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Background The importance of the IGF system in HPT has been previously demonstrated. Additionally, the role of vitamin A in HPT has been reported. Retinoic acid (RA), a derivative of vitamin A, is a ligand for the IGF II receptor (IGF2R). We have evaluated the interactions of RA with the IGF system in a primary parathyroid cell culture model. Materials and Methods Primary cell cultures were prepared from nine patients. Following adhesion, the cells were transferred to serum-free medium and dosed once with growth factors ± RA for 96 hours. Proliferation was assessed by measuring tritiated thymidine incorporation. Results Compared with the control group (100%), both IGF I and II increased DNA synthesis significantly. Retinoic acid significantly reduced the basal DNA synthesis to 82.2% ± 4.2% compared with control (P < 0.05). Retinoic acid ×10−5 M completely abrogated the proliferative actions of IGF II (70.2% ± 9.7%, P < 0.05) but had no significant effect on the IGF I response (P > 0.05). To evaluate the role of IGF2R or IGFBPs in mediating the actions of RA, the IGF II analogs [Leu27]IGF II (10–20-fold reduced IGF I receptor affinity) and des(1–6) IGF II (lower IGFBP binding affinity) were used. The IGF II inhibitory effect of RA was enhanced in the presence of analogs [Leu27]IGF II (P = 0.052) but not with des(1–6)IGF II (P > 0.05), compared with wild-type IGF II. Conclusions These data implicate a novel antiproliferative role for RA in enhancing the pericellular clearance of IGF II via the IGF2R preventing ligand activation of the IGF I receptor. This may have broader implications for RA effects in other tumors.

Background: Carcinoid tumours are rare neoplasms that secrete hormones and biogenic amines, most commonly serotonin. Octreotide and long acting lanreotide are found to be useful in the management of carcinoid syndrome by its interaction with somatostatin receptor, found on the carcinoid tumour. The aim of this study is to look at the efficacy of octreotide and long acting lanreotide in the treatment of symptomatic non-resectable carcinoid tumours. Method: The effects of octreotide and long-acting lanreotide were studied in 10 patients with symptomatic non-resectable carcinoid tumours. Results: Symptom improvement occurred in nine of 10 patients. Three patients responded only to octreotide, three patients responded to both octreotide and long-acting lanreotide and three patients only responded to long-acting lanreotide. Slight reductions in 24-h urine 5-hydroxyindoleacetic acid levels occurred in three of six patients but no patients were found to have objective tumour regression on computed tomography scan. Conclusions: Octreotide and long-acting lanreotide are useful palliative treatments for the control of symptoms in patients with non-resectable carcinoid tumours but there is no evidence of tumour stasis.

Despite adverse side effects, phenoxybenzamine has been widely used for the preoperative management of patients with pheochromocytoma. Doxazosin, a specific a 1-adrenoceptor antagonist, has a pharmacologic profile more suited to controlling blood pressure in such patients. A sequential study of 35 patients with pheochromocytoma encompassed a definite and prescribed change in preoperative drug management from phenoxybenzamine to doxazosin. Hemodynamic, pharmacologic, and biochemical indicators of a- and b-adrenoceptor blockade were measured before, during, and after anesthesia and surgery in 8 patients pretreated with phenoxybenzamine and 27 patients pretreated with doxazosin. Doxazosin (2-16 mg/day) was as effective as phenoxybenzamine in controlling arterial pressure and heart rate before and during surgery, but doxazosin caused fewer undesirable side effects both before and after surgery. Following phenoxybenzamine therapy substantial a 1-adrenoceptor blockade, detected as a right shift of phenylephrine dose-response curves, persisted for more than 2 days postoperatively, whereas after doxazosin it was undetectable on the first postoperative day. Doxazosin provided safe, efficacious pre- and perioperative control of arterial pressure. In patients with predominantly norepinephrine-secreting tumors, pretreatment 24-hour urinary norepinephrine excretion gave an indication of the daily doxazosin requirement.

