Showing papers in "British Journal of Cancer in 1996"

Mortality from smoking in developed countries 1950-2000

Abstract: This book represents an impressively comprehensive report on deaths from tobacco smoking between 1950 and 2000. It is a unique and authoritative record, tracing the smoking epidemic in developed countries over the past four decades and projecting how many more deaths tobacco will cause in the final decade of the century. It contains previously unpublished data for each major developed country (including figures for the individual countries within the former USSR). In addition, there are aggregated statistics for deaths from tobacco in the following groups: all developed countries, the former Socialist economies, the OECD developed countries, the current European Union (EU) (12 countries) and the planned EU (16 countries). It also contains some projections on deaths in developing countries. The work is aimed at clarifying for international governments, health professionals and the public, the real importance of the epidemic. Many of the figures and tables presented are designed for use as visual aids, and so most parts of the book may be reproduced freely without seeking copyright permission from the publisher or authors. Current death rates from smoking are presented for each separate developed country. These demonstrate the rapidly increasing mortality caused by smoking in both sexes which contrasts with the steadily decreasing mortality rates that have been seen among non-smokers in the 'OECD' developed countries. On almost every page, the scale of the numbers of deaths caused by smoking is alarming. The estimated average loss of life for those killed from smoking is about 16 years, and half of all regular smokers are eventually killed by their habit. On present trends, 4-5 million of young people (aged under 20) now living in the UK will eventually become regular smokers and tobacco will kill nearly half of them, with about 1 million of them killed by tobacco in middle age and another million in old age. Tobacco still causes one-third of all cancer deaths in the UK and between 1950 and 2000, tobacco will have killed about 6 million people in the UK. This is not to imply that all the data in this book is discouraging. Mortality from smoking in the UK has declined by about a fifth since 1970 as a result of a decline in cigarette sales and reductions in cigarette tar yields, and is still declining. Internationally, there are some striking differences. Thus in 1965, the UK had the worst mortality rates from smoking in the world whereas Poland had quite low rates. Now, however, the situation is reversed and Poland, like some of the other former socialist economies, is one of the worst-affected countries in the world. The final chapter deals with the spread of the epidemic to developing countires. Over the next few decades worldwide deaths from tobacco are projected to rise from 3 million a year now (including 'only' 1 million in the less-developed countries) to 10 million a year in about 2025 (including 7 million a year in less-developed countries). The contents of this book are overwhelmingly chastening. They also amount to a compelling case for governments everywhere to implement the World Health Organization's plea that children be protected from the advertising and promotion of tobacco. No-one and no organisation with an interest in public health or disease causation should be without this book.

The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.

Abstract: The role of sun exposure in development of basal cell and squamous cell carcinomas among different populations from south Europe was investigated. Between 1989 and 1993 we interviewed incident cases and a random population sample of controls from five centres where a cancer registry was operating, whereas we selected a sample of hospital-based cases and controls from the other three centres. We gathered information on life-long exposure to sunlight during different activities. Results are analysed for 1549 basal cell carcinoma (BCC) cases and 228 squamous cell carcinoma (SCC) cases compared with 1795 controls. We observed a statistically significant increase of risk of SCC with increasing sun exposure beyond a threshold of 70,000 cumulated hours of exposure in a lifetime. Sun exposures during work and holidays were, however, inversely correlated. Odds ratios (ORs) of SCC were up to eight or nine times the reference for the highest exposures (200,000 cumulated hours or more). BCC exhibited a 2-fold increase of risk for lower exposure (8000-10,000 cumulated hours in a lifetime) with a plateau and a slight decrease of risk for the highest exposures (100,000 cumulated hours or more). Outdoor work showed a significantly increased risk of SCC (OR 1.6 for more than 54,000 cumulated hours of exposure in a lifetime), whereas recreational activities such as sun exposure during holidays at the beach (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) or during water sports (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) were associated with an increased risk of BCC. Risk patterns were different in poor or good tanners with a significant risk trend for good tanners, whereas poor tanners were on a plateau of increased risk at any level of exposure. Solar radiation is associated with a risk of BCC even for relatively short periods of exposure such as during holidays and sports, whereas SCC develops later if exposure continues. The skin's ability to tan modulates the risk of BCC; subjects who tan poorly have a steady risk increase, whereas people who tan easily develop cancer only after prolonged exposures.

