Congenital abnormalities in children with cancer and their relatives: results from a case-control study (IRESCC).

Several studies have revealed an excess of malformations in children with certain malignancies. A few environmental causes have been identified which may damage the foetus and lead to malformation and cancer. However, most of the numerous recognised cancer/malformation syndromes are genetically determined. This report describes a case-control study of 555 newly diagnosed children with cancer and 1,110 matched controls, chosen from general practitioner lists (GP controls) and hospital admissions (H controls). Their parents were interviewed on topics of possible aetiological significance and medical records were checked to confirm reports at interview. The numbers of congenital malformations in the index and GP control children, and the relatives of the index children, the GP and H controls are described. There were more children with malformations among the cases (60/555) than among the GP controls (27/555), P < 0.001. The abnormalities in the cases included eight with specific chromosomal/genetic conditions (e.g. Down's syndrome, XY gonadal dysgenesis, Von Recklinghausen's neurofibromatosis, Goldenhar's syndrome) whereas only one GP control child had a chromosomal defect (P < 0.05). Five case children but no GP controls had neural tube defects; this is not statistically significant. No excess of malformations was found in the siblings of cases compared with GP and H control siblings. Case mothers had a small excess of malformations (22/555) compared with GP controls (8/555), P < 0.05. Among more distant relatives the results were difficult to interpret because of the relatively small numbers in the diagnostic subgroups and because of apparent under reporting in grandparents, but no striking differences were seen between case and control relatives. The excess of malformations found in children with cancer, compared with controls, without a similar excess of malformations in their close relatives may indicate that in some (perhaps very roughly one in 20) cases antenatal events may lead both to the malformation and the malignancy.

The Epping jaundice outbreak: a 24 year follow up.

STUDY OBJECTIVE: The aim was to trace 84 cases of jaundice that occurred following accidental ingestion of methylene dianiline (MDA) in Epping in 1965, and to look at long term health effects. DESIGN: The original case notes of the cases were used to identify the patients. Subsequent tracing procedures included local general practitioners, the Central NHS Registry, electoral rolls, and company records. SETTING: This was a community based survey. MAIN RESULTS: The health status of 68 (81%) of the group was established with 18 deaths. Of the 50 cases known to be alive, 58% completed a health questionnaire. The causes of death were unremarkable except for one case of carcinoma of the biliary tract. Two surviving cases had suffered retinal pathology. Four other surviving cases had had a further, perhaps unrelated, episode of jaundice. CONCLUSIONS: Although the dose and route of administration in the epidemic differed from occupational exposure, this follow up study a generation on provides little, if any, evidence of long term health sequelae. Nevertheless, in the absence of well documented exposure and health effects data, such accidental poisonings with proven animal carcinogens warrant long term follow up. The identified cohort will be the subject of further study.

West Midlands Oncology Association trial of adjuvant chemotherapy in node-negative breast cancer.

Between 1976 and 1984, 574 patients with operable breast cancer and histologically negative axillary lymph nodes were randomly assigned after mastectomy to receive either no further treatment or chemotherapy with oral LMF (fluorouracil, 500 mg, methotrexate, 25 mg, and chlorambucil, 10 mg, on day 1; fluorouracil, 500 mg, and chlorambucil, 10 mg, on day 2). There is no overall survival or relapse-free survival benefit at a median follow-up of 10 years and 8 years, respectively. There are significantly more local relapses in the control group (P less than .01), but an excess of distant relapses in the treated group is not statistically significant (P = .24). A positive treatment effect in small tumors (relapse-free survival, odds ratio = 0.55, P = .01) and a negative effect in progesterone receptor-positive tumors (survival, odds ratios = 2.04, P = .04) is probably ascribable to chance. Analysis of various prognostic factors shows that tumor size and histological grade have a clear effect on both relapse-free interval and survival.

Interphase nucleolar organiser regions and survival in squamous cell carcinoma of the bronchus: a 10 year follow up study of 138 cases.

BACKGROUND: Good prognostic indicators for patients with squamous cell carcinoma of the lung would help to determine the most appropriate treatment for individual patients. METHODS: A silver colloid technique that shows interphase nucleolar organiser regions (AgNORs) has been applied to representative paraffin sections from 138 cases of squamous cell carcinoma of the bronchus treated by surgical resection of the primary tumour at East Birmingham Hospital in 1977. Of the 138 patients, 23 (17%) were alive 10 years after their operation. RESULTS: The mean (SD) AgNOR count per cell was significantly higher for all grades of malignancy (well differentiated 10.5 (2.6), moderately differentiated 10.7 (3.2), and poorly differentiated 12.7 (4.5)) than for normal pseudostratified columnar epithelium from non-affected areas (2.3 (0.78)). There was a trend for AgNOR counts to be higher in poorly differentiated tumours, but a wide range of AgNOR counts was observed in all histological grades. AgNOR counts did not predict clinical outcome, irrespective of the stage of the disease, and did not relate to DNA ploidy or the percentage of cells in the proliferation phase of the cell cycle. Nine of 47 patients (19%) with tumours classified as DNA diploid and eight of 63 patients (13%) with DNA aneuploid tumours were alive 10 years after operation. Principal component analysis identified the clinicopathological stage of disease as the variable best related to survival. The percentage of patients surviving 10 years was 30% for stage I, 20% for stage II, 10% for stage IIIa, 9% for stage IIIb, and none for stage IV. CONCLUSION: The AgNOR technique is not of prognostic value in postoperative patients with squamous cell carcinoma of the bronchus.

