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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.

This study examined the relationship between indices of self-reported emotional distress and absolute versus change in cortisol levels. Fifty-four women attending a diagnostic breast clinic completed scales measuring stress, anxiety and depression and provided five saliva samples over the course of a single day for the measurement of cortisol. No significant relationships were evident between absolute cortisol levels and the distress measures. Analysis of the change in cortisol levels revealed a non-linear interaction effect between stress and anxiety and time of day. There was a non-linear relation between time of day and cortisol levels, but the extent of the non-linearity was dependent upon levels of stress and anxiety, not depression. A relationship was apparent between indices of distress and change in cortisol levels, but not absolute levels of the hormone.

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.

This study investigated whether existence of a cohabiting relationship and its quality was related to psychological distress in women facing an acute stressor - a health threat. Levels of social support and self-esteem were tested as predictors of distress. One hundred and fifty-eight women with symptomatic breast problems referred to a diagnostic one-stop breast clinic participated in the study. Levels of psychological distress (stress, anxiety, depression), social support, self-esteem and, for women with partners, quality of partner relationship were measured using standardized self-report instruments. No differences were found between women with and without partners in terms of distress and psychosocial variables. However, women in low quality relationships experienced significantly more distress and received less support than women in high quality relationships. Self-esteem was not related to partner relationships. Low personal self-esteem significantly predicted distress on the appointment day for al...

Effects of extracellular calcium ([Ca(2+)](ext)) on parathyroid cells are mainly due to the activation of a plasma membrane calcium receptor (CaR) coupled with release of intracellular calcium. In addition, high [Ca(2+)](ext) activates the sphingomyelin pathway in bovine parathyroid cells, generating ceramides and sphingosine. This study explored the direct effects of synthetic ceramides on [Ca(2+)](i) in human parathyroid cells. Cells from five parathyroid adenomas removed from patients with primary hyperparathyroidism were dispersed and maintained in primary culture. Intracellular calcium concentration ([Ca(2+)](i)) [Ca(2+)](i) was monitored using standard quantitative fluorescence microscopy in Fura-2/AM-loaded cells. Laser scanning microscopy was used to monitor the intracellular distribution of a fluorescent ceramide analogue (BODIPY-C5). After addition of 10 microM C2-ceramide (N-acetyl-d-erythro-sphingosine), [Ca(2+)](i) increased rapidly (30-60 s) to a peak three times above basal levels in 70% of cells (37/55 cells in four experiments). This effect appeared to be due to release of Ca(2+) from intracellular stores rather than Ca(2+) entry from the extracellular medium. C2-responsive cells had a smaller [Ca(2+)](i) response to subsequent stimulation with the CaR agonist-neomycin (1 mM). These responses were specific to C2 since C6-ceramide (N-hexanoyl-d-erythro-sphingosine) did not affect basal [Ca(2+)](i) nor the responses to an increase in [Ca(2+)](ext) and to neomycin. C5-BODIPY generated intense perinuclear fluorescence, suggesting targeting of the ceramides to the Golgi apparatus. These data demonstrate that endogenous generation of ceramides has the potential to modulate changes in [Ca(2+)](i) and secretion in response to [Ca(2+)](ext) in human parathyroid cells.

Variability in response to chemotherapy is poorly understood. Paclitaxel-induced apoptosis was assessed in human Hs578T breast cancer cells, using the MTT assay, cell counting, morphological features and flow cytometry. Pre-dosing cells with non-glycosylated insulin-like growth factor binding protein-3 (ngIGFBP-3) had no effect on the cells per se but accentuated paclitaxel-induced apoptosis. The apoptotic pathway was further examined by measuring caspase-3 activity in cell lysates at time points over 48 hr after dosing with paclitaxel. Activity increased significantly, and Western immunoblots for caspase-3 in conditioned media showed that the inactive precursor decreased after incubation with paclitaxel. Endogenous production of IGFBP-3 by the cells after incubation with paclitaxel was evaluated using Western ligand blotting, specific IGFBP-3 immunoblotting and radioimmunoassay. Paclitaxel increased endogenous IGFBP-3, which was further increased if the cells had been pre-dosed with ngIGFBP-3. These findings suggest that IGFBP-3 may be an important modulator of paclitaxel-induced apoptosis.

Objective: To evaluate the influence of a specialized vascular-led community leg ulcer service on assessment and diagnosis of leg ulcers. Design: Before-and-after study with prospective and retrospective data collection. Setting: East Gloucestershire, England, UK. Subjects: Patients treated for chronic leg ulcers before and within a specialized service incorporating a one-stop assessment including ankle–brachial pressure index (ABPI) and colour venous duplex. Main outcome measures: The means of assessment and the identified aetiology of leg ulcers in community patients. Results: Before clinics, only 40 (26%) limbs had a diagnosis recorded. After clinics, 83 (21%) limbs had arterial disease, including 64 (16%) with mixed arterial/venous disease. Venous duplex identified 279 (70%) limbs with venous disease of which 121 (43%) had superficial venous disease alone. Conclusion: A one-stop assessment clinic with ABPI and colour venous duplex ultrasound within a specialized community service improves diagnosis of leg ulcers. This is essential before appropriate and safe management by specialist nurses in the community.