Application of the multidimensional fatigue inventory (MFI-20) in cancer patients receiving radiotherapy

Abstract: In this paper the psychometric properties of the multidimensional fatigue inventory (MFI-20) are established further in cancer patients. The MFI is a 20-item self-report instrument designed to measure fatigue. It covers the following dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue. The instrument was used in a Dutch and Scottish sample of cancer patients receiving radiotherapy. The dimensional structure was assessed using confirmatory factor analyses (Lisrel's unweighted least-squares method). The hypothesised five-factor model appeared to fit the data in both samples (adjusted goodness of fit; AGFI: 0.97 and 0.98). Internal consistency of the separate scales was good in both the Dutch and Scottish samples with Cronbach's alpha coefficients ranging from 0.79 to 0.93. Construct validity was assessed by correlating the MFI-20 to activities of daily living, anxiety and depression. Significant relations were assumed. Convergent validity was investigated by correlating the MFI scales with a visual analogue scale measuring fatigue and with a fatigue-scale derived from the Rotterdam Symptom Checklist. Results support the validity of the MFI-20. The highly similar results in the Dutch and Scottish sample suggest that the portrayal of fatigue using the MFI-20 is quite robust.

Phase II study of gemcitabine in patients with advanced pancreatic cancer.

Abstract: The efficacy and safety of gemcitabine at a starting dose of 800 mg m2 administered once a week for 3 weeks with 1 week's rest was investigated in chemonaive patients with advanced and/or metastatic pancreatic cancer. Of 34 patients, 32 were evaluable for efficacy, 20 patients had metastatic stage IV disease, 25 had a performance status of 1 and 26 (76%) patients has significant pain on presentation. All responses were independently validated by an external oncology review board: two patients achieved a partial response that lasted 5.8 and 5.2 months (6.3%) and six patients were stable for at least 4 weeks. The median duration of survival for evaluable patients was 6.3 months (range 1.6-19.2 months). The tumour markers, CEA, CA 19-9 and CA 195 were serially measured in 16 patients. There was a good correlation with tumour response when all three markers were significantly decreased. In 4 of 16 patients, tumour marker levels decreased by > or = 60%, including the two responders, one patient who survived for 12 months and one patient who showed objective tumour shrinkage but was deemed ineligible for response evaluation because the disease was considered not to be bidimensionally measurable. Symptomatic benefits included improvement in performance status (17.2%), analgesic requirement (7.4%), pain score (28.6%) and nausea (27.3%). The mean number of cycles administered was 2.5 and the mean dosage received was 890 mg m2 per injection. Seventy-four per cent of dose administrations were given on schedule. Toxicity, particularly haematological toxicity, reported as the maximum WHO grade experienced by patients was mild. Infective episodes were rare and limited to WHO grade 2 (6.7%). Nausea and vomiting was generally modest (WHO grade 3, 26.7%). Other side-effects included mild transient flu-like symptoms (seven patients) and peripheral oedema (three patients), which was not associated with abnormal cardiac hepatic or renal function. Gemcitabine has modest activity in pancreatic cancer, a limited positive improvement on a range of patient benefit parameters and has a mild toxicity profile. For these reasons and because of its novel mode of action, gemcitabine warrants further investigation in combination studies in pancreatic cancer.

Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma

Abstract: Vascular endothelial growth factor (VEGF) expression, vascularisation and tumour cell proliferation were analysed in 91 human epidermoid lung carcinomas using immunohistochemistry. A polyclonal anti-VEGF antibody was used for VEGF expression, a polyclonal antibody directed against human von Willebrand factor (factor VIII) to identify blood vessels and the proliferating cell nuclear antigen (PCNA) as a marker for proliferating cells. Positive staining for VEGF was obtained in 54 out of 91 cases (59%), the number of blood vessels varied from zero to 64 counts (mean 9.4) and the proportion of PCNA-positive cells varied from 1.3% to 72.1% (mean 25.2%). The mean PCNA labelling index and mean microvessel count in VEGF-positive tumours were significantly higher than those in VEGF-negative tumours (Wilcoxon rank sum test, P<0.0001; p<0.05). In addition, PCNA labelling index significantly increased with increasing VEGF expression (Jonckheere test, P<0.0001). In contrast, no association was found between PCNA labelling index and tumour vascularity (r=0.07, P=0.48). The close correlation of VEGF expression with tumour cell proliferation and microvessel density suggests that VEGF acts both as an autocrine growth factor and as stimulator for angiogenesis. However, tumour cell proliferation and microvessel growth and/or density may be regulated by separate mechanisms.

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer.