West Midlands Oncology Association trials of adjuvant chemotherapy in operable breast cancer: results after a median follow-up of 7 years. I. Patients with involved axillary lymph nodes.

The aim of this study was to test the effectiveness of a regimen of combination chemotherapy known to be active in advanced breast cancer when given as an adjuvant treatment after mastectomy. A total of 569 patients with cancer of the breast and involvement of axillary lymph nodes were randomised, after simple mastectomy with axillary sampling, to receive either no adjuvant treatment or intravenous adriamycin 50 mg, vincristine 1 mg, cyclophosphamide 250 mg, methotrexate 150 mg and fluorouracil 250 mg (AVCMF) every 21 days for eight cycles. Randomisation was stratified according to menopausal status and tumour size. Treatment was started within 14 days of surgery in 94% of patients. Eighty-eight per cent of patients received at least seven cycles of chemotherapy with no dose reduction. The median relapse-free survival was prolonged by 14 months in patients treated with AVCMF (chi2 1 = 11.7; P = 0.0006). In the premenopausal group this period was 17 months (chi2 1 = 8.8; P = 0.003) compared with 8 months in the post-menopausal group (chi2 1 = 3.3; P = 0.07). Neither overall survival nor survival in these subgroups was significantly influenced by treatment.

West Midlands Oncology Association trials of adjuvant chemotherapy in operable breast cancer: results after a median follow-up of 7 years. II. Patients without involved axillary lymph nodes.

The aim of this study was to test the effectiveness of a regimen of combination chemotherapy when given as an adjuvant treatment after mastectomy to patients with histologically negative axillary lymph nodes. A total of 574 patients with cancer of the breast and no involvement of axillary lymph nodes were randomised, after simple mastectomy with axillary sampling, to receive either no adjuvant treatment or oral fluorouracil 500 mg, methotrexate 25 mg and chlorambucil 10 mg p.o. on day 1 and fluorouracil 500 mg and chlorambucil 10 mg p.o. on day 2 (LMF) every 21 days for eight cycles. Randomisation was stratified according to menopausal status and tumour size. Treatment was started within 14 days of surgery in 97% of patients. Ninety per cent of patients received eight cycles of chemotherapy with no dose reduction. At a median follow-up of 7 years, there was no evidence that relapse-free or overall survival time were influenced by treatment.

Renal disease and occupational exposure to organic solvents: a case referent approach.

Several recent studies have suggested that a relation may exist between exposure to occupational organic solvents and diseases of the kidney--particularly malignancy and glomerulonephritis. Two case referent studies were undertaken in the West Midlands to investigate these possibilities. In the case of renal cancer 54 live cases of biopsy proved adenocarcinoma of the kidney were compared with an equal number of community based healthy referents matched for age, sex, place of residence, and socioeconomic and ethnic grouping. For glomerulonephritis, 50 biopsy proved cases were matched in the same manner with 50 referents. Fourteen other patients were also reviewed who, on biopsy, proved not to have glomerulonephritis. For both sets of cases and their referents each individual was interviewed and a detailed account obtained of medical history and environmental exposures. Exposure to solvents was assessed independently and "blind" in a semiquantitative way by an experienced occupational hygienist. Past exposure was estimated for 10 different solvent types and 17 material types. No relation was found between exposure to solvents and renal cancer or glomerulonephritis. In the case of renal cancer the numbers studied only precluded a fourfold excess risk. For glomerulonephritis, the study, although methodologically superior to most other published studies and of similar size, was of similar power to the renal cancer investigation.

Childhood cancers and their association with pregnancy drugs and illnesses.