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.

Background The advantages of preoperative localization in the management of primary hyperparathyroidism have not been clearly demonstrated. The aim of this study was to investigate prospectively the accuracy of three localization techniques in patients with this condition. Methods Forty-nine consecutive patients with primary hyperparathyroidism underwent ultrasonography, magnetic resonance imaging (MRI) and technetium-thallium (Tc-Tl) subtraction scanning before surgery, during which an attempt was made to identify all parathyroid glands. A scan was regarded as correct if it identified an enlarged parathyroid gland on the correct side of the neck as subsequently demonstrated at surgery. Results Ultrasonography had a sensitivity of 38 per cent (18 correct scans in 47 patients) with a positive predictive value of 78 per cent. The sensitivity of MRI was 72 per cent (34 of 47) with a predictive value of 92 per cent. Tc-TI scanning was 60 per cent sensitive (28 of 47) with a predictive value of 85 per cent. Two patients with negative neck explorations were subsequently found to have mediastinal adenomas. Conclusion Ultrasonography, MRI and Tc-TI scanning have limited value as localization techniques and the relatively low sensitivity of these investigations means they are of no value before first-time surgery.

There is controversy as to the value of the radiological or pathological estimation of surgical clearance of microcalcifying breast lesions. An important part of this issue has been addressed by coordinated three-dimensional radiographic and histological examination of a prospective consecutive series of 40 benign and malignant mammographically detected lesions in surgical breast biopsy specimens containing microcalcifications, including 20 cases of ductal carcinoma in situ. They were radiographed from four viewpoints by means of rotation in a radiolucent tetrahedral container. The planes of histological examination were then chosen to correspond to the radiographic view showing the minimum separation of the edge of the specimen and the outermost microcalcification. There was a close correlation (Spearman ranked) between the least tetrahedral radiographic distance and the corresponding histological distance separating the surgical margin of excision. There were, however, incompatible Wilcoxon signed ranking orders when comparing the least tetrahedral distance or the histological distance with all four single radiographic views, including the conventional specimen radiographic view. Two-dimensional specimen mammography and standardized histological examination are suboptimal and may thus have contributed to confusion as to the value of determining adequate surgical excision of ductal carcinoma in situ of the breast. Although labour-intensive, use of four-view radiography and choice of the appropriate plane of histological examination give a better correlation of the radiographic estimates of surgical clearance with histology than single-view specimen radiography and arbitrary histological sectioning.

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.

Of 221 patients with breast cancer of known epidermal growth factor receptor (EGFR) and oestrogen receptor (ER) status, 99 had developed recurrences during the period of follow-up (range 3-60 months, median 24 months). Of these, 72 received endocrine therapy as first-line treatment for relapse. Immunohistochemical assessment of c-erbB-2 protein product expression was made using paraffin-embedded tumour tissue from 65 of these 72 patients. Including patients whose disease remained stable for more than 6 months with those showing an objective response (CR or PR for more than 3 months), only one (7%) of 14 c-erbB-2 positive tumours responded to endocrine manipulation compared with 19 (37%) of 51 c-erbB-2 negative tumours (P less than 0.05). Coexpression of c-erbB-2 reduced the response rate of ER positive patients from 48% to 20% and of ER negative cases from 27% to 0% (P less than 0.01). EGFR and c-erbB-2 protein appeared to have additive effects in reducing the likelihood of response, and none of eight patients with EGFR positive, c-erbB-2 positive tumours derived benefit from endocrine therapy. The results of this study suggest that c-erbB-2 protein overexpression, a marker of poor prognosis in breast cancer, is associated with a lack of response to endocrine therapy on relapse, and particularly in combination with EGFR may be useful in directing therapeutic choices.

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.

Objective: Different emotions are to some extent associated with different ways of coping. Cognitive processes involved in determining emotional reactions may influence coping (perhaps through directing attention or generating salient information). This study explored possible appraisal-coping associations by examining whether a set of appraisal components identified in emotion theory were also associated with coping. Design: The study examined concurrent associations between appraisal components, emotional adjustment, and coping in 148 women with suspected breast disease. Method: Questionnaire measures of primary and secondary appraisal components identified in emotion theory, anxiety, depression, and coping were sent to women during the waiting period between GP referral and attendance at a ‘one-stop’ breast-disease diagnosis clinic. Results: Consistent with expectations, appraisal components were associated with both emotions and coping. Elevated anxiety was associated with appraisals of low emotion-focused coping potential; avoidance coping was associated with motivational incongruence, self-accountability, and pessimistic appraisal of emotion-focused coping potential; acceptance/resignation coping was associated with self-accountability and pessimistic appraisals of both future expectancy and emotion-focused coping potential. Conclusion: This study presents a theoretically driven approach to exploring associations between emotions and adjustment efforts. In keeping with expectations, a number of appraisal components identified in emotion theory were found to be associated with both emotion and coping.