Abstract: The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was evaluated in post-menopausal women with breast cancer. Twelve patients progressing after treatment with tamoxifen were randomised to receive anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded crossover design. In vivo aromatisation and plasma oestrogen levels were determined before commencing treatment and at the end of each 4-week period. Treatment with anastrozole 1 and 10 mg reduced the percentage aromatisation from 2.25% to 0.074% and 0.043% (mean suppression of 96.7% and 98.1% from baseline) and suppressed plasma levels of oestrone, oestradiol and oestrone sulphate by > or = 86.5%, > or = 83.5% and > or = 93.5% respectively, irrespective of dose. Notably, several patients had their oestrone and oestradiol values suppressed beneath the sensitivity limit of the assays. In conclusion, anastrozole was found to be highly effective in inhibiting in vivo aromatisation with no difference in efficacy between the two drug doses. Contrary to previous studies on other aromatase inhibitors, this study revealed an internal consistency between the percentage aromatase inhibition and suppression of plasma oestrone sulphate.

Fat, fish, fish oil and cancer.

Abstract: There is an ecological association between total and animal fat consumption and colorectal and breast cancer risk. Mortality data for breast and colorectal cancer for 24 European countries correlated, as expected, with the consumption of animal, but not vegetable, fat. There was an inverse correlation with fish and fish oil consumption, when expressed as a proportion of total or animal fat, and this correlation was significant for both male and female colorectal cancer and for female breast cancer, whether the intakes were in the current time period, or 10 years or 23 years before cancer mortality. These effects were only seen in countries with a high ( > 85 g caput-1 day-1) animal fat intake. This evidence suggests that fish oil consumption is associated with protection against the promotional effects of animal fat in colorectal and breast carcinogenesis.

Estimating the efficacy of screening by auditing smear histories of women with and without cervical cancer. The National Co-ordinating Network for Cervical Screening Working Group.

Abstract: The screening histories of all 348 women with invasive cervical cancer diagnosed in 1992 in 24 self-selected district health authorities and health boards in England, Wales and Scotland were compared with those of 677 age- and residency-matched controls. The controls were randomly selected from the family health services authority (FHSA) register. Screening histories, comprising the dates and results of all smears taken before the date of diagnosis of the patient's cancer, were determined from the FHSA computer and laboratory records. We estimate that the number of cases of cervical cancer in participating districts in 1992 would have been 57% (95% confidence interval 28-86%) greater if there had been no previous screening. In women under the age of 70 it would have been approximately 75% (31-115%) greater. Extrapolation of the results from this pilot suggests that screening prevented between 1100 and 3900 cases of invasive cervical cancer in the UK in 1992. Women with stage 1B cancer or worse were more likely to have no record of previous screening than controls: 47% of these women under the age of 70 had been adequately screened according to current (5 yearly screening) guidelines, compared with 75% of matched controls. Thirteen per cent of all patients under age 70 had screening histories indicative of inadequate follow-up of smears requiring colposcopy. The proportion of microinvasive cases with screening predating diagnosis was similar to the proportion of controls. There was a strong correlation between stage and age: 56% of cancers in women under 35 were microinvasive compared with just 9% in women 65 years or over. The 'relative protection' following a negative smear was greatest in the first 12 months and fell off towards the end of the fifth year. These data suggest that full adherence to current guidelines could perhaps have prevented another 1250 cases, but additional steps would have been required to prevent some of the 2300 remaining cases in women under the age of 70.

Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma.

Abstract: Proteinases are involved in tumour invasion and metastasis. Several matrix metalloproteinases (MMPs) have been shown to be increased in various human carcinomas. We assessed the levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in 50 gastric carcinomas and corresponding mucosa using quantitative gelatin zymography. Both MMP levels were significantly enhanced in gastric carcinomas compared with adjacent mucosal tissue, showed a relatively poor intercorrelation and no relation was found with histopathological carcinoma classifications according to Lauren, WHO and tumour-node-metastasis (TNM). Cox's multivariate proportional hazards analyses revealed that high carcinomatous MMP values are of prognostic significance for a poor overall survival of the patients, independent of the major clinicopathological parameters.