Background It is uncertain whether biochemical markers of catecholamine secretion in patients with phaeochromocytoma correlate with tumour ultrastructure granule morphology. Methods Fifteen patients with an adrenal phaeochromocytoma (n=13) or paraganglioma (n = 2) (three men, 12 women; age 17–79 years) were studied. Catecholamine secretion was estimated by measuring urinary levels of free noradrenaline, adrenaline and dopamine. The number and type of secretory granules were evaluated by two independent observers on electron micrographs (area analysed approximately 70 µm2). Large round or elongated medium-density granules were adrenaline-type granules, whereas electron-dense granules lying in a vacuole were of noradrenaline type. Results No correlation was found between noradrenaline output and the number or percentage of noradrenaline-type granules, although tumours with normal noradrenaline output had only a minority of this type of granule (less than 25 per cent). Adrenaline-type granules were predominant (77 per cent of 163 granules) in a tumour secreting only adrenaline, but the proportion of adrenaline-type granules in six tumours with normal adrenaline output varied significantly (range 7–89 per cent). It was not possible to evaluate the granule type associated with dopamine secretion because one tumour secreting 14900 nmol dopamine and 1570 nmol adrenaline daily had a predominance of noradrenaline-type granules (63 per cent of 132 granules) and two dopamine-secreting tumours (5500 and 4250 nmol per day respectively) had 93 and 13 per cent noradrenaline-type granules. Conclusion The lack of correlation between hormone output and granularity suggests that other factors determine secretory patterns in these tumours.

Objectives: to assess a management protocol for mixed arterial/venous leg ulcers in a community service. Design: two-year prospective study of outcome with intention of assessing limbs with mixed arterial/venous ulcers when managed by a new protocol. Method: limbs were assessed for venous reflux by duplex and arterial insufficiency by ankle-brachial pressure index (ABPI) and defined into three categories: ABPI>0.85, 0.5>ABPI≤0.85 (moderate), ABPI≤0.5 (severe). Four-layer compression was applied to limbs with normal arteries. Modified compression was applied to limbs with venous and moderate arterial disease with treatment failure triggering arterial imaging and revascularisation. Limbs with venous and severe arterial disease were investigated for revascularisation. Results: of 267 consecutive limbs, 221 had pure chronic venous ulcers and 46 had mixed arterial/venous ulcers with 33 having moderate and 13 having severe arterial disease. Thirty-six week healing rates for chronic venous, moderate arterial/venous and severe arterial/venous ulcers were 70%, 64% and 23%, respectively. Conclusion: limbs with mixed moderate arterial/venous ulcers achieved rates comparable with venous ulcers with this protocol although nurse-led surveillance was required. Limbs with mixed severe arterial/venous ulcers healed slowly despite an aggressive approach to correct arterial disease.

The Haemocell S-350 device has recently been introduced for intraoperative autotransfusion. The system uses a novel membrane filter to process shed blood. In the first part of this study a 0.2-μm pore size filter was used in a randomized trial comparing the use of autotransfusion (n = 8) with bank blood controls (n = 9) during aortic reconstruction. This part of the trial was abandoned because of unexpected non-surgical bleeding. Bank blood requirements fell from a median of 3.0 (range 0.0-9.0) units to 1.5 (range 0.0–7.0) units when autotransfusion was used, but these patients had a greater perioperative blood loss (1791 (range 932–3104) versus 1140 (range 440–3840) ml). There was evidence of postoperative heparin excess with an activated partial thromboplastin time ratio of 1.3 (range 0.9–3.0) versus 1.0 (range 1.0–1.2) in controls and an activated clotting time of 206 (range 143–280) versus 137 (range 107–142) s. This was confirmed by raised plasma heparin levels and a prolonged thrombin time normalized by protamine. To improve performance a 0.6-μm pore size filter was studied in ten patients. Filtration efficiency doubled from 19 to 38 per cent. Electron micrographs demonstrated better filter clearance, but 44 per cent of the original concentration of heparin remained in the reinfusate. The S-350 device may be an attractive alternative to centrifugation for intraoperative autotransfusion but, until efficiency is improved, it should only be used for cardiovascular surgery when excess heparin can be reversed with protamine.

