Mutation and methylation analysis of TP53 in adrenal carcinogenesis.

AIM: To investigate the role of coding region mutation and promoter hypermethylation of TP53 in adrenocortical cancer formation. METHODS: Twenty sporadic adrenocortical cancers (ACCs) and five normal adrenal tissue samples were available for analysis. Coding region mutation of TP53 in 20 ACCs was examined by polymerase chain amplification using intronic primers for exons 2-11 and direct sequencing of the product. In 10 ACCs and five normal adrenal tissue specimens, methylation of the 16 CpG sites within the TP53 promoter was examined using bisulphite methylation sequencing. RESULTS: Coding region mutation in TP53 was demonstrated in 5 of 20 ACCs. There were four mis-sense mutations and one frameshift mutation. Four of 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter and 3 of 4 died of disease within 12 months of surgical resection. No methylation was seen in the TP53 promoter in 10 ACC and the five normal adrenal tissues examined. CONCLUSION: Coding region mutation in TP53 occurs in 25% of ACCs with a trend toward a poorer prognosis. Promoter methylation of TP53 is not present in ACC as a mechanism for tumour suppressor gene (TSG) inactivation and, therefore, other genes in the 17p13 region are implicated in adrenal carcinogenesis.

Seroma formation after axillary lymphadenectomy with and without the use of drains.

Seroma formation after axillary lymphadenectomy is common. We performed a randomised controlled trial comparing seroma rate and volume after axillary lymphadenectomy with and without use of drains. In this study, there was no difference in incidence of seroma formation between patients who did and did not have a drain inserted after axillary lymphadenectomy for breast cancer. Undrained patients, however, had larger volume seromas of longer duration which required more aspirations. There was a tendency for undrained patients to have fewer complications when compared to patients with drains.

Echogenicity of breast cancer: is it of prognostic value?

Echogenicity of colorectal metastases to the liver has been shown to correlate with prognosis. While there have been many studies looking at the echogenicity of breast cancer, there has been no study relating the issue of echogenicity to prognosis of breast cancer. In this study, we found that hyperechoic and mixed echogenicity breast cancers are rare compared to hypoechoic breast cancers. There was, however, no difference in the groups with respect to histological size, grade, axillary metastases, hormone receptor status and lymphovascular invasion.

Histamine, mast cells and tumour cell proliferation in breast cancer: does preoperative cimetidine administration have an effect?

Endogenous histamine has been shown to effect growth mechanisms in experimental mammary carcinomas via H2 membrane receptors (Cricco et al, 1994). Both H1 and H2 binding sites are present in human mammary glands but only 75% malignant carcinomas express H2 receptors (Lemos et al, 1995). The presence of mast cells around tumour tissue raises questions concerning the source of histamine in breast tumour tissue. While cimetidine, an H2 antagonist, has been shown to influence the presence of tumour infiltrating lymphocytes (TIL) in colorectal cancer (Adams and Morris, 1994, 1997) that was not found to be the case in breast cancer (Ng et al, 1995). In recent studies tumour cell proliferation, as measured by Ki-67 antibody labelling, has been seen as an additional prognostic indicator in breast cancer (Railo et al, 1993, 1997; Ferno, 1998; Schauer et al, 1998). We investigated the possibility that cimetidine may influence tumour proliferation by blocking the growth-promoting effects of histamine. No relationship between preoperative cimetidine administration and tumour cell proliferation was seen overall. A weak correlation was seen between tissue histamine content and mast cell count which was not influenced by cimetidine. Tumour cell proliferation correlated well with other prognostic indicators such as grade and differentiation.

Cimetidine does not influence TIL in breast cancer.

Cimetidine is known to have immunomodulatory effects and this study aimed to examine the effect of pre-operative cimetidine treatment on lymphocytic infiltration in n = 72 women with breast cancer randomised to 400 mg bd or placebo for five days presurgery. A combined index was devised by adding infiltrating lymphocyte percentage and lymphoid score. There were no significant differences in circumferential infiltrate and lymphoid follicles in cimetidine treated patients and control patients with breast cancer.

Histamine in human breast cancer.