In a case/control study of 8059 matched pairs, the effect of maternal exposure to drugs and illnesses during pregnancy on the relative risk (RR) of cancer in the child was investigated using conditional logistic regression techniques. Acute respiratory infections, particularly viral infections such as influenza, were associated with a significantly increased RR of all childhood cancers and of neoplasms of the reticulo-endothelial system (RES) in particular, (RR = 1.69 all cancers, RR = 1.81 RES neoplasms, RR = 1.59 solid cancers). An analysis of illnesses according to their physiological effects yielded a significant association between childhood leukaemia and febrile illnesses (RR = 1.27 RES neoplasms). A significant increase in RR was associated with maternal history of epilepsy (RR = 1.31 all cancers) rather than with exposure to anticonvulsant drugs. Vaccines showed a pattern of RR similar to that of acute viral infections. Consumption of antipyretics and analgesics significantly increased the RR of childhood cancer (RR = 1.36 all cancers). An analysis of drugs according to their metabolic reactions yielded a significant association between those undergoing amino acid conjugation (predominantly antipyretics and analgesics) and childhood cancer risk (RR = 1.76 solid cancers).

Mortality in the British rubber industry 1946-85.

The mortality experienced by a cohort of 36,691 rubber workers during 1946-85 has been investigated. These workers were all male operatives first employed in any one of the 13 participating factories in 1946-60; all had worked continuously in the industry for a minimum period of one year. Compared with the general population, statistically significant excesses relating to cancer mortality were found for cancer of the pharynx (E = 20.2, O = 30, SMR = 149), oesophagus (E = 87.6, O = 107, SMR = 122), stomach (E = 316.5, O = 359, SMR = 113), lung (E = 1219.2, O = 1592, SMR = 131), and all neoplasms (E = 2965.6, O = 3344, SMR = 113). Statistically significant deficits were found for cancer of the prostate. (E = 128.2, O = 91, SMR = 71), testis (E = 11.0, O = 4, SMR = 36), and Hodgkin's disease (E = 26.9, O = 16, SMR = 59). Involvement of occupational exposures was assessed by the method of regression models and life tables (RMLT). This method was used to compare the duration of employment in the industry, the duration in "dust exposed" jobs, and the duration in "fume and/or solvent exposed" jobs of those dying from causes of interest with those of all matching survivors. Positive associations (approaching formal levels of statistical significance) were found only for cancers of the stomach and the lung. The results of the RMLT analysis are independent of those from the SMR analysis, and the study continues to provide limited evidence of a causal association between the risks of stomach cancer and dust exposures, and the risks of lung cancer and fume or solvent exposures in the rubber industry during the period under study.

A mortality study of nickel/chromium platers.

The mortality experienced by a cohort of 2689 nickel/chromium platers between 1946 and 1983 has been investigated. All members of the study cohort had some period of chrome exposed employment. Overall, compared with the general population of England and Wales, statistically significant differences relating to cancer were found for cancer of the stomach (E = 16.2, O = 25), primary cancer of the liver (E = 0.8, O = 4), cancer of the nose and nasal cavities (E = 0.3, O = 3), cancers of the lung and bronchus (E = 48.1, O = 72), and all cancers (E = 164.2, O = 213). Chrome bath workers are the more heavily exposed workers, and a striking difference in SMRs was found for lung cancer among men first employed as chrome bath workers (SMR = 199) and men first employed as other chrome workers (SMR = 101). The method of regression models in life tables (RMLT) was used to compare the durations of chrome exposed employment of those dying from causes of interest with those of all matching survivors in the same year of follow up, while controlling for sex, and for year and age of starting employment. Significant positive associations were found only for cancers of the lung and bronchus and duration of chrome bath work. In this study exposure to nickel was shown not to be an important confounding exposure.

The inter-regional epidemiological study of childhood cancer (IRESCC): a case control study of aetiological factors in leukaemia and lymphoma.

The inter-regional epidemiological study of childhood cancer analysed data on 234 children diagnosed with leukaemia or lymphoma and 468 controls matched for age and sex. A wide range of potential risk factors was examined, including prenatal exposure to x rays, maternal drug ingestion and smoking, child's medical history, and parental medical conditions and occupation. Calculations were completed for leukaemia or lymphoma and diagnostic subgroups, as defined by laboratory confirmed cell type. In utero exposure to narcotic analgesics was weakly associated with leukaemia or lymphoma but no other antenatal factors gave significant risks. New associations were identified for skin diseases in both parents and congenital abnormalities in the mothers of children with leukaemia. For past medical conditions in the child, viral disease occurring under 6 months of age increased the risk for acute lymphoblastic leukaemia. Fewer children in the leukaemia or lymphoma group had been immunised compared with the control groups. Case children diagnosed over the age of 9 years were more likely than controls to have had four or more previous episodes of illness. Overall, these results indicate that prenatal factors may be less important than postnatal or genetic influences in the development of leukaemia or lymphoma in children.

Cancer mortality in the British rubber industry: 1946-80.