During the first 2 years (July 1989 to July 1991) of the Avon Breast Screening Service, fine-wire localization biopsy was indicated in 213 impalpable breast lesions. A total of 144 lesions were benign and 69 malignant. Only four of 213 lesions (1.9 per cent) were not excised at the first localization. Factors influencing reoperation in the 69 patients with malignant impalpable lesions were examined. There was a significant association (P < 0.001) between parenchymal disturbances on mammography and invasive carcinoma, and between non-invasive carcinoma and microcalcification (P < 0.001). In 31 patients the localization biopsy was the only surgical procedure. Thirty-eight patients required further surgery: 12 underwent further local excision and 26 mastectomy. Reoperation was more frequent in patients with calcification than in those with parenchymal disturbance (P < 0.001). The most frequent indications for mastectomy were inadequate excision of widespread comedo ductal carcinoma in situ or invasive ductal carcinoma combined with extensive ductal carcinoma in situ. Fine-wire localization biopsy was a combined therapeutic and diagnostic procedure in 31 of 69 women with impalpable screen-detected lesions. The majority of patients required further surgery because radiological abnormalities underestimated the extent of disease.

132 patients with advanced recurrent breast cancer were treated with four courses of mitozantrone 14 mg/m2 intravenously every 3 weeks (9 weeks). Patients showing disease stabilisation or objective response were randomised to stop chemotherapy or to continue until disease progression. At that stage 27% showed partial responses, 3% complete responses, and 10% disease stabilisation. 22 patients were randomised to continue chemotherapy and 21 to stop. There was no difference in time to disease progression, response duration, or survival between the two groups. Toxicity was mild during the first four courses of therapy. Thus, short courses of single-agent chemotherapy can produce similar therapeutic results to long-term chemotherapy, which has major implications for cost, resource allocation, and toxicity of therapy. Stopping chemotherapy early in responders did not cause rapid relapse. Since drug resistance apparently develops early during therapy, new approaches to modify resistance should be more useful than continuous chemotherapy.

Background Genetic mutations and upregulation of growth factors are implicated in the pathogenesis of hyperparathyroidism. The aim of this study was to evaluate the role of Wilms' tumour suppressor gene (WT-1) and the insulin-like growth factor (IGF) axis in hyperparathyroidism. Methods The expression of WT-1 and IGF components was examined by immunohistochemistry, reverse transcriptase–polymerase chain reaction and western immunoblotting in a panel of parathyroid specimens from both primary and secondary hyperparathyroidism. A human parathyroid cell culture model was established to examine the parathyroid response to IGF stimulation. Results There was a significantly lower level of WT-1 expression in parathyroid tumours than in normal parathyroid glands. Most tumours expressed IGF-I and IGF-II receptors and responded to IGF stimulation. Only IGF-I was present in normal parathyroid glands, whereas IGF-II was expressed exclusively in parathyroid tumours. Conclusion Abnormal expression of WT-1 and the IGF axis may play a role in the pathogenesis of hyperparathyroidism.

Background In most cell types, influx of calcium (Ca2+) induces a growth or secretory response. The opposite occurs in parathyroid (PTH), cells where there is an inverse relationship between intracellular Ca2+ concentration and PTH secretion. We have examined the effects of calcium channel and metabolism modulators on insulin-like growth factors (IGFs) in a parathyroid cell culture model. Methods Cell cultures were prepared from 9 patients undergoing operation for hyperparathyroidism. Following adhesion, the cells were transferred to serum-free medium and dosed with IGF I, II ± ethyleneglycol-bis(β-aminoethyl)-N, N, N′,N′-tetraacetic acid (EGTA), nifedipine, nickel, 2-aminoethoxy-diphenylborate (2-APB), or dantrolene. Proliferation (96 hours) was assessed by measuring tritiated thymidine incorporation and PTH release (1 and 3 hours) assayed by IRMA. Results Both IGF I and II increased DNA synthesis to 162.8% ± 10.6% (SEM) and 131.1% ± 7.7%, respectively (P < 0.05). EGTA at 0.2 mmol (ionized Ca2+ 0.2mmol) did not affect the response to both IGFs. EGTA at 2 mmol (ionized Ca2+ 0 mmol) reduced the DNA synthesis of IGF I and II to 29% and 26%, respectively (P < 0.05). Nifedipine and nickel (nonspecific Ca2+ channel blocker) were equally potent in negating the mitogenic effects of both IGFs. 2-APB (IP3R blocker) reduced the basal DNA synthesis to 51.3% ± 8.4% but had no effect on either IGF. Dantrolene (ryanodine receptor blocker) negated IGF II induced mitogenisis (74.2% ± 6.7%) and partially inhibited IGF I mitogenesis (123% ± 6%) (P < 0.05). The rate of PTH secretion was greater after IGF II stimulation than after IGF I stimulation. Conclusions IGFs I and II induce mitogenesis by different calcium signaling pathways. These data suggest that parathyroid cells may utilize different calcium signaling pathways to distinguish growth factors and serum calcium changes.