Catalog of Chromosome Aberrations in Cancer

Abstract: Mitelman's catalogue is the only comprehensive reference book of aberrant karyotypes in malignancy. The fifth edition provides us with a staggering collection of karyotypes from more than 22 000 individual neoplasms. Drawn from 5224 references this latest edition reflects the explosive growth in this field of research in' recent years. Twelve years ago when Mitelman first identified the need for such a catalogue the total number of karyotypes was little more than 3000. The catalogue comes in two volumes with chromosomes 1-12 and 13-22XY. Cases are classified first by chromosome and are entered under each abnormal chromosome in the karyotype. It follows that any one case may appear under several different chromosomes. The relative contribution of solid tumour entries in this edition is 27% of cases compared with 12% of entries in 1983. Clearly solid tumours are still underrepresented in terms of their natural incidence but the extreme complexity of many solid tumour karyotypes (the record being held by a fibrosarcoma karyotype with no less than 1051 characters) means their contribution to the catalogue is substantial. Apart from bringing the number of cases up to date this edition describes every karyotype according to the most recent terminology, namely the International System for Cytogenetic Nomenclature 1991. The number of karyotypes investigated by molecular techniques for genetic rearrangements or fusion genes and described at the end of each chromosomal section has also been updated. Entries are subclassified by types of disease which include 46 haematological disorders, 35 malignant lymphomas and 98 benign and malignant solid tumours. Drawn from all over the world, cases are taken from publications in more than 30 scientific journals. The geographical distribution of cases reflects national or local interest in cytogenetics. In this context, it is of interest that the largest contributing continent is Europe and that the UK features fourth largest among contributing countries or states. Over the past 25 years many clinically important chromosomal subgroups have been detected within morphologically identical types of malignant disorder. Their identification has resulted from the drawing together of large numbers of individual cases. Nevertheless, the numbers of aberrant karyotypes found in any series of any one tumour type are many and various. The overwhelming impression is one of diversity. New subgroups only emerge when newly described cases can be checked against previously published cases and here the catalogue is indispensible. Chromosomal aberrations in human cancer highlight regions of the genome …

Multicentricity of breast cancer: whole-organ analysis and clinical implications

Abstract: We studied the spatial relationship within the breast between multicentric foci (MCF) and the primary tumour in 30 modified radical mastectomy specimens using Egan's correlated pathological-radiological method using 5 mm slices of the whole breast. The relative positions within the breast of the primary tumour and MCF were used to calculate the relative distribution of primary tumour and MCF in the four quadrants of the breast and the per cent breast volume that would be required to be excised to include all MCF. Nineteen (63%) breast harboured MCF. The relative distribution of primary tumour and MCF in the four breast quadrants was significantly different (P = 0.034). MCF were present beyond the index quadrant (25% of breast volume including the tumour) in as many as 79% (15/19) of breasts that harboured MCF; and in half the cases (15/30) when all breast were considered. This is in variance with the suggestion put forward previously that MCF are contained within the index quadrant in 90% of cases. Although the number of patients in the present series is small, the probability of our finding being due to play of chance is 1 in 1500. In a large series of breast conservation studies > 90% of early breast recurrences have been found to occur in the index quadrant. Our finding, that in half the patients (15/30) MCF are present in quadrants other than the index quadrant, suggests that MCF do not give rise to early breast recurrence.

Pain and other symptoms during the first year after radical and conservative surgery for breast cancer

Abstract: This study assessed pain, neurological symptoms, oedema of the ipsilateral arm, anxiety and depression occurring in women treated surgically for breast cancer, the impact of these symptoms on daily life and how they evolved during the 1 year follow-up. Ninety-three consecutive patients with non-metastasised breast cancer who were treated during 1993-94 were examined before surgery and after 1, 6 and 12 months. They were asked about pain, neurological symptoms and oedema in the breast scar region and/or ipsilateral arm. Sensory testing was performed, and gripping force and the circumference of the arm were measured. Anxiety and depression were evaluated. One year after surgery, 80% of the women had treatment-related symptoms in the breast scar region and virtually all patients had symptoms in the ipsilateral arm. The incidence of chronic post-treatment pain was higher after conservative surgery than after radical surgery (breast area: 33% vs 17%, NS; ipsilateral arm: 23% vs 13%, NS). Numbness occurred in 75% and oedema of the ipsilateral arm in over 30% of the patients after both radical and conservative surgery. Phantom sensations in the breast were reported by 25% of the patients. No difference in psychic morbidity was detected after the two types of surgery. Both the anxiety and depression scores were highest before surgery, decreasing with time, and were significantly correlated with preoperative stressful events.

Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma.

Abstract: Epidermal growth factor receptor (EGFR) content was determined by a radioligand receptor assay in 140 primary laryngeal squamous cell carcinomas (median value of 8.4 fmol mg-1 protein, range 0-169.9 fmol mg-1 protein). Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels are directly associated with the risk of death (chi 2 = 14.56, P-value = 0.0001) and relapse (chi 2 = 7.77, P-value = 0.0053). A significant relationship between EGFR status and survival was observed at the different arbitrary cut-off values chosen (8, 16 and 20 fmol mg-1 protein). The cut-off value of 20 fmol mg-1 protein was the best prognostic discriminator. In fact, the 5 year survival was 81% for patients with EGFR- tumours compared with 25% for patients with EGFR+ tumours (P < 0.0001). The 5 year relapse-free survival was 77% for patients with EGFR- tumours compared with 24% for patients with EGFR+ tumours (P < 0.010). When clinicopathological parameters and EGFR status were examined in the multivariate analysis, T classification and EGFR status retained an independent prognostic value. In this study we demonstrated that high EGFR levels single out patients with poor prognosis in laryngeal cancer.