BACKGROUND: Histamine inhibits lymphocyte function in vitro at concentrations of greater than 10(-6) mol/l. The aim of this study was to determine whether histamine concentrations in breast cancers were sufficient to produce an immunological effect. METHODS: Tumour and adjacent normal breast content of histamine was measured using a radioenzymatic assay in 29 patients having surgery for breast cancer. RESULTS: The median content of histamine in breast cancer tissue was 5.4 (range 0.9-27.3) microg/g (median concentration 4.5 x 10(-5) mol/l), and was significantly greater than that in adjacent breast tissue (P = 0.007). CONCLUSION: The concentration of histamine in breast cancer was sufficient to inhibit lymphocyte function and could be locally immunosuppressive.

A cohort study of hormone replacement therapy given to women previously treated for breast cancer.

UNLABELLED: Women who have been previously treated for breast cancer are usually advised to avoid hormone therapy for fear of increasing their risk of tumor recurrence. However, for some women, menopausal symptoms are so severe that their quality of life is poor. Because ethic committees are reticent to permit a double-blind randomized trial, we performed a cohort study of hormone therapy after breast cancer. METHODS: The study group comprised 1472 women with breast cancer. A total of 167 subjects had used an oral or transdermal estrogen after their treatment for breast cancer. Amongst these estrogen users, 152 (91%) had also used a progestin. In total, 106 other women had used a progestin alone as a treatment for menopausal flushes and not as a treatment for breast cancer. Cox regression analysis was performed using estrogen as a time-dependent covariate with disease-free interval as the outcome. RESULTS: The uncorrected hazard ratio for the estrogen-progestin users was 0.67 (95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85 (95% CI 0.44-1.65). CONCLUSIONS: This study was unable to demonstrate a significant increase in risk of breast cancer recurrence for women who used HRT and suggests that the time is now appropriate for a randomized prospective trial of hormone therapy after breast cancer.

Estrogen replacement may be an alternative to parathyroid surgery for the treatment of osteoporosis in elderly postmenopausal women presenting with primary hyperparathyroidism: a preliminary report.

Parathyroid surgery is indicated in patients presenting with primary hyperparathyroidism (PHPT) and osteoporosis (defined as bone mineral density more than 2 standard deviations below normal). Many are elderly women with complex medical problems, either unwilling or considered unfit for surgery. Estrogen replacement therapy (ERT) may potentially be an alternative form of therapy in this group. We studied 15 consecutive postmenopausal women presenting with PHPT and osteoporosis. Group 1 comprised 5 women who elected to be treated with ERT (conjugated equine estrogen, 0.3-0.625 mg/day). The other 10 women underwent successful parathyroidectomy. These 10 patients were randomly subdivided into group 2 (5 patients who received calcitriol 0.25 micrograms b.i.d. for 12 months following surgery) and group 3 (5 patients who received elemental calcium 1 g/day for 12 months following surgery). Lumbar spine and femoral neck bone mineral density (BMD) were measured prior to and after 12 months of therapy, using a dual-energy X-ray absorptiometer (Lunar DPX-L). The three groups did not differ with respect to their ages (group mean 71.8 years), or baseline serum calcium (group mean 2.77 mmol/l), serum parathyroid hormone (group mean 11.0 pmol/l), lumbar spine BMD (group mean 0.93 g/cm2) and femoral neck BMD (group mean 0.73 g/cm2). Serum calcium normalized in all patients who underwent surgery and none developed hypoparathyroidism. A non-significant decrease in serum calcium was seen in patients treated with ERT only. Lumbar spine (+5.3% per year; 95% CI, 1.1% to 9.6%) and femoral neck BMD (+5.5% per year; 95% CI, -2.1% to 13.2%) increased significantly after 12 months of ERT (p < 0.001 compared with pre-therapy values). These increases in BMD did not differ significantly from those in patients who underwent successful parathyroidectomy followed by either calcitriol therapy or calcium replacement (lumbar spine BMD increase of +6.2% per year, 95% CI 3.1% to 9.4%; and femoral neck BMD increase of +3% per year, 95% CI 0 to 6%). In summary, increases in lumbar spine and femoral neck BMD occur following treatment of PHPT. ERT appeared as effective as parathyroidectomy (combined with either calcitriol or calcium supplements) for the treatment of osteoporosis in elderly postmenopausal women presenting with PHPT.

Extraperitoneal 'laparoscopic' adrenalectomy.