This study evaluated early postoperative serum calcium concentration as a predictor of hypocalcaemic symptoms and the need for calcium supplements. A total of 64 consecutive patients undergoing curative para- thyroidectomy for primary hyperparathyroidism were studied. Twenty patients (31 per cent) developed hypocalcaemic symptoms requiring calcium supplements. Plasma calcium levels in the preoperative and early postoperative periods were similar in patients who required calcium supplements and those in whom they were not necessary. There was no significant difference in the percentage decrease in early calcium levels after operation between the two groups. In those undergoing reoperative surgery and subtotal parathyroidectomy the percentage decline was significantly higher in patients who required calcium supplements (12.8 versus 5.6 percent, P

In the UK an estimated 40 000 trusses are issued annually. The rate of 700 per million is higher than that presently found in other countries and may be because of reduced access to surgery. Despite the high use of trusses little has been published on their effectiveness, complication rates and value. This review summarizes current knowledge, and concludes that further studies on the benefits and effectiveness of trusses need to be performed to enable patients to receive appropriate advice and guidance.

Epidermal growth factor (EGF) receptor status is a useful prognostic indicator in women with breast cancer. Lack of standardization and correlation of methodology for the detection of EGF receptor has hampered its further evaluation. EGF receptor status was ascertained by immunohistochemistry and radioligand assay in 120 breast cancers. Of 52 tumours negative for EGF receptor on radioligand assay, 47 were negative on immunohistochemistry and, of 68 tumours positive for the receptor on assay, 52 were positive on immunohistochemistry. If the more widely evaluated radioligand assay is assumed to be the ‘gold standard’, immunohistochemistry has a sensitivity of 81 per cent and a specificity of 91 per cent.

Background. Primary hyperparathyroidism (HPT) predominately affects perimenopausal women, leading to speculations that an estrogen imbalance may be liable. We have previously demonstrated the importance of the insulin-like growth factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to modulate the IGF axis, we examined the interactions of selective estrogen receptor modulators (SERMs) and IGF in HPT. Methods. Estrogen receptors were evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19 patients were included. After adhesion, the cells were treated with IGF (I or II) ± estrogen ± SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media. Proliferation was assessed by measuring tritiated thymidine incorporation. Results. Both primary and secondary HPT express estrogen receptors α and β. Primary and secondary HPT had comparable responses to SERMs, they were analyzed together. Compared with control (100%), IGFs (I and II) induced a significant increase in DNA synthesis. Estradiol at 10−8 and 10−7 mol/L (physiologic range) had no significant effects on IGF (I and II, P > .05). Both tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P < .05) and abolished the effects of both IGF I and II (P < .05). Conclusions. SERMs are capable of reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation has implications for cancer biology and therapeutic potential for SERMs in HPT.

Abnormalities of the p53 gene and protein were examined in 81 primary breast carcinoma samples. Using a polymerase chain reaction–single-strand conformational polymorphism (PCR—SSCP) analysis, mutations in p53 exons 5–8 were identified in 13 of 81 tumours (16 per cent) and confirmed by DNA sequencing. Positive staining for p53 protein was detected in ten of 77 (13 per cent) of these tumours using polyclonal CM1 antibody on formalin-fixed tissue. Mutations detected by PCR—SSCP analysis were more common in grade III tumours (P = 0·015), but no correlation was found with tumour size, node status or level of epidermal growth factor receptor expression. A p53 mutation was associated with positive antibody staining in only two patients. Positive immunohistochemical staining using a p53 antibody may detect p53 protein expression, but this may not correlate directly with an underlying mutation in the hot spot region examined.