Intake of dairy products and the risk of breast cancer

Abstract: The relationship between intake of dairy products and risk of breast cancer was studied in 4697 initially cancer-free women, aged 15 years or over. During a 25 year follow-up period after the collection of food consumption data, 88 breast cancers were diagnosed. Intakes of foods were calculated from dietary history interviews covering the habitual diet of examinees over the preceding year. There was a significant inverse gradient between milk intake and incidence of breast cancer, the age-adjusted relative risk of breast cancer being 0.42 (95% confidence interval=0.24-0.74) between the highest and lowest tertiles of milk consumption. The associations with respect to other dairy products were not significant. Adjustment for potential confounding factors, i.e. smoking, body mass index, number of childbirths, occupation and geographic area, resulted in only a minor change in the milk intake-breast cancer relation. Nor did adjustment for intake of other foodstuffs and nutrients, e.g. energy, carbohydrates, protein, fat, vitamins and trace elements, alter the results. No significant interactions between milk intake and demographic or dietary variables or time of cancer diagnosis were observed. Our data suggest that there is a protective effect, dietary or habitual, associated with consumption of milk that overwhelms the associations between different other factors and risk of breast cancer.

Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients

Abstract: Immunohistochemical staining for oestrogen receptor (ER) has been carried out using antibody ER ID5 on 170 women who received first-line tamoxifen treatment for evaluable metastatic breast cancer. ER status had been determined some years previously, using a ligand-binding cytosol assay. The adequacy of the tissue used for the cytosol assay was always checked by histology on an adjacent block and was deemed to be typical of the tumour overall as was the block used for immunohistochemistry. Six different methods were used to assess the degree of staining and comparisons were made to determine which method gave the most clinically relevant results. Clinical outcome was assessed both in terms of duration of response to tamoxifen determined by log-rank analysis and type of response using the chi-squared test. The ER immunohistochemical assay gave superior results compared with the cytosol assay, with all of the subjective methods of assessment of staining giving statistically significant correlations with clinical outcome. The additional contribution of progesterone receptor (PR) staining with antibody NCL PGR was also studied.

Occult axillary node metastases in breast cancer: Their detection and prognostic significance

Abstract: Although the presence of axillary node metastases in breast cancer is a key prognostic indicator and may influence treatment decisions, a significant proportion of patients diagnosed as axillary node negative (ANN) using standard histopathological techniques may have occult nodal metastases (OMs). A combination of limited step-sectioning (4 x 100 microns intervals) and immunohistochemical staining (with cytokeratin (MNF.116) and MUC1 (BC2) antibodies) was used to detect OM in a retrospective series of 208 ANN patients. OMs were found in 53 patients (25%), and both step-sectioning and immunohistochemical detection significantly improved detection (P 0.05). Cox multivariate proportional hazard regression analyses showed that the presence and increasing size of OMs were significantly associated with poorer disease-free survival, independently of other prognostic factors (P < 0.05). However there was not a significant independent association of the presence of occult metastases with overall survival (P = 0.11). These findings have important implications with regard to selection of ANN patients for adjuvant therapy.

Phase I trial of elactocin

Abstract: Elactocin is a novel anti-tumour antibiotic which has potent activity in vitro against a range of tumours. This phase I trial of elactocin identified the dose-limiting toxicity as profound anorexia and malaise. The schedules used included 1 h infusion 3 weekly, 24 h infusion 3 weekly, 1 h infusion daily x 5 (3 weekly), 1 h infusion weekly and finally continuous 5 day intravenous infusion. On all these schedules dose-limiting toxicity was the same and as no partial or complete responses were identified, we do not recommend that further trials of elactocin are performed.

Risk of cutaneous melanoma in relation to the numbers, types and sites of naevi: a case-control study.

