In silico screening for tumour-specific expressed sequences in human genome.

A computer-based differential display tool named HsAnalyst has been developed and successfully used for the comparison of expression patterns in a set of tumours versus a set of normal tissues. A list of EST clusters highly represented in tumours and rarely observed in normal tissues has been developed as a resulting output file of the program. These differentially expressed EST clusters (genes) can be useful for developing new tumour markers and prognostic indicators for a wide set of human malignancies. Tumour-specific protein-coding genes may be considered a manifestation of tumour-specific gene expression.     

Principles of antibody therapy.

The success of monoclonal antibodies in clinical practice is dependent on good design. Finding a suitable target is the most important part as other properties of the antibody can be altered by genetic engineering. Antibodies that target lymphocyte antigens offer less toxic immunosuppressive treatment than currently available drugs and the first monoclonal antibody approved for human use is an immunosuppressive agent for treating rejection of renal transplants. Human trails of monoclonal antibodies to treat septic shock have been done and antibodies are also being developed to target common pathogens such as herpes simplex virus. Although monoclonal antibodies against cancer have been much heralded, their success has been limited by the poor access to the inside of tumours. Treatment of blood cancers has been more successful and a human antibody against B cell malignancies is being clinically tested. As knowledge about natural immune responses and antibody engineering increases many more monoclonals are likely to feature in clinical practice.     

Using clinicopathological analysis of general practitioner skin surgery to determine educational requirements and guidelines.

OBJECTIVE--To study the impact of skin surgery in general practice on the workload of a pathology laboratory and to identify what further training might be helpful. DESIGN--Analysis of skin biopsy specimens from general practitioners before and after their new contract to determine numbers of specimens, changes in diagnoses, adequacy of treatment of malignant tumours, and areas of low diagnostic accuracy. SETTING--District general hospital. SUBJECTS--All 1017 skin biopsy specimens from general practice for 15 months before and 12 months after the new general practitioner contract. RESULTS--The number of pathology specimens received increased from 16 to 65 per month (median = 6 submitted by each general practitioner in the post-contract year). The proportion of the more common pathological diagnoses was unchanged between the two periods, but the proportion of correctly diagnosed naevi, cysts, and seborrhoeic keratoses increased in the second. Although few diagnoses were overtly incorrect, accurate diagnosis of dermatofibromas and malignancies decreased after the contract, and the overall correct diagnosis rate for seborrhoeic keratoses, dermatofibromas, rashes, and malignancies was below 30%. Only nine out of 21 squamous cell carcinomas were adequately excised with tumour free margins, and follow up of malignant tumours may have been inadequate. CONCLUSIONS--Skin surgery in general practice has advantages but matters of concern are the increase in laboratory workload, the excision of some benign lesions, and the inappropriateness of biopsy of rashes. Squamous cell carcinoma and other malignant tumours submitted for pathological examination were often unsuspected and inadequately excised, and heightened suspicion is recommended. Pathology request forms may need redesigning to encourage provision of clinical details.     

Differential Expression of Prognostic Proteomic Markers in Primary Tumour,Venous Tumour Thrombus and Metastatic Renal Cell Cancer Tissue and Correlation with Patient Outcome