Background The role of fine-needle aspiration cytology (FNAC) in the diagnosis and management of discrete parotid swellings remains controversial. Controlled enucleation can be appropriate with accurate preoperative diagnosis. This study (1985–1995) reviewed the role of FNAC in the diagnosis and surgical management of adenolymphoma. Methods Review of cytological smears by two observers concentrated on the features of infarction and squamoid metaplasia. Sensitivity, interobserver and intraobserver variation were evaluated statistically in a two-run ‘blinded’ analysis of 80 cytological slides from a variety of lesions. Results Of 222 epithelial neoplasms of the parotid, 33 were adenolymphomas. FNAC was performed before operation in 32, producing 34 slides, and a correct cytological diagnosis was made in 21 patients. Retrospective review of the 34 slides, to examine specific features of squamoid metaplasia and infarction, improved diagnostic accuracy. The reliability and reproducibility of cytodiagnosis was confirmed by analysis of interobserver and intraobserver agreement. The sensitivity was high (0·76–0·88). Controlled enucleation was performed in 12 patients and superficial parotidectomy in 11. There were no tumour recurrences. Conclusion Attention to the features of squamoid metaplasia and infarction improves cytological diagnosis and directs appropriate surgical management.

Thallium isotope scintigraphy is used to localize parathyroid adenomas but the mechanism underlying the technique is poorly understood. While larger adenomas are reliably localized the results are less certain for small tumours. This study explores the relationship between cellular DNA profile and thallium uptake (localization accuracy) in 24 parathyroid adenomas. The DNA profile was assessed using flow cytometry and standard subtraction thallium scintigraphy was performed before surgery. Fifteen of the 24 adenomas demonstrated excessive mitotic activity and 13 of these glands were accurately localized. Of the remaining nine glands, only five were localized accurately (P < 0.01, χ2 test including Yates' correction). This difference in thallium uptake could not be accounted for on the basis of gland weight. Thallium localization of parathyroid adenomas is related to mitotic activity. This may explain some of the limitations of this technique.

Controversy exists about whether preoperative localization procedures are indicated in patients with primary hyperparathyroidism before first neck exploration. Currently, thallium subtraction scintigraphy and ultrasonography are the techniques used most frequently. This paper examines prospectively the accuracy and value of these techniques in a group of 71 patients with primary hyperparathyroidism. When considering all glands, thallium scanning produced a sensitivity of 46·6 per cent with a specificity of 91·5 per cent, compared with a sensitivity of only 21·4 per cent and specificity of 94·5 per cent for ultrasonography. Accuracy rates, for all glands, were 80 per cent and 75·7 per cent respectively. Both localization procedures were consistently ineffective in localizing adenomas weighing less than 500 mg, over 80 per cent of which went undetected by both scanning modalities. While both scans produced satisfactory results in localizing adenomas weighing more than 1 g, these adenomas should not represent a challenge to an experienced endocrine surgeon and, therefore, neither localization is recommended before first neck exploration.

No satisfactory medical therapy exists for the treatment of primary hyperparathyroidism. Calcitonin and diphosphonates do not give good long-term control. This work examines the efficacy of the somatostatin analogue octreotide in the management of hyperparathyroidism. Twenty-one patients were admitted before parathyroid surgery and were treated for 6 days with subcutaneous octreotide 100 μg twice daily. Fasting blood samples were taken for determination of serum levels of calcium and parathyroid hormone, and 24-h urinary calcium excretion was measured before and after treatment. A significant decrease in urinary calcium was demonstrated, but the reduction in serum calcium level was not statistically significant and there was no change in serum parathyroid hormone concentration. Octreotide may provide therapy for patients with hyperparathyroidism and for those who have undergone unsuccessful neck exploration or who are unfit for operation. It may ameliorate hypercalciuria and reduce stone formation. The octapeptide may also have a potential role as a diagnostic test in primary hyperparathyroidism by determining the symptomatic effect of reducing raised levels of serum and urinary calcium.

