N2
Prof. Emanuel Van der Schueren (Leuven, Belgium)
PERSPECTIVES FOR CANCER IN BRITAIN & THE EUROPEAN COMMUNITY Prof. Nicholas Day, MRC Biostatistics Unit, Cambridge
NO ABSTRACT RECEIVED
NO ABSTRACT RECEIVED
THE PLACE OF RADIOTHERAPY IN THE 21st CENTURY
N3
N4
SCREENING J
D
FOR
LARGE
HARDCASTLE,
BOWEL
Department
University of Nottingham
THE MOLECULAR PATHOGENESIS OF LUNG CANCER
NEOPLASIA of
J.Minna. D. D'Amico, J. Broers, D. Buchhagen, D. Carbone, I. Chiba, D. Curial, F. Kaye, L. Linnoila, R. Maneckjee, T. Mitsudomi, H. Pass, J. Schuitte, T. Takahashi, J. Viallet, J. Whang-Peng, M.Nau, A. Gazdar. Na-Navy Medical Oncology Branch, National Cancer Institute & USUHS, Bethesda, USA
Surgery,
The primary aim of screening for colorectat neoplasia is a reduction in the mortality from colorectal cancer - an objective which various treatment options have failed to realise over the last 30 years, but which may be achieved by performing surgery when the disease is at an early clinico-pathological stage.
Lung cancer cells exhibit a large number of genetic lesions mutations activating the dominant cellular proto-oncogenes involving and the recessive or "tumor suppressor" genes. The lesions in inactivating known and suspected tumor suppressor genes are highlighted by the large number of clonal cytogenetic abnormalities including chromosomal deletions and non-reciprocal translocations. These result in loss of hetezygosity at several loci confirend by RFLP analysis indicating involvment of multiple tumor suppressor genes including those on the chromosomes 1, 3p, 1 lp, 13q (rb gene), & 17p(p53 gene), as well as other chromosomes. Studies of the rb gene indicate it is altered in nearly all cases of small cell lung cancer (SCLC) and at least some cell lung cancers (non-SCLC), while pS3 appears mutant in non-small 40% or of all lung cancers. We often find absent expression of rb protein, inmore contrast to point or small mutations, leading to the production of mutant p53 proteins. Other candidate recessive oncogenes in lung cancer include a Wilm's related gene at 1 lpl3, the NM23/awd gene, and the DCC gene on 18. Lung cancer cells also exhibit receptors for opioids, endogenous opioid peptides, and have their growth inhibitedproduce by exogenously added opioids suggesting that this represents a new type of tumor suppression. They also express receptors for nicotine and while nicotine itself has no effect on tumor cell growth, in some cases it can reverse opioid induced growth inhibition suggesting a role in tumor promotion. In addition, lung cancer cells produce autocrine growth factors and jun family transcription factors which could aid in promotion. The number of lesions (10-20 per tumor) required tumor for tumors to become clinically evident raises the question of Mendelian inheritence and acquistion of lesions during embryonic development as well as from carcinogen exposure in adult life in lung cancer pathogenesis. Together, our findings suggest that detection of molecular genetic abnormaliaties in these genes may be applied in studies of prevention, early diagnosis, prognosis, and familial inheritence of cancer.
Furthermore there is an important secondary consider3tion: a decline in the incidence of colorectal carcinoma may be achieved by the detection and removal of premalignant adenomas.
Surveillance of patients treated for colorectal carcinoma, and those with inflammatory bowel disease or other risk factors for the development of colonic cancer, is well established but the majority of patients developing colorectal carcinoma do not belong to a high risk group, therefore if a major reduction in the mortality from the disease is to be achieved, screening will need to be applied to the whole population at risk. Epidemiological evidence suggests
that this should be those over the age of 50 years; screening is be cost effective in younger age groups.
unlikely
to
The earlier detection of symptoms by means of a symptom questionnaire has been shown to be an ineffective method of screening, with a low sensitivity and specificity for neoplasia and no apparent advantage in terms of tumour stage. Colonoscopic examination offers the most accurate assessment of the large bowel mucosa. However, this must be balanced against the risk of iatrogenic injury and the considerable cost involved, factors which preclude colonoscopy as a means of mass population screening, nevertheless it is the examination of choice for the surveillance of high risk individuals. Flexible sigmoidoscopy on the other hand, may provide an affordable alternative, and should detect approximately 70% of all colonic neoplasms. At the present time the most promising modality for mass population screening, offering an acceptable compromise of sensitivity, specificity and cost effectiveness, is faecal occult blood testing. This method of screening is the subject of five large randomised controlled trials. Already they have conclusively demonstrated that asymptomatic colorectal neoplasia can be diagnosed following the detection of faecal occult blood. Furthermore cancers diagnosed in this way are generally at a less advanced pathological stage than those appearing in matched populations which are not screened. The studies have also revealed evidence of a length bias, with a higher proportion of the screen-detected cancers being well or moderately differentiated. However, their randomised nature should enable a survival advantage attributable to screening, and independent of the inherent screening biases, to be assessed objectively. Long term mortality data is not yet available, although the
preliminary reports are encouraging.
