Cancer surveys最新文献

New data and approaches bring novel perspectives and possibilities to old problems. The speculation of this chapter attempts to merge the puzzling MS data observed in human tumours (Figs. 3 and 4B) within a multistep tumour progression model. Clearly the current models are gross simplifications and other, more sophisticated models may better account for the distribution of MS alleles found in human tumours. The findings and the data are also limited to MMR deficient tumours, and studies in non-mutator phenotype tumours may be more difficult since fewer polymorphisms will arise during progression. The current model, however, precisely defines proliferation and clearly delineates two very distinct patterns. Further studies using MS loci in MMR deficient tumours will allow fairer tests of alternative pathways (Fig. 4C) to cancer. Evolution proceeding in occult progenitor populations allows mutations to accumulate throughout life and not just in the last decades after polyps appear.

The Chemoprevention Branch, NCI, is supporting over 80 clinical trials of chemopreventive agents and has dozens of drugs under development. The structural and functional properties of epithelial precancer (also called preinvasive or IEN), such as increasingly aberrant nuclear size, shape and rates of cellular proliferation and apoptosis, measured by CAQIA, form the basis for specific and quantitative end markers in short term clinical trials of chemopreventive agents. IEN very frequently, if not invariably, is preceded by two conditions diffusely affecting the epithelium: genomic instability and chronic hyperplasia. Chronic subepithelial inflammation is also commonly present. Multicentricity and multipath genetic progression of individual lesions are important characteristics that must be considered when designing endpoint markers and planning for adequate biopsy sampling in clinical trials of chemopreventive agents. Use of CAQIA provides increased sensitivity and specificity when measuring the cellular changes of IEN, such as increasingly aberrant nuclear size, nuclear shape, integrated optical density of nuclear DNA and nuclear chromatin texture features. A software program called the Deep Valley Detector, which measures the optical density gradient at the margins of chromatin clumps in cell nuclei of histological sections stained for DNA, is one example of many nuclear chromatin texture features measured. In the image of the nucleus of a neoplastic cell from high grade IEN of the cervix, 111 deep valley sites were counted, whereas the nucleus of a non-neoplastic hyperplastic cell showed only 16 sites. The modulating effects of chemopreventive agents on IEN may be quantitated by the change they produce in the average number of deep valley sites per nucleus.

Using conventional morphological assessment, squamous change in bladder epithelium has been observed in 73% of bilharzial associated squamous cancers but only 28% of pure transitional cancers. However, more detailed studies of patients with TCC suggest that the latter figure may be an underestimate, since in one series it was reported to be more than 50%. The most significant risk factor for development of squamous carcinoma in the bladder is chronic persistent bacterial cystitis, although in the areas of the world where bilharzia is endemic this infestation also increases the risk of both squamous bladder cancer and chronic bacterial cystitis. Although it is clear that carcinogens are involved as co-factors in transformation from squamous metaplasia to cancer, the fact that in Zimbabwe one author has observed that TCC is more frequent in whites than squamous cancer is in bilharzia infected blacks is evidence that other unidentified risk factors are involved. This is increasing evidence for involvement of HPV subtypes in cervix, oropharynx and lung cancer. As all three of these tumours are associated with squamous metaplasia, there could be a case for investigation of bladder squamous tumours for HPV involvement. This is particularly so given the observation of the "hit and run" type of transient infection in cattle that develop BPV associated tumours and the tenfold difference (30% vs 3%) in frequency of HPV detection in squamous skin tumours developing in immunosuppressed individuals compared with those arising spontaneously. With new technology for cytological screening techniques using dot ELISA and evidence of differences in TP53 mutations that support the involvement of nitrous oxide, it is clear that there is more to learn from study of this tumour type that may be of general interest in understanding the clonal development of cancer.