Abstract: The atypical mole syndrome (AMS) phenotype, characterised by a large number of common naevi as well as atypical naevi, has been described in families with a genetic susceptibility to melanoma. However, the importance of this phenotype for melanoma in the general population has not been conclusively determined. This study was designed to examine the types and distribution of naevi as well as the prevalence of the AMS phenotype in melanoma patients in England compared with controls. A total of 426 cutaneous melanoma cases (61% of all incident cases) aged 16-75 years were recruited between 1989 and 1993 from the north-east Thames region of the UK and 416 controls from the same age group were recruited over the same period and from the same region. Each subject answered a questionnaire covering demographic details, sun exposure history and other risk factors and underwent a skin examination with total body naevus count performed by a dermatologist. The AMS phenotype was defined using a scoring system. Atypical naevi gave the highest relative risk for cutaneous melanoma, with an odds ratio (OR) of 28.7 (P < 0.0001) for four or more atypical naevi compared with none. Many common naevi were also an important risk factor: the OR for 100 or more naevi 2 mm or above in diameter compared with 0-4 naevi was 7.7 (P < 0.0001). Melanoma was also associated with naevi on sun-exposed sites but also with naevi on non-sun-exposed sites such as the dorsum of the feet, buttocks and anterior scalp. Sixteen per cent of the cases had the AMS phenotype compared with 2% of the controls (OR 10.4, P < 0.0001). The AMS phenotype was more common in males than females (P = 0.008). The odds ratio for the presence of the AMS phenotype was dependent on age, with an odds ratio of 16.1 (95% CI 4.6-57.5) for the presence of the AMS phenotype if aged less than 40 compared with an odds ratio of 6.9 (95% CI 2.9-16.6) if aged 40 or more. The AMS phenotype was strongly predictive of an increased risk of melanoma outside the familial context.

The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer.

Abstract: The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.

Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer.

Abstract: Amplification of the CCDN1 gene encoding cyclin D1 was examined by Southern blotting and multiplex polymerase chain reaction (PCR) and occurred in 8 of 53 patients (15%) with primary resected non-small-cell lung cancer (NSCLC). These tumours and 17 additional tumours with a normal gene copy number showed overexpression of cyclin D1 (25/53, 47%), as assessed by immunostaining using a monoclonal antibody. In 22/25 cases, cyclin D1 was localised in the cytoplasm, but some (7/25) had simultaneous nuclear staining. This result is in marked contrast to that reported in breast, hepatocellular and colorectal carcinoma studies where immunostaining was invariably nuclear. Examination of a restriction fragment length polymorphic (RFLP) site within the 3'untranslated region of the cDNA following reverse transcriptase (RT)-PCR (29/53 informative cases) showed a strong association between cytoplasmic staining and imbalance in allele-specific message levels. Cyclin D1 overexpression was associated with a poorly differentiated histology (P = 0.04), less lymphocytic infiltration of the tumour (P = 0.02) and a reduction in local relapse rate (P = 0.01). The relative risk of local relapse was 9.1 in tumours without cyclin D1 overexpression (P = 0.01, Cox regression analysis). We conclude that genetic alteration of cyclin D1 is a key abnormality in lung carcinogenesis and may have diagnostic and prognostic importance in the treatment of resectable NSCLC.

Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity.

Abstract: The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours.

Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas.

Abstract: Hepatocyte growth factor/scatter factor (HGF/SF) stimulates the invasive growth of epithelial cells via the c-MET oncogene-encoded receptor. In normal lung, both the receptor and the ligand are detected, and the latter is known to be a mitogenic and a motogenic factor for both cultured bronchial epithelial cells and non-small-cell carcinoma lines. Here, ligand and receptor expression was examined in 42 samples of primary human non-small-cell lung carcinoma of different histotype. Each carcinoma sample was compared with adjacent normal lung tissue. The Met/HGF receptor was found to be 2 to 10-fold increased in 25% of carcinoma samples (P = 0.0113). The ligand, HGF/SF, was found to be 10 to 100-fold overexpressed in carcinoma samples (P < 0.0001). Notably, while HGF/SF was occasionally detectable and found exclusively as a single-chain inactive precursor in normal tissues, it was constantly in the biologically-active heterodimeric form in carcinomas. Immunohistochemical staining showed homogeneous expression of both the receptor and the ligand in carcinoma samples, whereas staining was barely detectable in their normal counterparts. These data show that HGF/SF is overexpressed and consistently activated in non-small-cell lung carcinomas and may contribute to the invasive growth of lung cancer.

Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

Abstract: We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

Familial breast cancer: a controlled study of risk perception, psychological morbidity and health beliefs in women attending for genetic counselling.

Abstract: The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance [mean (s.d.) total Impact of Event Scale score, 14.1 (14.3) cases; 2.4 (6.7) controls, P < 0.001]. Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination (monthly, 66% of cases vs 47% of controls), although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately.