Renal cell carcinoma (RCC) is the most deadly of urological malignancies. Metastatic disease affects one third of patients at diagnosis with a further third developing metastatic disease after extirpative surgery. Heterogeneity in the clinical course ensures predicting metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been shown to have prognostic significance, including Ki67, p53, vascular endothelial growth factor receptor 1 (VEGFR1) and ligand D (VEGFD), SNAIL and SLUG. Previous pathway analysis has been from study of the primary tumour, with little attention to the metastatic tumours which are the focus of targeted molecular therapies. As such, in this study a tissue microarray from 177 patients with primary renal tumour, renal vein tumour thrombus and/or RCC metastasis has been created and used with Automated Quantitative Analysis (AQUA) of immunofluorescence to study the prognostic significance of these markers in locally advanced and metastatic disease. Furthermore, this has allowed assessment of differential protein expression between the primary tumours, renal vein tumour thrombi and metastases. The results demonstrate that clinico-pathological parameters remain the most significant predictors of cancer specific survival; however, high VEGFR1 or VEGFD can predict poor cancer specific survival on univariate analysis for locally advanced and metastatic disease. There was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared with the primary tumours and renal vein tumour thrombi. With the exception of p53, these differences in protein expression have not been shown previously in RCC. This confirms the importance of proliferation, angiogenesis and epithelial to mesenchymal transition in the pathogenesis and metastasis of RCC. Importantly, this work highlights the need for further pathway analysis of metastatic tumours for overcoming drug resistance and developing new therapies.     

Acromegaly and cancer

In recent years, it has become increasingly recognized that acromegaly is associated with an increased prevalence of colorectal cancer and pre-malignant tubular adenomas. The aetiology of these tumours is unknown but is likely to reflect increased levels of both insulin-like growth factor I (IGF-I), which is implicated in the development of sporadic colorectal cancer, and environmental factors, such as the bile acid deoxycholic acid. There is also evidence to suggest that the prevalence of breast and perhaps haematological malignancies might be increased in acromegaly, although these associations have been based on mostly small epidemiological surveys and clarification will come in the future once large-scale epidemiological studies have been completed.     

Oncologist’s/haematologist’s view on the roles of pathologists for molecular targeted cancer therapy

In the past two decades there has been a tremendous increase in the understanding of the molecular basis of human malignancies. In a variety of neoplasms, specific molecular markers became part of disease classifications and are now routinely used to define specific entities. Molecular analyses discriminate prognostic groups, guide differential treatment strategies and identify targets for molecular defined cancer therapy. A battery of new drugs has been developed to specifically inhibit oncogenic pathways. For an increasing number of solid and haematological malignancies, the availability of molecular targeted drugs has fundamentally changed treatment algorithms. However, the diagnostic, prognostic and therapeutic impact of selected molecular markers is still limited in many cases. After all, the success of a molecular targeted therapy is clearly determined by the significance of the targeted structure for the biology of cancer and the ability of the malignant cell to evade specific inhibition.     

Gene expression signatures in lymphoid tumours

Lymphoid tumours comprise the acute and chronic leukaemias, the broad spectrum of lymphomas, including Hodgkin's disease, and multiple myeloma. The subdivision of the acute leukaemias according to the proliferating type of white blood cells has had a major impact on the care of these patients. More recently, specific chromosomal translocations have been used to identify patients who may benefit from more intensive therapies. The novel high-throughput genomic technologies, such as microarrays, provide new avenues for the molecular diagnosis of the haematological malignancies. Rapid advances in genome sequencing and gene expression profiling provide unprecedented opportunities to identify specific genes involved in complex biological processes, including tumorigenesis. The features of microarray technology and the variety of experimental approaches to elucidate lymphoid malignancies are discussed. Microarray technology has the potential to lead to more accurate prognostic assessment for patients and is expected to ultimately allow the clinician to select therapies optimally suited to each patient.     

Epstein-Barr virus infection: basis of malignancy and potential for therapy

The Epstein-Barr virus (EBV) is a human herpesvirus that is usually carried lifelong as an asymptomatic infection. EBV is the causative agent of infectious mononucleosis and has been linked to the development of several malignant tumours, including B-cell neoplasms such as Burkitt's lymphoma and Hodgkin's disease, certain forms of T-cell lymphoma, and some epithelial tumours, such as undifferentiated nasopharyngeal carcinoma and a proportion of gastric cancers. All these tumours are characterised by the presence of multiple extrachromosomal copies of the circular viral genome in the tumour cells and the expression of EBV-encoded latent genes, which appear to contribute to the malignant phenotype. An increasing understanding of the function of EBV latent genes and of the nature of the immune response to the virus is providing exciting new possibilities for the treatment of EBV-associated malignancies. For example, adoptive transfer of virus-specific cytotoxic T lymphocytes has already been of value in the treatment of EBV-positive B-cell lymphomas arising in post-transplant patients, and this approach is currently being investigated in other EBV-associated tumours. In addition, gene therapy offers the opportunity to deliver agents that might directly interfere with the function of specific EBV genes. This review summarises the role of EBV in malignancy. In particular, it focuses on the latent proteins as a basis for understanding how EBV might contribute to the process of transformation. Strategies to target EBV in tumours, potentially providing alternative therapeutic approaches, are also discussed.     