The mortality experienced by a cohort of 36445 rubber workers during 1946-80 has been investigated. These workers were all male operatives first employed in any one of the 13 participating factories in 1946-60; all had worked continuously in the industry for a minimum period of one year. Compared with the general population, statistically significant excesses relating to cancer mortality were found for cancer of the stomach (E = 245.9, O = 282, SMR = 115), primary cancer of the liver (E = 12.8, O = 22, SMR = 172), cancer of the lung (E = 892.7, O = 1191, SMR = 133), and all neoplasms (E = 2165.2, O = 2487, SMR = 115). Statistically significant deficits were found for cancer of the prostate (E = 79.7, O = 59, SMR = 74) and cancer of the testis (E = 10.3, O = 4, SMR = 39). The method of regression models in life tables (RMLT) was used to compare the duration of employment in the industry, the duration in "dust exposed" jobs, and the duration in "fume and/or solvent exposed" jobs of those dying from causes of interest with those of all matching survivors. Significant positive associations were found only for cancer of the stomach and cancer of the lung. The results of the RMLT analysis are independent of those from the SMR analysis, and the study has provided further evidence of a causal association between the risks of lung and stomach cancer and certain occupational exposures in the rubber industry.

The Inter-Regional, Epidemiological Study of Childhood Cancer (IRESCC): case-control study in children with germ cell tumours.

In 1980-1983 members of IRESCC interviewed parents of 555 children with newly diagnosed cancer on topics of possible aetiological significance. Identical questions were asked of the parents of 1100 control children chosen from hospital admissions and general practitioner lists. Medical information was confirmed whenever possible by cross-checking with NHS records. Data for the 41 children with germ cell tumours and their 82 controls are reported here. The cases had more major congenital malformations than controls, including one neural tube defect. More case than control mothers and fathers reported occupational exposure to chemicals. Nine close relatives of cases had multiple primary tumours, which were often benign or of low-grade malignancy, compared with 1 hospital control and 3 general practitioner control relatives. Cases and controls differed with respect to birth weight and paternal age. No case-control differences were shown for: birth rank, maternal age, chronic illnesses and smoking, mothers' reproductive histories and oral contraceptive usage. In index pregnancies there were no case-control differences for maternal illness, infections, alcohol intake and X-ray and ultrasound exposure. There was no difference between cases and controls for the frequency of twinning the families.

The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCO). Study design, control selection and data collection.

The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) was established to investigate the role of possible aetiological factors in childhood cancer, with particular emphasis on environmental exposures to the foetus and family history of certain diseases including cancer. Incident cases occurring in three Health Service regions (the West Midlands, Yorkshire and North Western) were matched for age and sex with two sets of control children. A total of 555 cases and 1110 controls were entered into the study. The parents of each index child were interviewed with respect to events during the relevant pregnancy, occupation, smoking habits, and past medical history of themselves, the child's siblings and other relatives. Ninety-three per cent of case parents approached agreed to be interviewed, and approximately 90% of controls were ranked first or second on the control selection lists. After the interview information was verified by reference to antenatal and other medical records. Obstetric and general practitioner records were abstracted for approximately 90% of cases and controls. Information derived from the interview and that from medical records was coded separately. The data collected by each region have been pooled and case-control comparisons of potential aetiological factors will be carried out, using matched triplet analyses.

Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): childhood cancer and the consumption of debendox and related drugs in pregnancy.

Attention has recently focused on the possible teratogenic effects of the combination antiemetic doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride (Debendox/Bendectin) prescribed to pregnant women. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC), a case-control investigation has analysed data derived from interview reports and medical records of 555 mothers of children (under 15 years) with cancer and 1110 mothers of matched control children. Separate analyses of interview reports and medical records both suggested that antiemetic ingestion during the index pregnancy does not increase the risk of developing childhood malignant disease in the exposed foetus. No dose-response relationship was evident. The lack of any significant relative risks held good for diagnostic sub-groups and when the trimester of ingestion was considered. Our results suggest that antimetics of this type are unlikely to be transplacental carcinogens.

Cancer incidence and cancer mortality in a cohort of semiconductor workers.

The cancer mortality experienced by a cohort of 1807 workers from a semiconductor factory during the period 1970-82 has been investigated (as has cancer morbidity for 1970-81). Expectations for mortality were calculated on the basis of rates of mortality for the general population of England and Wales. Expectations for cancer incidence were calculated on the basis of incidence rates for the West Midland Region. For the total study cohort, observed numbers of deaths and incident cases for all cancers were close to expectation. For melanoma incidence, an observed of 3 cases was compared with an expectation of 0.68.

Selection, follow-up, and analysis in the Birmingham Study.

The Birmingham, England, Cancer Registry is so organized that every case of cancer in its territory of 5,200,000 persons is included. This coverage allows the staff to detail every epidemiologic aspect of the cancer experience of a whole population. For example, this registry system made it possible for us not only to demonstrate that the Birmingham region had four times the incidence of scrotal cancer as another region had but to identify the locations and the specific practices in the workplace responsible for the excess. The result was the successful adoption of protective measures. Other instances are presented of the inestimable value of a population-based registry to cancer epidemiology.