3
Prof. Emanuel Van der Schueren (Leuven, Belgium)
PERSPECTIVES FOR CANCER IN BRITAIN & THE EUROPEAN COMMUNITY Prof. Nicholas Day, MRC Biostatistics Unit, Cambridge
NO ABSTRACT RECEIVED
NO ABSTRACT RECEIVED
THE PLACE OF RADIOTHERAPY IN THE 21st CENTURY
N3
N4
SCREENING J
D
FOR
LARGE
HARDCASTLE,
BOWEL
Department
University of Nottingham
THE MOLECULAR PATHOGENESIS OF LUNG CANCER
NEOPLASIA of
J.Minna. D. D'Amico, J. Broers, D. Buchhagen, D. Carbone, I. Chiba, D. Curial, F. Kaye, L. Linnoila, R. Maneckjee, T. Mitsudomi, H. Pass, J. Schuitte, T. Takahashi, J. Viallet, J. Whang-Peng, M.Nau, A. Gazdar. Na-Navy Medical Oncology Branch, National Cancer Institute & USUHS, Bethesda, USA
Surgery,
The primary aim of screening for colorectat neoplasia is a reduction in the mortality from colorectal cancer - an objective which various treatment options have failed to realise over the last 30 years, but which may be achieved by performing surgery when the disease is at an early clinico-pathological stage.
Lung cancer cells exhibit a large number of genetic lesions mutations activating the dominant cellular proto-oncogenes involving and the recessive or "tumor suppressor" genes. The lesions in inactivating known and suspected tumor suppressor genes are highlighted by the large number of clonal cytogenetic abnormalities including chromosomal deletions and non-reciprocal translocations. These result in loss of hetezygosity at several loci confirend by RFLP analysis indicating involvment of multiple tumor suppressor genes including those on the chromosomes 1, 3p, 1 lp, 13q (rb gene), & 17p(p53 gene), as well as other chromosomes. Studies of the rb gene indicate it is altered in nearly all cases of small cell lung cancer (SCLC) and at least some cell lung cancers (non-SCLC), while pS3 appears mutant in non-small 40% or of all lung cancers. We often find absent expression of rb protein, inmore contrast to point or small mutations, leading to the production of mutant p53 proteins. Other candidate recessive oncogenes in lung cancer include a Wilm's related gene at 1 lpl3, the NM23/awd gene, and the DCC gene on 18. Lung cancer cells also exhibit receptors for opioids, endogenous opioid peptides, and have their growth inhibitedproduce by exogenously added opioids suggesting that this represents a new type of tumor suppression. They also express receptors for nicotine and while nicotine itself has no effect on tumor cell growth, in some cases it can reverse opioid induced growth inhibition suggesting a role in tumor promotion. In addition, lung cancer cells produce autocrine growth factors and jun family transcription factors which could aid in promotion. The number of lesions (10-20 per tumor) required tumor for tumors to become clinically evident raises the question of Mendelian inheritence and acquistion of lesions during embryonic development as well as from carcinogen exposure in adult life in lung cancer pathogenesis. Together, our findings suggest that detection of molecular genetic abnormaliaties in these genes may be applied in studies of prevention, early diagnosis, prognosis, and familial inheritence of cancer.
Furthermore there is an important secondary consider3tion: a decline in the incidence of colorectal carcinoma may be achieved by the detection and removal of premalignant adenomas.
Surveillance of patients treated for colorectal carcinoma, and those with inflammatory bowel disease or other risk factors for the development of colonic cancer, is well established but the majority of patients developing colorectal carcinoma do not belong to a high risk group, therefore if a major reduction in the mortality from the disease is to be achieved, screening will need to be applied to the whole population at risk. Epidemiological evidence suggests
that this should be those over the age of 50 years; screening is be cost effective in younger age groups.
unlikely
to
The earlier detection of symptoms by means of a symptom questionnaire has been shown to be an ineffective method of screening, with a low sensitivity and specificity for neoplasia and no apparent advantage in terms of tumour stage. Colonoscopic examination offers the most accurate assessment of the large bowel mucosa. However, this must be balanced against the risk of iatrogenic injury and the considerable cost involved, factors which preclude colonoscopy as a means of mass population screening, nevertheless it is the examination of choice for the surveillance of high risk individuals. Flexible sigmoidoscopy on the other hand, may provide an affordable alternative, and should detect approximately 70% of all colonic neoplasms. At the present time the most promising modality for mass population screening, offering an acceptable compromise of sensitivity, specificity and cost effectiveness, is faecal occult blood testing. This method of screening is the subject of five large randomised controlled trials. Already they have conclusively demonstrated that asymptomatic colorectal neoplasia can be diagnosed following the detection of faecal occult blood. Furthermore cancers diagnosed in this way are generally at a less advanced pathological stage than those appearing in matched populations which are not screened. The studies have also revealed evidence of a length bias, with a higher proportion of the screen-detected cancers being well or moderately differentiated. However, their randomised nature should enable a survival advantage attributable to screening, and independent of the inherent screening biases, to be assessed objectively. Long term mortality data is not yet available, although the
preliminary reports are encouraging.
3
