Tissue microarray constructs to predict a response to chemoradiation in rectal cancer

Purpose

To identify, using tissue microarray (TMA), an immunohistochemical panel predictive of response to ionizing radiation (IR) in rectal cancer.

Methods

TMA constructs were prepared from archived stage II/III rectal tumors and matching adjacent mucosa (n = 38) from patients treated with pre-operative chemoradiation. Immunohistochemistry (IHC) was performed for MIB, Cyclin E, p21, p27, p53, survivin, Bcl-2, and BAX. Immunoreactivity along with clinical variables was subjected to univariate and forward stepwise logistic regression analyses.

Results

Pathological complete response (pCR) was 23.9%. The number of positive lymph nodes obtained in the resected specimen was associated with pCR. Immunoreactivity for MIB (Sn 15%, Sp 65%, OR 0.33), p53 (Sn 3%, Sp 84%, OR 0.16), Bcl-2 (Sn 11%, Sp 74%, OR 0.35), and BAX (Sn 92%, Sp 80%, OR 46) was associated with pathological response (all p's < 0.001). Forward stepwise logistic regression analysis demonstrated that MIB was an independent predictor of a response to chemoradiation (p = 0.001).

Conclusions

A combined panel of mediators of apoptosis alone or combined with clinical factors is a feasible approach that can be applied to rectal tumor biopsies to predict a response to chemoradiation. The most sensitive factor was BAX; while MIB independently predicted a response to chemoradiation.     

Chipping away at breast cancer: insights from microarray studies of human and mouse mammary cancer

Breast cancer is the most prevalent tumor in American woman. Multiple factors, including age, diet, genetics, environment, geographic location, parity, as well as race, influence the development of this heterogeneous disease. As the process of oncogenesis involves the disruption of diverse cellular pathways including cell cycle, growth, survival, and apoptosis, the high throughput technique of microarray analyses provides a powerful insight into multiple cellular processes. These techniques have identified particular expression patterns that can classify tumors into new groups and aid in the prediction of the natural history of the disease and the therapeutic response. This wealth of information may also form the basis for the development of new types of targeted therapies. Studies to identify the earliest molecular events in oncogenesis and progressive changes in the human disease have been difficult to perform within the same patient. The use of transgenic mouse mammary cancer models provides an opportunity to decipher molecular changes that occur at progressive stages of tumor development. This paper reviews microarray technology, and the insights gained from published breast cancer microarray analyses, and considers the contribution of microarray studies in identifying mouse cancer models that may be appropriate for answering particular experimental questions.     

Chemotherapy studies in autochthonous rat tumors. Forestomach and bladder cancer.

Acetoxymethyl-methyl-nitrosamine (AMMN) induced only carcinomas of the forestomach in female Sprague-Dawley rats after an induction time of about 100 days when applied orally twice weekly in single doses (d) of 3.5 mg/kg body weight, Butyl-butanol-nitrosamine (BBN) selectively produced bladder tumors in female Sprague-Dawley rats after about 280 days when given in daily oral single doses (d) of 10 mg/kg body weight. The reactions of a total of 520 rats with chemically induced tumors were tested using 4-drug combination chemotherapy with different equitoxic doses of Adriamycin (Adm), Methotrexate (Mtx), 5-Fluorouracil (5-FU) and Bleomycin (Blm). The influences of combined therapy on mean sruvival time, tumor weight, histology of tumors, and adverse side effects of therapy are herein described. The results showed to be tumorspecific. In addition, the comparability of experimental chemotherapy in autochthonous rat tumors to clinical experience is discussed.     