Medullary thyroid carcinoma accounts for 5–10 per cent of thyroid malignancies and occurs sporadically, and in three familial settings with autosomal dominant inheritance. Calcitonin, a 32 amino acid 3.5-kDa protein, is a biochemical marker of the tumour. Serum levels correlate with disease burden. Treatment initiated by screening allows disease removal at a premalignant phase: C cell hyperplasia. Genetic linkage studies locate the multiple endocrine neoplasia type 2A gene near the centromere of chromosome 10. Flanking genetic markers may allow polymorphic probes to examine DNA from a once-only blood sample to identify affected individuals. At what age thyroidectomy should be carried out in these patients is unclear.

Background The precise cause of hyperparathyroidism (HPT) is uncertain. Alteration of growth factors (epidermal growth factor, fibroblast growth factor) and genetic mutations (parathyroid hormone (PTH) gene (11p15), PRAD1 oncogene (11q13) and multiple endocrine neoplasia type 1 (MEN1) gene (11q13)) are implicated in the pathogenesis. The escape of secretory function from physiological control and excess growth is still incompletely understood. The insulin-like growth factor (IGF) axis is a ubiquitous growth and regulatory system (IGF-1 and -II, IGF receptors (IGFRs) and binding proteins (IGFBPs)). Hormonal/endocrine signals (e.g. androgens, thyroid-stimulating hormone) and tumour supressor genes (e.g. Wilms' tumour suppressor gene (WT-1) (11p13) and p53) modulate the IGF axis. Expression of the WT-1 gene is tissue specific (kidney, mesothelium, prostate). Wild-type WT-1 governs normal kidney development and mutation results in Wilm's tumour. Loss of transcriptional repression of WT-1 and IGF control can lead to mitogenesis. A mutation (chromosome 11) appears to be the key event in the evolution of primary HPT. This mutation may increase IGFR expression, IGF production giving rise to unregulated autocrine growth. In polyclonal hyperplasia (secondary HPT and MEN1) a serum factor initiates polyclonal growth, thereby increasing the susceptibility to mutation and resulting in nodular hyperplasia. Methods Immunohistochemical examination of paraffin-embedded parathyroid glands was done using polyclonal anti-WT-1 (C19, Santa Cruz) and anti-IGFR-I (C20, Santa Cruz) antibodies and a horseradish peroxidase-labelled secondary antibody for detection. The strength of immunoreactivity was graded using a standardized colour chart and assessed independently by three observers. Results Two hundred and fifty-four parathyroid glands from 112 patients were examined. There were 81 women and 31 men (2·6: 1). Of these, 94 had primary HPT (70 women) and 18 secondary HPT (11 women). Immunoreactivity to WT-1 was found in normal parathyroid glands. In contrast, reduced WT-1 immunostaining was observed in abnormal parathyroid glands. Positive immunostaining for IGFR-I was found in all parathyroid glands. Increased immunoreactivity was found in pathological compared with normal glands. Conclusion WT-1 and IGFR are expressed in parathyroid cells. Abnormal expression of WT-1 and the IGF axis may play a role in the pathogenesis of HPT.