Targeting of stealth liposomes to erbB-2 (Her/2) receptor : in vitro and in vivo studies

Abstract: Long-circulating (stealth) liposomes coated with polyethylene glycol (PEG), which show reduced uptake by the reticuloendothelial system (RES) and enhanced accumulation in tumours, were used for conjugation to monoclonal antibodies (MAbs) as a drug-targeting device. A MAb (N-12A5) directed against erbB-2 oncoprotein, a functional surface antigen, was used. Amplification and overexpression of the erbB-2 gene product, being unique to malignancy, confer onto this antibody-mediated therapy high tumour specificity. In vitro binding of [3H]cholesteryl ether ([3H]Chol ether) labelled anti-erbB-2 conjugated liposomes to N-87 cells (erbB-2-positive human gastric carcinoma) was compared with the binding of non-targeted liposomes and indicated a 16-fold increase in binding for the targeted liposomes. No difference in binding to OV1063 cells (erbB-2-negative human ovary carcinoma) was observed. These results indicate highly selective binding of antibody-targeted liposomes to erbB-2-overexpressing cells. Despite increased cell binding, doxorubicin (DOX) loaded in anti-erbB-2-conjugated liposomes did not cause increased in vitro cytotoxicity against N-87 cells, suggesting lack of liposome internalisation. In vivo, the critical factor needed to decrease the non-specific RES uptake and prolong the circulation time of antibody-conjugated liposomes is a low protein to phospholipid ratio ( < 60 micrograms mumol-1). Using these optimised liposome preparations loaded with DOX and by monitoring the drug levels and the [3H]Chol ether label, biodistribution studies in nude mice bearing subcutaneous implants of N-87 tumours were carried out. No significant differences in liver and spleen uptake between antibody-conjugated and plain liposomes were observed. Nevertheless, there was no enhancement of tumour liposome levels over plain liposomes. Both liposome preparations considerably enhanced DOX concentration in the tumour compared with free drug administration. Therapeutic experiments with N-87 tumour-bearing nude mice indicated that anti-tumour activity of targeted and non-targeted liposomes was similar, although both preparations had an increased therapeutic efficacy compared with the free drug. These studies suggest that efficacy is dependent on drug delivery to the tumour and that the rate-limiting factor of liposome accumulation in tumours is the liposome extravasation process, irrespective of liposome affinity or targeting to tumour cells.

Primary chemotherapy in breast invasive carcinoma: predictive value of the immunohistochemical detection of hormonal receptors, p53, c-erbB-2, MiB1, pS2 and GST pi.

Abstract: Primary chemotherapy in operable breast invasive carcinoma enables tumour reduction and conservative surgery. In order to search for one or more biological factors capable of predicting tumour behaviour under primary chemotherapy, and subsequent patient survival, an immunohistochemical study was performed with specific antibodies to p53, c-erbB-2 (Her-2/neu), Mib1 (antiKi-67), pS2, GST pi, oestrogen receptors (ERs) and progesterone receptors (PRs). Core biopsies, obtained before primary chemotherapy, were available from a series of 128 breast invasive carcinomas treated between January 1985 and April 1989, with a median follow-up of 93.3 months. Univariate statistical analysis showed that negative ER detection by immunohistochemistry (IHC) was highly correlated with chemosensitivity (P = 0.001). A high percentage of Mib1-positive tumour cells (> 40%), as well as initial tumour size less than 4 cm, were also correlated with tumour responsiveness to chemotherapy (P = 0.009 and P = 0.03). By multivariate analysis IHC-ER, Mib1 and initial tumour size were independent predictors, the last parameter being the most important. Concerning subsequent patient survival, c-erbB-2 overexpression, as detected by IHC, was significant with respect to overall survival (OS) (P = 0.0006), disease-free interval (DFI) (P = 0.03) and metastasis-free interval (MFI) (P = 0.008) by univariate analysis. Furthermore, c-erbB-2 was the major independent prognostic factor for OS and MFI by multivariate analysis.

What do cancer patients mean when they complain of concentration and memory problems

Abstract: Cognitive function items are increasingly included in quality of life measures, and complaints of concentration and memory difficulties are often reported by cancer patients. The aim of this study was to examine the factors influencing patients' level of complaint by comparing subjective reports with objective test performance of a sample of adult lymphoma patients, disease-free and > or = 6 months after treatment. There was no significant difference between complainers and non-complainers in sociodemographic or clinical characteristics or in their performance on standard neuropsychometric tests of concentration and memory. Those reporting concentration and memory difficulties had significantly higher scores on measures of anxiety, depression and fatigue. This calls into question the validity of including cognitive function items in self-report quality of life measures. Patients who report concentration and memory difficulties should be screened for clinically significant and potentially remediable mood disorder. Objective testing remains the method of choice for assessing higher mental function.