Tissue microarray for high-throughput analysis of gene expression profiles in hepatocellular carcinoma

AIM: To study the expression profiles of HBsAg, HBcAg, p21WAF1/CIP1 (p21), Rb genes in hepatocellular carcinoma (HCC) and to investigate their roles in the hepatocar-cinogenesis. METHODS: HCC tissue microarray containing 120-min tissues of 40 HCC cases was constructed. HBsAg, HBcAg, p21 and Rb proteins were immunohistochemically stained by streptavidin-peroxidase conjugated method (S-P). The expression loss of these genes in cancerous, para-cancerous tissues and adjacent normal liver tissues of 40 HCCs were comparatively examined. RESULTS: The positive rate of HBsAg expression in cancerous tissues of 40 HCCs was 7.5%, which was lower than that in para-cancerous and adjacent normal liver tissues (X2=12.774, P<0.01; X2=18.442, P<0.01). The positive rate of HBcAg expression in cancerous tissues of 40 HCCs was 20.0%, which was also lower than that in para-cancerous and adjacent normal liver tissues (X2=9.482, P<0.01; X2=14.645, P<0.01). p21 protein deletion rate in cancerous tissues of 40 HCCs was 27.5%, which was higher than that in para-cancerous and adjacent normal liver tissues (X2=7.439, P<0.01; X2=11.174, P<0.01). p21 protein deletion correlated remarkably with the pathological grade of HCC (X2=0.072, P<0.05). Rb protein deletion rate in cancerous tissues of 40 HCCs was 42.5%, which was also higher than that in para-cancerous and adjacent normal liver tissues (X2=10.551, P<0.01; X2=18.353, P<0.01). Rb protein deletion rate did not correlate remarkably with tumor size or pathological grade of HCC (X2=0.014, P>0.05; X2=0.017, P>0.05). CONCLUSION: Expression deletion of HBsAg, HBcAg, p21 and Rb proteins in HCCs may play important roles in the carcinogenesis of HCC. Tissue microarray is an effective high-throughput technique platform for cancer research.     

Cyclophosphamide-induced bladder cancer

Cyclophosphamide is a known risk factor for the development of bladder cancer. We report 3 cases of cyclophosphamide-induced bladder carcinoma in 2 individuals treated for Wegener's granulomatosis and in 1 patient with neuroblastoma. Included is a review of the literature on the relative risk of cyclophosphamide therapy, the mechanisms by which the drug induces bladder cancer, and suggestions on how to minimize the deleterious effects of the drug. We conclude that cyclophosphamide should be used in the lowest possible dose and that patients receiving more than 20 g of the drug should undergo routine urinalysis for microscopic hematuria every 3-6 months for up to 11 years after the treatment has been discontinued. Dosages as small as 600 mg in the pediatric population may warrant lifelong monitoring.     

Hereditary bladder cancer

First degree relatives of patients with bladder cancer have a two-fold increased risk of bladder cancer but high-risk bladder cancer families are extremely rare. There is no clear Mendelian inheritance pattern that can explain the increased familial risk. This makes classical linkage studies for the mapping of susceptibility genes impossible. The disease is probably caused by a combination of exposure to exogenous carcinogens and a large number of susceptibility genes with modest effects. Genome-wide association studies are better suited to identify these genes. Three such studies are currently underway and are expected to report their results in 2008.     

Colon cancer in rectal bladder

Received: April 7, 2000 / Accepted: October 20, 2000     

胃癌组织芯片中Argonaute蛋白表达分析

目的 检测胃癌Argonautel、Argonaute2、Argonaute3和Argonaute4蛋白表达,探讨其临床意义.方法 利用组织芯片技术结合免疫组化法检测100例胃癌组织和癌旁组织中Argonaute1、Argonaute2、Argonaute3和Argonaute4蛋白的表达.结果 胃癌组织中Argonautel、Argonaute2,Argonaute3和Argonaute4蛋白表达均显著高于癌旁组织(P＜0.05);Ⅱ～Ⅱ期胃癌中4种蛋白表达均显著高于癌旁组织(P＜0.05);Argonaute4蛋白在Ⅲ期胃癌中的表达显著高于Ⅰ～Ⅱ期胃癌(P＜0.05),Argonaute1、Argonaute2、Argonaute3蛋白在在Ⅰ～Ⅱ期胃癌与Ⅲ期胃癌间差异无统计学意义(P＞0.05).四种Argonaute蛋白的表达与胃癌患者的性别、年龄、淋巴结转移无相关性(P＞0.05).在胃癌组织中Argonautel、Argonaute2、Argonaute3和Argonaute4蛋白两两间表达存在相关性(P＜0.01).结论 胃癌的发生发展可能与Argonaute1、Argonaute2、Argonaute3和Argonaute4蛋白过表达有关.     

