), D and G and X-ray repair cross-complementing group 1 and 3 genes, and p53 expression and allelic imbalance at the TP53 locus in Japanese patients with muscle-invasive bladder cancer. p53 expression and the allelic imbalance were evaluated using immunohistochemistry and a microsatellite marker, respectively. RESULTS: Positive p53 expression was significantly less frequent in patients with the CC genotype of the XPC gene than in those with the AA or AC genotype (p = 0.0005). C alleles of the XPC gene were also less frequent in patients with positive p53 expression (p = 0.01). CONCLUSION: Our results suggested that the XPC polymorphism might affect p53 alteration and the molecular pathway defined by the p53 alteration in the development of muscle-invasive bladder cancer.     

CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer

Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen-presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-β chain (hCG-β), a tumor antigen frequently expressed by epithelial cancers including bladder cancer. In Phase I studies of cancer patients, CDX-1307 was well tolerated and induced significant hCG-β-specific cellular and humoral immune responses when co-administered with GM-CSF and the Toll-like receptor agonists resiquimod and poly-ICLC. An ongoing Phase II trial evaluates CDX-1307 in patients with newly diagnosed, resectable, hCG-β-expressing bladder cancer, where low tumor burden and early intervention may provide greater potential for benefit.     

Comparison of survival outcomes between primary and secondary muscle-invasive bladder cancer: An updated meta-analysis

Objective: Studies have showed that different follow-up starting points might potentially impact the comparison between primary (PMIBC) and secondary muscle-invasive bladder cancer (SMIBC), but the only previous meta-analysis did not differentiate the follow-up starting points of included studies. With more trials published, we aim to update the meta-analysis comparing PMIBC and SMIBC.Methods: PubMed, Embase, Cochrane Library and ClinicalTrial.gov. systematically searched. Literatures comparing the survival outcomes of PMIBC and SMIBC were selected. Outcomes of cancer-specific mortality (CSM), overall mortality (OM) and recurrence-free survival (RFS) were pooled and grouped based on the starting point of follow-up (after initial diagnosis or radical cystectomy (RC)). Newcastle-Ottawa Scale (NOS) and funnel plot were employed to assess the study quality and publication bias, respectively.Results: A total of 17 high-quality studies were selected, with 5558 patients aged from 59.8 to 72.7 (mean value) involved. The male-to-female ratio was roughly 4:1 (4390/1124). SMIBC had lower risk of CSM after initial diagnosis (HR 0.81, 95%CI 0.67-0.98, P=0.03, I²=70%), but higher risk of CSM after RC (HR 1.45, 95%CI 1.27-1.65, P<0.00001, I²=64%). In terms of OM and recurrence, outcomes were pooled only after RC, which both turned out to be higher for SMIBC (OM: HR 1.50, 95%CI 1.30-1.73, P<0.00001, I²=0%; Recurrence: HR 1.66, 95%CI 1.36-2.02, P<0.00001, I²=48%). No obvious publication bias was observed from funnel plot.Conclusion: The current study suggested SMIBC had higher risk of CSM, OM and recurrence after RC, but lower risk of CSM after initial diagnosis.     

A randomized study of combination chemotherapy (VAC-FMC) with or without immunostimulation by corynebacterium parvum in metastatic breast cancer

Summary A total of 156 patients with metastatic breast cancer were entered into a prospective multicenter trial in September 1975. All patients were treated monthly with vincristine, adriamycin and cyclophosphamide (VAC) six times, followed by 5-fluorouracil, methotrexate and cyclophosphamide (FMC) until progression was documented. By random assignment, the patients received 5 mg/m² Corynebacterium parvum (CP) subcutaneously on day 1, in addition to VAC/FMC. Of the 150 evaluable patients, 33 of 76 (45%) and 36 of 74 (49%) had complete or partial response to VAC/FMC plus CP, respectively. The Kaplan-Maier curves of duration of remission and survival were almost identical (medians 14.5 vs 12.1 months and 22.2 vs 21.1 months, respectively). The hematologic and gastrointestinal toxicity were also similar in the two study groups. However, 19 of 74 (26%) patients developed skin ulcers after repeated injections of CP. These patients showed prolonged survival (P=0.002, log rank test). These results suggest that adding nonspecific immunostimulation with CP to currently available chemotherapy on day 1 is of no benefit to most patients with metastatic breast cancer, but may select an immunoreactive subgroup with increased local toxicity and survival.     

Prognostic value of Bcl-2 and Bax tumor cell expression in patients with non muscle-invasive bladder cancer receiving bacillus Calmette-Guerin immunotherapy

Apoptosis is the distinctive form of programmed cell death that complements cell proliferation in maintaining normal tissue homeostasis. The significance of constitutive apoptosis in the recurrence of Non Muscle Invasive Bladder Cancer has yet to be investigated. The aim of this study is to investigate the prognostic significance of Bax and Bcl-2 in terms of recurrence after BCG immunotherapy. Immunohistochemical analysis was performed on frozen biopsies to evaluate bcl-2 and Bax proteins expression in 28 cases of NMIBC. All patients with confirmed NMIBC were treated with intravesical BCG-immunotherapy. The follow up was performed for 26 months. The correlation between clinicopathological, immunohistochemical data and the response to BCG therapy was performed. Univariate analysis showed that, PT1 stage, High grade and Bax expression increased significantly the risk of recurrence (P = 0.015, P = 0.015 and P= 0.034 respectively). In addition, multivariate analysis selected the model involving stage, age, Bax and Bcl-2 expression as the best independent variables of recurrence. In conclusion, the expression of Bcl-2 and Bax in NMIBC could have a prognostic value in assessing the risk of recurrence after BCG immunotherapy. These findings require further investigations on larger cohort in order to ascertain new molecular markers of the response to BCG immunotherapy.     