Non-Hodgkin's lymphomas, chronic lymphocytic leukaemias and skin cancers

Abstract: Data from the Cancer Registries of the Swiss Cantons of Vaud and Neuchâtel were analysed to examine possible associations between skin cancers (including basal cell carcinoma, BCC), non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukaemias (CLL). Between 1974 and 1993, 1767 cases of NHL, 351 of CLL, 1678 of cutaneous malignant melanoma (CMM), 4131 of squamous cell carcinoma (SCC) and 10575 of BCC were registered, and contributed to a total of 120103 person-years at risk. Following NHL, 36 cases of SCC were registered compared with 5.1 expected, corresponding to a standardised incidence ratio (SIR) of 7.0 (95% confidence interval, CI, 4.9-9.7); 37 cases of BCC were observed compared with 10.2 expected (SIR = 3.6; 95% CI 2.6-5.0). Following CLL, nine cases of SCC were observed compared with 1.8 expected (SIR = 5.0; 95% CI 2.3-9.5) and nine cases of BCC were observed compared with 3.3 expected (SIR = 2.7; 95% CI 1.2-5.2). After SCC, 23 cases at NHL were observed compared with 9.0 expected (SIR = 2.6; 95% CI 1.6-3.8); after BCC, 43 cases of NHL were registered compared with 22.5 expected (SIR = 1.9; 95% CI 1.4-2.6); and after CMM, four cases of NHL were observed compared with 2.0 expected (SIR = 2.0). No significant excess of CLL was recorded following skin cancer, but the absolute numbers were small and the SIR was above unity. The findings of this study, conducted in populations with a high level of ascertainment and registration of skin cancers, confirm an excess of skin cancers including BCC, following NHL and CLL, and an excess of NHL following skin cancers. This may be related to shared aetiological factors such as U.V. radiation and associated immunosuppression. Individual-based data on the relationship between U.V. exposure and lymphoid neoplasms are needed to clarify the issue.

Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status

Abstract: Cyclin E is a G1 cyclin which has been proposed to be one of the key regulators of the important G1/S transition, and could consequently be a potential deregulated molecule in tumours. Recently, it has been observed that cyclin E is overexpressed in a variety of malignancies including breast cancer and that several isoforms of the protein exists. In this study we have characterised the cyclin E expression in 114 tumour specimens from patients with primary breast cancer using Western blotting. Various expression of cyclin E was observed among tumours and a group of 27 patients out of 100 patients with stage I-III disease, identified as having tumours with high cyclin E levels, had a significantly increased risk of death and relapse from breast cancer (P = 0.0002 and P = 0.015 respectively). Even in the subgroup of axillary node-negative patients the cyclin E level was of prognostic importance. There was also a strong association between cyclin E expression and oestrogen receptor status (P < 0.00001), and tumours with high cyclin E expression were in general oestrogen receptor negative, suggesting a potential role for cyclin E in mechanisms responsible for oestrogen-independent tumour growth.

Transcriptional analysis of Epstein-Barr virus gene expression in EBV-positive gastric carcinoma: unique viral latency in the tumour cells.

Abstract: Although case-oriented evidence for an association of Epstein-Barr virus (EBV) with gastric carcinoma has been accumulating recently, the interaction(s) between EBV and gastric epithelial cells is/are largely unknown. In this study, we examined seven EBV-positive gastric carcinoma tissues for viral gene expression at the mRNA level, from which studies on the EBV oncogenicity in human epithelial cells will benefit. Reverse transcription-PCR analysis showed that all seven EBV-positive tumour tissues constitutively expressed EBV nuclear antigen (EBNA) 1 mRNA, but not EBNA2 mRNA. The EBNA transcription was initiated from one of three EBNA promoters, Qp: by contrast, both Cp and Wp were silent, thus resulting in the lack of EBNA2 mRNA. Latent membrane protein (LMP) 2A mRNA was detected in three of seven cases; however, neither LMP1 nor LMP2B mRNA was detected in any of the tumours tested. Transcripts from the BamHI-A region of the viral genome were detectable in all cases. BZLF1 mRNA and the product, an immediate-early gene for EBV replication, was not expressed in any of them, thereby suggesting that the tumour cells carried EBV genomes in a tightly latent form. These findings further extended our previous data regarding EBV latency in gastric carcinoma cells at the protein level, and have affirmed that the programme of viral gene expression in the tumour more closely resembles 'latency I' represented by Burkitt's lymphoma than 'latency II' represented by the majority of nasopharyngeal carcinomas.