Seventy-three patients with chronic renal failure who underwent parathyroidectomy between March 1978 and April 1987 were reviewed. Thirty-four patients had undergone sub-total parathyroidectomy, and 39 patients had undergone total parathyroidectomy with parathyroid autograft into the forearm. Eight patients showed persistent hyperparathyroidism requiring a second surgical procedure. In all other patients there was highly statistical improvement in parathyroid hormone, total calcium, ionized calcium, alkaline phosphatase and a significant reduction in calcium x phosphate product. Histological evidence of osteitis fibrosa was present in 21 of 22 patients before surgery. Postoperatively, four showed complete resolution and improvement. Three patients developed histological evidence of osteomalacia during the study period. Only four of the 39 patients who underwent total parathyroidectomy with autograft had true recurrent hyperparathyroidism and only two of the 34 patients who underwent sub-total parathyroidectomy had recurrent disease, indicating that there is little to choose between the two techniques in the control of secondary hyperparathyroidism and its subsequent recurrence. In one patient with recurrence of hyperparathyroidism from a forearm parathyroid graft the histological picture was different from that of normal hyperplastic parathyroid tissue. Although it is probable that abnormal parathyroid tissue had been implanted there was no evidence of invasive growth into the forearm muscle. The most striking feature of long term follow-up was the difference in calcium x phosphate product in patients in whom vascular calcification increased compared to those patients with no change or regression of calcification. Mean calcium phosphate product in those patients with progressive vascular calcification was 4.93 for small and medium size vessels and 5.38 for large vessels compared to 4.10 for small and medium vessels and 4.09 for large vessels. In the former case the serum phosphate was 2.00 and 2.17 as compared to 1.75 or 1.73, suggesting that the aim in patients with end stage renal failure maintained by dialysis should be to control the serum phosphate concentration to 1.8 mmol or less and the calcium x phosphate product to less than 4.2.

Abnormalities of the p53 gene and protein were examined in 81 primary breast carcinoma samples. Using a polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis, mutations in p53 exons 5-8 were identified in 13 of 81 tumours (16 per cent) and confirmed by DNA seguencing. Positive staining for p53 protein was detected in ten of 77 (13 per cent) of these tumours using polyclonal CM1 antibody on formalin-fixed tissue. Mutations detected by PCR-SSCP analysis were more common in grade III tumours (P=0.015), but no correlation was found with tumour size, node status or level of epidermal growth factor receptor expression. A p53 mutation was associated with positive antibody staining in only two patients

Background Quality of life (QL) measurement is important for patients with oesophageal cancer but longitudinal studies may contain a bias because assessments only include healthy survivors who are able to complete questionnaires. This study examined QL in patients undergoing oesophagectomy by comparing results from those surviving 2 years after operation with results from patients dying within 2 years. Methods Between November 1993 and May 1995, 52 patients (36 men; mean age 67 years) underwent oesophagectomy. Prospective QL assessments were performed with the European Organisation for Research on Treatment of Cancer QLQ-C30 and the dysphagia scale from the oesophageal cancer module before treatment, 6 weeks, 3, 6, 9 and 12 months after operation, and at 6-month intervals thereafter, for a minimum of 3 years after operation. Mortality and morbidity rates and survival data were recorded. Results Two years after operation, 17 patients (33 per cent) were alive (group 1) and 35 had died (group 2). Groups were comparable for age, sex, tumour histology and length, dysphagia grade and performance scores. Six weeks after surgery patients in group 1 had worse functional, symptom and global health QL scores than before treatment. These subsequently improved such that by 9 months after operation most QL scores had returned to preoperative levels, except for persisting problems with dyspnoea and diarrhoea. Six weeks after operation patients in group 2 also reported worse QL in all domains, but this never recovered. Six months after treatment patients in group 2 had significantly worse physical, role, emotional and social function than those surviving 2 years and significantly more problems with appetite loss (P < 0·001). The notable exception in both groups was dysphagia, which improved after operation. This improvement was maintained until death or for the duration of the study. Conclusion Patients dying within 2 years of operation suffer an irreversible loss of QL, except that dysphagia is relieved. Further work is needed to assess whether additional postoperative support or the use of multimodality adjuvant treatment can improve the outcome for this group of patients.

Definition The radial arm maze, originally developed by David Olton, is an apparatus that taps into natural foraging abilities of rodents and can be used to test different types of memory, including short-term (working), longterm (reference), nonspatial and spatial memory. The arena consists of a number of arms (typically ranging from 4 to 16) that extend from a central hub, and food is placed in the ends of some or all of the arms. The food cannot be seen from the central platform. Versions that test spatial memory require rats or mice to navigate through the environment using allocentric spatial cues placed around the maze. Thus, animals must recall which arms had been entered or remain to be entered using the location of each arm relative to the different cues around the maze. Numerous studies have shown that rats do indeed use a spatial strategy to solve this task, as elaborate control experiments have been used to ensure that the rats do not simply use their sense of smell either to sense unclaimed food objects or to sense their own tracks.