Targeting claudins in cancer: diagnosis,prognosis and therapy

Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation, suggesting their promise as biomarkers for diagnosis and prognosis or targets for treatment. Claudin binders (Clostridium perfringens enterotoxin and monoclonal antibody) have been tested in preclinical experiments, and some of them have progressed into clinical trials involving patients with certain cancers. However, the clinical development of many of these agents has not advanced to clinical applications. Herein, I review the current status of preclinical and clinical investigations of agents targeting claudins for diagnosis, prognosis and therapy. I also discuss the potential of combining claudin binders with other currently approved therapeutic agents.     

端粒酶：肿瘤治疗研究的新希望

端粒是染色体末端的一段富含GC的重复序列，端粒双链中3＇端突出形成3＇悬端（3＇-overhang）。端粒酶是由RNA和蛋白质组成的反转录DNA合成酶，以端粒3＇突出端为引物，RNA组分为模板，蛋白组分催化合成、延长端粒重复序列。1978年Blackburn和Gall首次在四膜虫染色体末端发现了由重复序列组成的端粒。1985年Greider和Blackbum。在四膜虫中发现能合成延伸端粒重复序列的端粒酶。1989年Morin首次在端粒酶阳性的人Hela细胞开始了端粒酶的研究。近年来，端粒及端粒酶的研究已成为生物学热点，也是人类抗肿瘤药物研究的新“靶点”。     

Testicular cancer: what's new in staging, prognosis, and therapy

Improvements in the clinical staging of testicular cancer may permit the identification of clinical stage I patients at low risk of harboring metastatic disease, who could be spared treatment and observed only. Both retrospective, single-institution studies and studies of unselected, consecutive patients have confirmed that vascular invasion, lymphatic invasion, and percentage of embryonal carcinoma are predictive of metastasis in patients with low-stage nonseminoma. Whether patients with these risk factors have a worse outcome if managed with surveillance, rather than with aggressive therapy, is unclear. Low MIB-1 staining (which identifies the Ki-67 antigen) in conjunction with a low percentage of embryonal carcinoma in the testicular specimen appears to be predictive of a low probability of metastasis. Computed tomography (CT) is a useful staging tool. A new prognostic classification system for seminomas and nonseminomas was recently developed by an international consensus conference. Laparoscopic retroperitoneal lymphadenectomy appears to be a feasible staging tool with acceptable short-term morbidity. Whether laparoscopic lymph node dissection is equivalent to the open procedure when used as a therapeutic modality is not yet known. At present, laparoscopy should be used only in selected patients in a study setting. Primary chemotherapy is not recommended currently because it has not yet been proven to be superior in patients with high-risk clinical stage I nonseminoma and can cause significant long-term sequelae.     

Pertuzumab: new hope for patients with HER2-positive breast cancer

BackgroundHuman epidermal growth factor receptor 2 (HER2) overexpression is detected in approximately 15% to 20% of all breast cancers (BCs). A revolutionary change in the prognosis of this subgroup of patients has occurred since trastuzumab therapy was introduced into daily clinical practice. However, because trastuzumab resistance is common, new molecules with complementary and/or synergistic mechanisms of action have been developed. Pertuzumab is a new anti-HER2 humanized monoclonal antibody that prevents the formation of HER2 dimers.Material and methodsA computer-based literature search was carried out using PubMed (keywords: breast neoplasm, dimerization, HER-2, pertuzumab); data reported at international meetings are included.ResultsThis paper describes pertuzumab's mechanism of action, safety, and role in HER2-positive BCs. It also explores the role of pertuzumab as a single agent or combined with trastuzumab by reviewing data from preclinical research to ongoing clinical trials. Recently published trials, particularly the CLEOPATRA study, highlight the efficacy, tolerability, and increase in disease-free survival associated with this novel agent when combined with trastuzumab.ConclusionThe pertuzumab and trastuzumab anti-HER2 dual blockade is likely to represent a substantial advance for patients with HER2-positive BCs and a new milestone on the way to personalized medicine.     

Optimizing tumor markers in breast cancer: monitoring, prognosis, and therapy control

The clinical validity of tumor markers in breast cancer is reevaluated. Though ideal tumor markers are presently not available for breast cancer patients, optimizing markers can be achieved, applying markers in special situations and in selected fields of oncology. Tumor markers like carcinoembryonic antigen (CEA) and tissue polypeptide antigen are only of limited value in the primary diagnosis of breast cancer due to their low sensitivity and their poor specificity. Single postsurgical CEA values in selected groups of mammary carcinomas, however, can be used to predict patients with high risk of recurrence and they imply considerable prognostic information. Serial CEA determination in the follow-up of patients with operated breast cancer are highly sensitive in early detection of recurrences and are also useful in controlling therapy in individual cases. The biological basis of tumor marker measurements reflecting tumor growth is pointed out and newly developed methodologies for the potential establishment of more specific tumor markers for serodiagnosis and for immunolocalization of tumors are discussed.     