Review of recent studies on resistance to cytotoxic deoxynucleoside analogues

Cytotoxic deoxynucleoside analogues are widely used in the treatment of haematological malignancies and solid tumours. Their metabolism and mechanisms of action are relatively well known, but with ongoing technological development, a continuous flow of scientific data is constantly adding new knowledge to this field. Thus, what was already a well-developed area some years ago has continued its expansion and become a better understood part of medical sciences. In order to keep abreast of the latest advances on cellular and clinical resistance to deoxynucleoside analogues, we have reviewed the recent literature and provide here an update on the subject. We have particularly focused on changes in gene products involved in the metabolic pathway of these drugs, such as membrane transporters, kinases, deaminases and 5'-nucleotidases. We also gave an overview on the chemical and biological development of modified deoxynucleoside analogues such as conjugates and pronucleotides.     

Wnt signalling pathway in bladder cancer

Bladder cancer (BC) is one of the most common tumours of the urinary system and is also known as a highly malignant tumour. In addition to conventional diagnosis and treatment methods, recent research has focused on studying the molecular mechanisms related to BC, in the hope that new, less toxic and effective targeted anticancer drugs and new diagnostic markers can be discovered. It is known that the Wingless (Wnt) signalling pathway and its related genes, proteins and other substances are involved in multiple biological processes of various tumours. Clarifying the contribution of the Wnt signalling pathway in bladder tumours will help establish early diagnosis indicators, develop new therapeutic drugs and evaluate the prognosis for BC. This review aims to summarise previous studies related to BC and the Wnt signalling pathway, with a focus on exploring the participating substances and their mechanisms in the regulation of the Wnt signalling pathway to better determine how to promote new chemotherapeutic drugs, potential therapeutic targets and diagnostic biomarkers.     

The current status of immunotherapy for cervical cancer

BackgroundImmunotherapy has been proven effective in several tumours, hence diverse immune checkpoint inhibitors are currently licensed for the treatment of melanoma, kidney cancer, lung cancer and most recently, tumours with microsatellite instability. There is much enthusiasm for investigating this approach in gynaecological cancers and the possibility that immunotherapy might become part of the therapeutic landscape for gynaecological malignancies.Cervical cancer is the fourth most frequent cancer in women worldwide and represents 7.9% of all female cancers with a higher burden of the disease and mortality in low- and middle-income countries. Cervical cancer is largely a preventable disease, since the introduction of screening tests, the recognition of the human papillomavirus (HPV) as an etiological agent, and the subsequent development of primary prophylaxis against high risk HPV subtypes. Treatment for relapsed/advanced disease has improved over the last 5 years, since the introduction of antiangiogenic therapy. However, despite advances, the median overall survival for advanced cervical cancer is 16.8 months and the 5-year overall survival for all stages is 68%. There is a need to improve outcomes and immunotherapy could offer this possibility. Clinical trials aim to understand the best timing for immunotherapy, either in the adjuvant setting or recurrent disease and whether immunotherapy, alone or in combination with other agents, improves outcomes.     

Cyberknife: A double edged sword?