Skeletal metastasis in gall bladder cancer

This report describes an interesting and unusual case of carcinoma gallbladder with skull metastasis.     

Intravesical mitoxantrone in superficial bladder cancer

Twenty-five patients with Ta-T1 transitional cell carcinoma of the bladder were treated by transurethral resection (TUR) followed by intravesical chemoprophylaxis with mitoxantrone (10 mg diluted in 50 ml normal saline) administered weekly for 6 weeks. After a mean follow-up of 12 months, 76% of patients in the whole group, 69% in the newly diagnosed patients and 89% in the group of previously relapsed patients remained relapse free. These rates compare favorably with the other prophylactic agents available. Therapy was well tolerated in most patients, with only two patients reporting grade 3 local toxicity. We conclude that mitoxantrone is an effective and safe agent for intravesical chemotherapy.     

Radiation-associated urinary bladder cancer

A few data sets have been used for assessing the risk of radiation-associated bladder cancer. The most important are the Japanese atomic bomb survivors and patients exposed to ionizing radiation for medical purposes. According to a report from the United Nations Commission on the Effect of Ionizing Radiation, there is convincing evidence of a relationship between exposure to ionizing radiation and bladder cancer. In contrast to many other malignancies it is not clear how age at exposure and gender affect the risk of bladder cancer. Furthermore, the potential interaction between smoking and radiation exposure needs to be studied in greater detail.     

Expression of HLA-G in cancer bladder

This study comprised 42 patients with cancer bladder, who underwent radical cystectomy. The aim of work is to determine if HLA-G is expressed on tumor cells, derived from cancer bladder. We studied HLA-G-mRNA expression using RT-PCR and HLA-G cell surface expression by immunohistochemistry (IHC) staining technique. HLA-G was expressed in 28.6 % of cancer cases as determined by PCR and on 16.7% of cases determined by IHC staining. The sensitivity, specificity and accuracy of IHC were 58.3%, 96% and 81.7% respectively as compared to PCR results. There was a highly significant increase in the expression of HLA-G on cancer bladder cases with metastatic prostate infiltration (P= 0.021). It is concluded that HLA-G is ectopically expressed on cancer bladder malignant cells both at molecular and protein levels. However, it is not significantly associated with histologic type, tumor grade, stage, T category, schistosomiasis and lymph node involvement.     

Innovations in superficial bladder cancer treatments

Bladder cancer treatment is a challenge for both urologists and oncologists. Particularly during these last years many changes have been made in the management of superficial bladder cancer. In the case of superficial bladder cancer, intravesical instillation of chemo/immunotherapeutic agents after transurethral resection is the standard. The treatment goals include: complete removal of the initial tumor, prevention of recurrences and inhibition of disease progression. This work aims at reviewing the new developments in the therapeutic field of superficial bladder cancer. A growing trend involves the use of multimodality treatment to obtain the activation of the host immunity against the tumor, and to enhance the cytotoxic effects of chemotherapeutic agents. The new therapeutic modalities, which are under preclinical and clinical investigations, are showing promising results.     

Tissue factor and angiogenesis in cancer

Idiopathic thrombosis often precedes the diagnosis of occult cancer by several years. Whether hypercoagulability predisposes for malignancy or the converse holds true is an unresolved paradigm that stems from the known vicious cycle of clot formation and tumor growth. Central to this paradigm is the interplay between tissue factor (TF), the initiator of coagulation, and angiogenesis, the life support of tumors. Both clotting-dependent and -independent mechanisms of TF-induced angiogenesis have been elucidated that may signal through distinct pathways. This review focuses on the latest studies of TF and angiogenesis and highlights recent applications that have led to the development of promising new TF-targeted cancer therapeutics. Finally a cautionary note is given about unexpected complications arising from antiangiogenic therapy that may potentially involve TF.