Immunochemistry and lung cancer: application in diagnosis, prognosis and targeted therapy

Immunochemistry is now an established ancillary technique in lung cancer diagnosis. Not only does it help in supporting the morphological diagnosis of malignancy, but its role now extends to the determination of cell lineage, ascertaining the primary site of tumour origin and contributing to decisions on prognosis and treatment. Early detection and confirmation of lung cancer facilitate early treatment decisions. Lung cancer management now has a multidisciplinary approach which includes cytopathologists and clinicians. Some clinicians may not understand what immunochemistry is and what its role is in lung cancer diagnosis, prognosis and therapy. The purpose of this paper is to define immunochemistry, on the background of basic respiratory airway epithelial structure and cancer biology, and discuss its application in the diagnosis, treatment and determination of prognosis of lung cancer.     

乳腺神经内分泌癌的临床诊治及预后分析

背景与目的：近年来国内外对乳腺神经内分泌癌(neuroendocrine breast cancer,NEBC)这一临床上罕见类型的乳腺癌开展了越来越多的临床研究,但目前检索到的国内外有关NEBC的文献大多是病例报道,大规模的临床研究少见,报道的病例数不多,大多数研究在流行病学特点、诊断、治疗及预后方面的报道存在差异,需要更多的研究提高对NEBC的总体认识和诊治水平。本文主要探讨NEBC的临床诊断、治疗以及预后情况。方法：回顾分析了新疆医科大学附属肿瘤医院2004年１月—2013年6月收治的25例经病理明确诊断为NEBC患者的临床资料并对其随访。结果：25例NEBC患者平均发病年龄58.2岁,临床特点及影像学检查无特征性表现,免疫组化中雌激素受体(estrogen receptor,ER)和孕激素受体(progesterone receptor,PR)阳性率分别为76%和64%,无1例出现原癌基因人表皮生长因子受体2(human epidermal growth factor receptor-2,HER-2)强阳性,全部患者随访9~115个月,1、2、5年的总生存率(overall survival,OS)分别为100%、95%、88%,无病生存率(disease-free survival,DFS)为96%、90%、78%。结论：本组NEBC患者的发病年龄低于国外,术后综合治疗方案的选择仍需进一步研究,发病年龄、肿瘤大小、术后病理分期可能与患者的预后相关。有关NEBC的治疗及预后还需要大样本长时间的随访观察。     

Evolution of breast cancer therapeutics: Breast tumour kinase’s role in breast cancer and hope for breast tumour kinase targeted therapy

There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients’ overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase (Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current “state of play” with respect to targeted therapy for breast cancer, as well as discussing Brk’s role in the processes underlying tumour development and metastasis and its potential as a therapeutic target in breast cancer.     

Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis

In the past several years, the importance of microRNA (miRNA) in cancer cells has been recognized. Proper control of miRNA expression is essential for maintaining a steady state of the cellular machinery. Recently, it was discovered that extracellular miRNAs circulate in the blood of both healthy and diseased patients, although ribonuclease is present in both plasma and serum. Most of the circulating miRNAs are included in lipid or lipoprotein complexes, such as apoptotic bodies, microvesicles, or exosomes, and are, therefore, highly stable. The existence of circulating miRNAs in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function, as well as the meaning of the existence of extracellular miRNAs, remain largely unclear. In this review, we summarize the usefulness of circulating miRNA for cancer diagnosis, prognosis, and therapeutics. Furthermore, we propose a mechanism for the secretion and incorporation of miRNA into the cells. (Cancer Sci 2010)     

Antiprogestins, a new form of endocrine therapy for human breast cancer

The antitumor, endocrine, hematological, biochemical, and side effects of chronic second-line treatment with the antiprogestin mifepristone (RU) 486) were investigated in 11 postmenopausal patients with metastatic breast cancer. We observed one objective response, 6 instances of short-term stable disease, and 4 instances of progressive disease. Mean plasma concentrations of adrenocorticotropic hormone (P less than 0.05), cortisol (P less than 0.001), androstenedione (P less than 0.01), and estradiol (P less than 0.002) increased significantly during treatment accompanied by a slight decrease of sex hormone binding globulin levels, while basal and stimulated gonadotropin levels did not change significantly. The increased basal cortisol levels could not be further stimulated by synacthen, nor suppressed by 1 mg of dexamethasone. Plasma estradiol concentrations were significantly correlated with both androstenedione (P less than 0.05) and cortisol levels (P less than 0.01). The percentage of eosinophilic white blood cells (P less than 0.02) and mean plasma creatinine concentration (P less than 0.05) increased significantly. Side effects frequently occurred during long-term treatment and appeared to be caused mainly by the antiglucocorticoid properties of the drug. It is concluded that antiprogestins form a new treatment modality in the endocrine treatment of human breast cancer. New antiprogestins with less antiglucocorticoid side effects might be especially of value as an adjunct to antiestrogenic treatment in view of our finding that combined antiestrogenic and antiprogestational treatment caused additive growth-inhibitory effects in rat mammary tumors.     