The Cyberknife represents a new, frameless stereotactic radiosurgery system which efficiently incorporates advance robotics with computerized image reconstruction to allow highly conformal image guided radiation delivery. This review focus is on the pros and cons of this new radiotherapy tool, its current indications, safety profile and future directions. A literature search of Medline, Pubmed, Biomed, Medscape and Cancer lit database were referred to retrieve relevant data/information. The authors conclude that the use of this system offers an invaluable solution to the treatment of selective tumours/lesions located close to critical structures, salvage of recurrent and metastatic lesions and potential of treatment of selective early stage malignancies like the carcinoma prostate and lung. However, it is still too premature, with insufficient follow up data to advocate it as the treatment of choice in any set up. There are several radiobiological issues that also remain in the greyzone.     

单克隆抗体药物与血液系统恶性肿瘤的治疗

单克隆抗体凭借其特异性强、副作用较小的优点,越来越广泛地应用于疾病的诊断与治疗。单克隆抗体药物在血液系统恶性肿瘤的治疗中也发挥了重要作用。目前,经美国食品与药品管理局(FDA)批准用于治疗血液系统恶性肿瘤的单克隆抗体药物已有六种,在临床取得良好的治疗效果。单克隆抗体药物主要通过对肿瘤细胞的直接杀伤作用、抗体依赖性细胞介导的细胞毒性反应(ADCC)、补体依赖性细胞毒性反应(CDC)和改变信号通路等机制达到治疗肿瘤的效果。另外,将单克隆抗体与放射性核素、化疗药物和毒素等偶联,用于肿瘤等疾病的靶向治疗研究,成为生物治疗领域的热点。该文对近年来国际上用于血液系统恶性肿瘤治疗的单克隆抗体药物进行了概括和总结,讨论了治疗性单克隆抗体药物存在的问题和应用前景。     

Holoprosencephaly

Cardiac tumours are benign or malignant neoplasms arising primarily in the inner lining, muscle layer, or the surrounding pericardium of the heart. They can be primary or metastatic. Primary cardiac tumours are rare in paediatric practice with a prevalence of 0.0017 to 0.28 in autopsy series. In contrast, the incidence of cardiac tumours during foetal life has been reported to be approximately 0.14%. The vast majority of primary cardiac tumours in children are benign, whilst approximately 10% are malignant. Secondary malignant tumours are 10–20 times more prevalent than primary malignant tumours. Rhabdomyoma is the most common cardiac tumour during foetal life and childhood. It accounts for more than 60% of all primary cardiac tumours. The frequency and type of cardiac tumours in adults differ from those in children with 75% being benign and 25% being malignant. Myxomas are the most common primary tumours in adults constituting 40% of benign tumours. Sarcomas make up 75% of malignant cardiac masses. Echocardiography, Computing Tomography (CT) and Magnetic Resonance Imaging (MRI) of the heart are the main non-invasive diagnostic tools. Cardiac catheterisation is seldom necessary. Tumour biopsy with histological assessment remains the gold standard for confirmation of the diagnosis. Surgical resection of primary cardiac tumours should be considered to relieve symptoms and mechanical obstruction to blood flow. The outcome of surgical resection in symptomatic, non-myxomatous benign cardiac tumours is favourable. Patients with primary cardiac malignancies may benefit from palliative surgery but this approach should not be recommended for patients with metastatic cardiac tumours. Surgery, chemotherapy and radiotherapy may prolong survival. The prognosis for malignant primary cardiac tumours is generally extremely poor.     

Considerations in the design of possible cell cycle effective drugs

Antineoplastic agents are known to induce differential cytotoxic and cytostatic effects throughout the cell cycle. Many drugs have greater toxicity for cycling cells and act selectively at one or more phases of the cycle and may cause partial synchrony of surviving cells. However, these observations have been generally carried out on in vitro systems only and present a variety of complexities and pitfalls. Furthermore, human tumours are often characterized by a relatively low fraction of proliferating cells and present a large cellular heterogeneity as far as their cytogenetic, cytokinetic, and clonogenic features and their responses to drugs are concerned. Therefore, resistance to chemotherapy is due to various factors characterizing, in some instances, each individual tumour. In spite of the advent of technological advances such as flow cytometry, it is still difficult to design kinetic-orientated therapies especially for the treatment of solid tumours. Consequently, it is also difficult to design protocols based on cell cycle effective drugs. The possibility remains, at least for the moment, to stratify tumours according to their cellular heterogeneity. Different protocols could then be assigned to classes of tumours. Such an approach could be completed by further advances in the cellular monitoring of individual tumours.     