Gliomas are thought to arise from the glial cells of brain tissue. The spectrum of tumours varies with age, implying that cells in a particular state of development are a prerequisite for the occurrence of some tumour types. Premalignant states are not recognized, so we know little about the earliest events in oncogenesis. However, progression of gliomas has been examined by studying large series of tumours of different malignancy grades and by following cases where the tumour is of low malignancy grade at first diagnosis and recurs later as a tumour of higher malignancy grade. When considering premalignant states we can only extrapolate from our knowledge of progression from the least to the most malignant tumour forms. The best studied variants are the astrocytic tumours. There are no consistent genetic aberrations known to characterize the most benign variant of astrocytoma, the pilocytic astrocytoma (malignancy grade I), which occurs mainly in children. Astrocytomas (malignancy grade II) show loss of alleles at 13q, 17p and 22q and occur mainly in early middle age. Loss of one TP53 allele (17p) is associated with mutation of the remaining allele. Loss of one RB1 allele is not. Anaplastic astrocytomas (malignancy grade III) have in approximately 50% of cases aberrations of genes coding for proteins involved in the control of entry into the S phase of the cell cycle, as well as other genetic defects affecting unknown genes. The greatest number of genetic abnormalities is seen in glioblastomas (malignancy grade IV), which have a peak incidence in late middle age. Around 80% of glioblastomas can be shown to have genetic alterations resulting in aberrant control of progression from G1 to the S phase of the cell cycle, and many show amplification of growth factor receptor genes as well as other abnormalities. The bewildering number of genetic anomalies becomes intelligible as we discover that different components of the same cellular control mechanisms are being targeted in individual tumours resulting in a similar phenotype.

There has been little change in bladder cancer survival for more than 40 years, although earlier diagnosis is now detecting more cases at an early, potentially curable stage. Radical cystectomy remains the most effective single treatment, although in the past the morbidity and mortality of treatment and the age of patients made it less favoured as primary treatment. Progress in continent bladder reconstruction is changing attitudes. However, because tissue damage from preoperative radiation, particularly when combined with chemotherapy, makes such operations less safe in patients with advanced disease, reconstruction is primarily of value in high risk superficial and early invasive cancers, though there remains a need for randomized trials or immediate vs deferred use of these operations to establish when they give most benefit. With new knowledge about the role of trauma released tissue repair cytokines and immunosuppressive effect of prolonged anaesthesia on increasing tumour recurrence after surgery, new approaches such as treatment with TNFA, anti-EGF antibody or neoadjuvant chemo/immunotherapy before TURBT to improve on the benefits of surgery need to be explored in randomized trials in both advanced invasive and early superficial disease. With progress in vaccine and gene therapy on the horizon, the central role of the urologist in both harvesting tumours for molecular diagnosis and monitoring response of local disease to treatment is undisputed. The relative underusage and value of bladder washings cytology to provide cells for such studies is also highlighted.

Animal studies in rabbit and cattle have clearly demonstrated the contribution of host genetics, chemical carcinogens and immunosuppression to the conversion of papillomavirus induced benign regressing warts into malignant cancers. More significant is the role of vaccination both with whole tumour cell suspensions with whole virus and viral proteins, particularly L2 molecules, in causing progressing warts to regress. Early results in small scale studies of HPV16 E6/E7 vaccine in patients with cervical cancer have provided evidence that tumour regression can be induced in human papillomavirus induced tumours. These observations provided added impetus for more research to firm up the increasing, but still principally anecdotal, evidence that papillomaviruses may be involved in the pathogenesis of bladder cancer. Studies of carcinomas arising in cattle after BBV 4 infection show absence of fully infectious virus in the majority of tumours, though the tumours have persistent E7, E8 and LCR sequences. As this is all that is required for transformation, it may require in vitro molecular studies in human bladder cancer screening for such elements before final proof of involvement is confirmed. However, even before this is achieved, given the success in animal models of whole tumour cell vaccines, serious thought should be given to how to develop protocols for study of crude tumour cell vaccines in vivo. Such studies would need in vitro assays to seek evidence for specific antitumour immunity, focusing on studies of tumour infiltrating lymphocytes and their T cell receptor polymorphisms.