Season of diagnosis and prognosis in breast and prostate cancer

Background  Patients with breast or prostate cancer diagnosed during the summer season have been observed to have better survival. The extent to which this is due to biological and/or health care system related factors is unclear. Methods  Using the Swedish Cancer Register and clinical databases, we analyzed overall survival by month of diagnosis among the incident cases of breast (n = 89,630) cancer and prostate (n = 72,375) cancer diagnosed from 1960 to 2004. We retrieved data on tumor stage from 1976 for breast cancer and 1997 for prostate cancer. Cox proportional hazards models were used to calculate relative risk of survival by the season of diagnosis. Results  There was a higher hazard ratio of death in men and women diagnosed with cancer in the summer with a relative hazard of 1.20 (95% confidence interval 1.15–1.25) for July for prostate cancer and 1.14 (95% confidence interval 1.09–1.19) for August for breast cancer when compared to being diagnosed in January. This difference coincided with a lower mean number of cases diagnosed per day, and a higher proportion of advanced cases diagnosed in the summer. This pattern of presentation was stronger in the later years. Conclusion  The difference in stage distribution explains the seasonal variation in prognosis seen in this study. The variation may be because of structure of the health care system and a strong tradition of vacationing from mid June to mid August. Thus, the health care infrastructure and the late presentation of symptomatic disease may influence cancer survival studied by season of diagnosis substantially.     

Group support in breast cancer: realistic hope,realistic benefits

Ductal carcinoma in situ (DCIS) is responsible for 25% of screen-detected breast cancers. Various prognostic classifications are in use, including the Van Nuys Prognostic Index and the European Organisation for Research and Treatment of Cancer grading system (well, intermediate or poorly differentiated) based on cytonuclear pattern. This has been modified in screening programs to low, intermediate and high grade. In comparison with normal epithelium, DCIS has a tenfold increase in growth and 15-fold increase in apoptosis. Patients with extensive or multifocal DCIS need mastectomy and sentinel node biopsy, together with reconstruction, if requested. Microinvasion associated with DCIS is an indication for sentinel node biopsy. Randomized trials have confirmed the value of breast irradiation after wide excision, in terms of DCIS relapse and progression to invasive disease. Patients with estrogen receptor-positive DCIS benefit from adjuvant tamoxifen after breast-conserving surgery.     

基因分型对乳腺癌诊治和预后判断的指导作用

乳腺癌是女性的常见恶性肿瘤之一,其临床治疗主要是以经典的TNM和临床分期为指导。近年来兴起的对乳腺癌相关的分子遗传学研究取得了令人瞩目的进展,提出了乳腺癌基因分型这一新概念。基因诊断对乳腺癌的辅助化疗以及预后的判断相对传统的病理分型有更高的专一性,为乳腺癌的治疗起到了更好的指导作用,本文主要对基因分型进行介绍并总结了几种与乳腺癌预后相关的基因标志,探讨其在临床治疗中的实际应用。     

Endocrine therapy, new biologicals, and new study designs for presurgical studies in breast cancer

The preoperative setting is increasingly popular for the clinical investigation of hormonal agents and new biological drugs. The effectiveness of endocrine agents is well established for estrogen receptor-positive disease, and the emphasis in preoperative studies is on their combination with agents targeted at resistance mechanisms over 3 or more months. New agents are also being assessed for early evidence of clinical efficacy in shorter-term window-of-opportunity studies. The establishment of Ki67 as an intermediate marker of treatment benefit and of long-term outcome, with endocrine drugs, provides the opportunity for new trial designs with Ki67 as the primary endpoint. The PeriOperative Endocrine Therapy for Individualizing Care (POETIC) trial is randomizing (2:1) 4000 estrogen receptor-positive patients to 2 weeks presurgical treatment with a nonsteroidal aromatase inhibitor or no presurgical treatment. It provides a unique opportunity for detailed study of the determinants of response and resistance to estrogen deprivation as well as testing the role of presurgical therapy for improved biomarker-based estimates of prognosis.