Childhood cancer and residential radon exposure – results of a population-based case-control study in Lower Saxony (Germany)

A population-based case-control study on risk factors for childhood malignancies was used to investigate a previously reported association between elevated indoor radon concentrations and childhood cancer, with special regard to leukaemia. The patients were all children suffering from leukaemia and common solid tumours (nephroblastoma, neuroblastoma, rhabdomyosarcoma, central nervous system (CNS) tumours) diagnosed between July 1988 and June 1993 in Lower Saxony (Germany) and aged less than 15 years. Two population-based control groups were matched by age and gender to the leukaemia patients. Long-term (1 year) radon measurements were performed in those homes where the children had been living for at least 1 year, with particular attention being paid to those rooms where they had stayed most of the time. Due to the sequential study design, radon measurements in these rooms could only be done for 36% (82 leukaemias, 82 solid tumours and 209 controls) of the 1038 families initially contacted. Overall mean indoor radon concentrations (27 Bq m^–3) were low compared with the measured levels in other studies. Using a prespecified cutpoint of 70 Bq m^–3, no association with indoor radon concentrations was seen for the leukaemias (odds ratio (OR): 1.30; 95% confidence interval (95% CI): 0.32–5.33); however, the risk estimates were elevated for the solid tumours (OR: 2.61; 95% CI: 0.96–7.13), mainly based on 6 CNS tumours. We did not find any evidence for an association between indoor radon and childhood leukaemia, which is in line with a recently published American case-control study. There is little support for an association with CNS tumours in the literature. Received: 14 December 1998 / Accepted in revised form: 10 June 1999     

Meal-stimulated and atropine-inhibited secretion of pancreatic polypeptide in healthy subjects, members of MEA I families and patients with malignant endocrine tumours of the gastrointestinal tract

Pancreatic polypeptide has been suggested as a marker for endocrine malignancies of the gastrointestinal tract. However, the secretion of PP shows great intra- and inter-individual variation, causing both false negative and positive results. In order to reduce these risks, we have evaluated a new combined stimulatory and inhibitory test of PP secretion. Six healthy subjects, 23 members of three MEA I families, seven patients with malignant pancreatic endocrine tumours and four patients with carcinoid tumours of the gastrointestinal tract were subjected to a standardized test meal, followed by intravenous atropine 60 min after the start of the meal. Serum PP was monitored during 2 h. In healthy subjects the meal caused a rapid increase in serum PP within 20 min and intravenous atropine caused a significant (P less than 0.05) decrease of serum PP within 15 min. Patients with malignant endocrine pancreatic tumours or carcinoids had a delayed response after the test meal, with maximum levels at 45 min, but still with a significant inhibition by atropine. Even tumour patients with initially normal or slightly increased basal PP levels showed this secretion pattern. Healthy members of MEA I families displayed identical PP curves to healthy subjects, whereas members with elevated basal PP levels who had been previously affected by hyperparathyroidism and/or prolactinomas showed similar secretion patterns to pancreatic tumour patients. We think that a meal stimulatory test is of great value in the diagnosis of gastrointestinal endocrine tumours and also in the identification of subjects with the MEA I trait, who are at high risk of having pancreatic endocrine tumours.     