血清YKL-40蛋白水平与非肌层浸润性膀胱癌复发的临床关系研究

目的:探讨患者血清YKL-40蛋白水平与非肌层浸润性膀胱癌(non muscle-invasive bladder cancer, NMIBC)复发的临床关系.方法:选取76例NMIBC患者,其中34例为术后随访两年内确诊复发患者、42例为术后随访两年未见复发患者,及健康对照组31例,采取清晨血清样本,采用酶联接免疫吸附剂测定法(ELISA)检测患者血清中YKL-40水平.结果:NMIBC患者血清YKL-40水平显著高于健康对照组(P<0.001),同时,NMIBC复发组患者血清YKL-40水平高于非复发组(P=0.001).结论:血清YKL-40蛋白水平在非肌层浸润性膀胱癌复发中有着较高的临床诊断价值,可作为监测患者术后复发的一种新分子标志物,为患者术后相关后续治疗提供参考.     

Differential proteomic analysis of nuclear matrix in muscle-invasive bladder cancer: potential to improve diagnosis and prognosis.

INTRODUCTION: Although several molecular markers for bladder cancer have been identified, at present little information on prognostic biomarkers is available in the literature. Prognostication of this tumor is largely based on clinicopathological characteristics. Our aim was to identify nuclear matrix (NM) proteins that might serve to better characterize the phenotype of the invasive bladder cancer and to investigate their diagnostic and prognostic roles. METHODS: NM proteins expressed in normal (n=3) or non-tumoral (n=9) tissue specimens and muscle-invasive bladder cancer (n=21) specimens were analyzed by two dimensional (2D) gel electrophoresis. PDQuest image analysis software was used to generate a comparative NM proteome analysis. Selected spots were characterized by liquid chromatography coupled to tandem mass spectrometry and Western blot. RESULTS: We detected over 800 protein spots in each 2D map and 43 spots were identified. 30 proteins were differentially expressed by bladder tumor cells; among these, 19 proteins were detected in bladder tumoral tissues but not in normal and non-tumoral tissues and seven proteins correlated with tumor stage. One protein (p54nrb) was strongly correlated with vascular invasions and appeared to be also significantly (P<0.0001) associated with a decreased probability of survival. CONCLUSION: Important alterations in NM proteins occur in muscle-invasive bladder cancer. The differentially expressed proteins include biomarkers potentially useful for disease diagnosis, progression and prognosis. Our findings beyond improving the understanding of the biology of bladder cancer, could help to stratify patients into different prognostic subgroups and to select those who might be better candidate to multimodal therapeutic approaches.     

Results of treatment of childhood localized non-Hodgkin's lymphoma with combination chemotherapy with or without radiotherapy

Combined radiotherapy and intensive chemotherapy have led to improved prognosis in children with non-Hodgkin's lymphoma, but the toxic effects of these forms of treatment are additive and seriously limit the benefits of their use. In an effort to limit the adverse acute and late effects of treatment, we conducted a randomized, controlled trial to determine whether irradiation of primary sites of involvement could safely be omitted from the treatment of children with localized non-Hodgkin's lymphoma (Stages I and II) who have a favorable prognosis. In addition, the chemotherapy regimen was less intense and shorter (eight months) than usual. A total of 129 patients were randomly assigned to receive either chemotherapy (vincristine, cyclophosphamide, doxorubicin, prednisone, mercaptopurine, and methotrexate) with irradiation (27 Gy) of the involved field (combined chemotherapy and radiotherapy) or chemotherapy alone. Half the patients have been followed for more than 38 months (range, 13 to 68), and the projected disease-free survival (+/- SE) at four years among patients assigned to chemotherapy alone is 87.9 +/- 8.8 percent, as compared with 87.3 +/- 9.4 percent among patients assigned to combined therapy (P = 0.44). The majority of patients tolerated therapy very well, although the toxic effects of treatment (myelosuppression, mucositis, and infection) were significantly worse among patients who received the combination of chemotherapy and radiotherapy. We conclude that most children with localized non-Hodgkin's lymphoma can be cured by a chemotherapy regimen of reduced intensity and duration. Radiotherapy can be safely omitted from the therapy of such children without substantially jeopardizing their excellent chance of cure.     

化疗对乳腺癌患者甲状腺功能或结构的影响

目的探讨化疗对乳腺癌患者甲状腺功能或结构的近期影响。方法选取蚌埠医学院第一附属医院于2017年3月至2018年12月收治的40例女性初治原发性乳腺癌患者,检测并比较化疗后2和4疗程与化疗前的甲状腺功能5项(包括T3、T4、FT3、FT4和TSH)及其结构的变化。结果乳腺癌患者化疗2和4疗程后T4、FT4水平明显低于化疗前(P<0.05);患者化疗4疗程后甲状腺TI-RADS分级及其结构异常的发生率较化疗前均明显升高(P<0.05)。结论化疗后近期可引起或加重乳腺癌患者甲状腺功能或结构的异常,适时进行检查并干预可防止病情进一步发展,具有重要的临床意义。