The technique of extraperitoneal 'laparoscopic' adrenalectomy is described in two cases, a left sided 1 cm Conn's tumour and a right sided 3.5 cm incidental non-functioning tumour. The extraperitoneal approach has the advantage of direct access to the adrenal gland without the need to mobilize abdominal organs, while maintaining all the advantages of minimal access surgery.

Aspects of the psychological management of breast cancer.

Psychological factors influence the survival of patients with breast cancer through the early detection of the cancer and through compliance with the treatment. There is now evidence that psychological factors also influence the immune factors which control micrometastases. In particular, stoical acceptance of cancer is associated with a shorter survival of the patient, while the expression of hostility towards the cancer is associated with a longer survival of the patient. Unrecognized psychological morbidity can impair the quality of a patient's life for years. Such psychological morbidity may be reduced by more open communication with the patient, by encouragement of the expression of feelings (especially anger), by preoperative diagnosis of the cancer by biopsy and by a greater time allowance before a mastectomy is performed. Morbidity may also be reduced by the encouragement of patients to take an active part in their treatment decisions, by the avoidance of a mastectomy, by immediate breast-reconstruction surgery, and by appropriate psychological support which includes self-help techniques, such as meditation. Breast cancer can be a positive turning-point in a person's life.

Holistic cancer therapy.

Medical technology has not reduced the death rate from cancer for 50 yrs, in spite of its physical and psychological morbidity. A broader approach is required and investigation of certain apparently successful unorthodox holistic cancer therapies suggests that the personality of the therapist is crucial. The spiritually convinced, charismatic healer has all the qualities of a meditator, and physiological measurement demonstrates that such a healer induces the state of meditation in his patients. Meditation is associated not only with physiological rest and stability, but also with the reduction of psychological stress and the development of a more positive attitude to life with an inner sense of calmness, strength and fulfilment. Holistic cancer therapy should include meditation, especially by the therapist; and psychosomatic research, like physics, should include the study of consciousness.

Diagnosis of breast cancer before operation.

Fifty clinically malignant breast masses were biopsied in the consulting room with a large bore needle to provide a histological diagnosis before definitive treatment was planned. A correct diagnosis was made for all but one of 39 carcinomas, and for all 11 benign masses. This is, therefore, a useful method of confirming the diagnosis when breast cancer is suspected, but other methods (including open biopsy) are more suitable when breast cancer is to be excluded.

Ego defences and affects in women with breast symptoms: a preliminary measurement paradigm.

Terms derived from psychoanalytic theory such as the concepts of ego defences and affects, have often been regarded as inaccessible to operational analysis and measurement and therefore devoid of empirical meaning. However, these explanatory terms are frequently employed in hypotheses concerning the determinants of behaviour and outcome in naturally occurring illnesses, such as breast cancer as well as other life crises and stress situations. The results of the present study demonstrate not only that it is possible to operationally define and measure the ego defences and affects associated with the crisis induced by finding a breast symptom suggesting cancer and awaiting biopsy, but also that on the basis of such measurement, behaviour related to breast cancer can be predicted and hypotheses concerning the relevance of these variables to aetiology put to the test. The operational definitions and measurement methods described could also be modified for application in other crisis situations to which ego defences and affects are thought to be pertinent and the results of these operations compared empirically to determine the extent of their convergence. the methods can be used by independent observers with different theoretical and professional backgrounds. The delay by women in reporting breast symptoms to their doctors was strongly related to a combination of non-rational, unconscious psychological factors. Those who delayed used the ego defences of denial and suppression, not intellectualization-isolation, and verbally expressed depression but not anxiety while showing behavioural manifestations of anxiety. Conscious factors such as fear and education were unrelated to the length of delay. These findings have important implications for educators and doctors concerned with the early detection of breast cancer.

The doctor and the patient in early breast cancer diagnosis.

Breast cancer mortality has not fallen in 30 years, and a renewed attempt at early diagnosis should be made. A study of women's attitudes to breast cancer and surgery has shown their behaviour to be influenced mainly by unconscious factors, including ego-defences, anxiety and depression. Doctors know that early breast cancer treatment is desirable, but the proportion of women having their breasts examined, or being taught breast self-examination, is small. Further attempts at reducing delay in breast cancer treatment must take into account the unconscious processes affecting behaviour, and individual doctors could play a greater part by the education of women in their surgeries.