Adventures in targeting

An overview of our experiences in the field of immunoliposomal anticancer drugs is provided with respect to choice of ligand, and choice of model system, in order to provide some guidance as to the rational use of this new technology. Liposomes targeted by either peptide or monoclonal antibodies showed significantly higher binding to their respective target cells in vitro compared to non-targeted liposomes in all model systems examined. This higher binding led to higher cytotoxicities relative to non-targeted liposomes. For the immunoliposomes to deliver their entrapped drug to target cell in vivo, long circulations half-lives are required. We have evaluated the pharmacokinetics of liposomes prepared by several different coupling techniques, and have found significant differences in the clearance of these immunoliposomes from the circulation. Immunoliposomes prepared with whole anti-CD19 IgG coupled by the Mal-PEG-DSPE method demonstrated a short plasma half-life, which may reflect the random orientation of the MAb on the liposome surface. Coupling methods that mask or eliminate the Fc region result in immunoliposomes that have clearance rates more similar to untargeted liposomes. Insertion of peptides or antibodies into pre-formed liposomes through incubation with ligand-coupled PEG micelles resulted in immunoliposomes, termed post-insertion liposomes, that demonstrated comparable in vitro binding, pharmacokinetic profiles and in vivo therapeutic efficacy to liposomes made by conventional coupling methods. The therapeutic efficacy of liposomes, prepared by various coupling methods and targeted by different ligands, was compared in several different animal models of either haematological malignancies, pseudometastatic disease or solid tumours. In our hands, successful in vivo targeting has been obtained when the target is either small or readily accessible from the vasculature, where the liposomes have longer circulating half-lives and/or where a ligand against an internalizing epitope has been chosen. These results should aid in the rational design of applications for immunoliposomal drugs in the future.     

以风湿病症状为突出表现的恶性肿瘤22 例临床分析

目的:提高以风湿病症状为突出表现的恶性肿瘤的早期的识别,有利于提高临床医生对此类疾病早期诊断,避免误诊,提高诊断的正确率。方法:对22例患者以骨骼、关节及肌肉疼痛为突出表现,拟诊风湿性疾病,最终确定诊断为恶性肿瘤患者的临床资料进行分析。结果:22例患者中18例属癌性风湿症,疼痛性质为隐痛,呈慢性反复渐进性加重,非甾体抗炎药和激素治疗的效果不佳,手术切除癌肿后,疼痛明显减轻;4例患者属恶性肿瘤骨转移,最初为隐痛,逐渐发展为剧烈持续性疼痛,血沉有明显升高,抗核抗体(ANA)阳性,非甾体抗炎药和激素治疗效果为无效。结论:对骨骼、关节及肌肉疼痛的患者出现于风湿病难以解释的临床表现,常规治疗效果不佳,应注意排查恶性肿瘤的可能。     

Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application

Therapeutic antibodies have revolutionised treatment of some cancers and improved prognosis for many patients. Over half of those available are approved for haematological malignancies, but efficacious antibodies for solid tumours are still urgently needed. Clinically available antibodies belong to the IgG class, the most prevalent antibody class in human blood, while other classes have not been extensively considered. We hypothesised that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumours such as ovarian and breast carcinomas. Our laboratory has examined this concept by evaluating two chimaeric antibodies of the same specificity (MOv18) but different isotype, an IgG1 and an IgE against the tumour antigen folate receptor α (FRα). The latter demonstrates the potency of IgE to mount superior immune responses against tumours in disease-relevant models. We identified Fcε receptor-expressing cells, monocytes/macrophages and eosinophils, activated by MOv18 IgE to kill tumour cells by mechanisms such as ADCC and ADCP. We also applied this notion to a marketed therapeutic, the humanised IgG1 antibody trastuzumab and engineered an IgE counterpart, which retained the functions of trastuzumab in restricting proliferation of HER2/neu-expressing tumour cells but also activated effector cells to kill tumour cells by different mechanisms. On-going efficacy, safety evaluations and future first-in-man clinical studies of IgE therapeutics constitute key metrics for this concept, providing new scope for antibody immunotherapies for solid tumours.