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.

Epidermal growth factor receptor (EGFR) is a sensitive prognostic indicator in women with breast cancer. A new technique for the detection of EGFR on breast cancer imprints is described and evaluated in relation to immunohistochemistry on frozen sections. The standard streptavidin-biotin method using the R1 antibody on frozen sections was modified for use on tumour imprints. In the first group (group 1 imprints) 43 tumours were assessed by frozen section and imprint staining. The group 1 imprint method had a sensitivity of 50% and a specificity of 89% compared with the frozen sections. Further modifications were made for the following 32 tumours (group 2) and this method had a much improved sensitivity of 94% while specificity was preserved. This method is simple and could be performed in any hospital histopathology department.

Whether activation of the calcium receptor (CaR) modulates secretory events was investigated by real-time fluorescence and confocal microscopy using fura 2 and FM1-43 fluorescent dye. Two paradigms were used: human parathyroid cells, which are stimulated by a step from a high to a low extracellular calcium concentration ([Ca(2+)](ext)), and rMTC6-23 cells, a rat medullary thyroid carcinoma cell line whose secretion is stimulated by an increase in [Ca(2+)](ext). Parathyroid cells were dispersed from parathyroid adenomas removed from 18 patients with primary hyperparathyroidism. In both cell types, incubation with FM1-43 (2 microM) resulted in staining of the plasma membranes, which was rapidly increased following changes in [Ca(2+)](ext) known to stimulate secretion. A high [Ca(2+)](ext) and lanthanum (La(3+)) decreased the membrane-associated FM1-43 fluorescence. Prolonged incubation (5-30 min) in the presence of FM1-43 resulted in accumulation of the dye in the cytoplasm, its granular distribution suggesting targeting of the secretory compartment. These data suggest that FM1-43 fluorescence is determined by: (i) changes in cell membrane surface area associated with secretion-associated events, (ii) displacement/quenching by extracellular cations and (iii) endocytosis of the dye. In parathyroid cells, a rise in FM1-43 fluorescence occurred during incubation in a high (inhibitory) [Ca(2+)](ext) if the cytoplasmic calcium concentration ([Ca(2+)](i)) was decreased by the calcium chelator BAPTA/AM [bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] (10-50 microM). Alternatively, the expected rise in FM1-43 fluorescence did not occur during incubation in a low (stimulatory) [Ca(2+)](ext) if [Ca(2+)](i) was increased by addition of the calcium ionophore A23187 (10-25 microM). These data suggest that [Ca(2+)](i), rather than the absolute value of [Ca(2+)](ext), is the main modulator of secretion from parathyroid cells.

Variability in response to chemotherapy is poorly understood. Paclitaxel-induced apoptosis was assessed in human Hs578T breast cancer cells, using the MTT assay, cell counting, morphological features and flow cytometry. Pre-dosing cells with non-glycosylated insulin-like growth factor binding protein-3 (ngIGFBP-3) had no effect on the cells per se but accentuated paclitaxel-induced apoptosis. The apoptotic pathway was further examined by measuring caspase-3 activity in cell lysates at time points over 48 hr after dosing with paclitaxel. Activity increased significantly, and Western immunoblots for caspase-3 in conditioned media showed that the inactive precursor decreased after incubation with paclitaxel. Endogenous production of IGFBP-3 by the cells after incubation with paclitaxel was evaluated using Western ligand blotting, specific IGFBP-3 immunoblotting and radioimmunoassay. Paclitaxel increased endogenous IGFBP-3, which was further increased if the cells had been pre-dosed with ngIGFBP-3. These findings suggest that IGFBP-3 may be an important modulator of paclitaxel-induced apoptosis.

Quality of life (QL) measurement provides detailed information about outcome from the patient's perspective. This study assessed the impact on short and long term QL of esophagectomy and palliative treatment in patients with esophageal carcinoma.Consecutive patients undergoing potentially curative esophagectomy or purely palliative treatment completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the dysphagia scale from the EORTC QLQ-OES24 before treatment and at regular intervals until death or for 3 postoperative years. Median scores were calculated for patients surviving more than 2 years after surgery (n = 17), for patients surviving less than 2 years after esophagectomy (n = 38), and for patients undergoing palliative treatment (n = 37).Baseline functional and symptom QL scores were similar in both groups of patients undergoing esophagectomy, and these were better than scores from patients selected for palliative treatment. Six weeks after esophagectomy, patients reported worse functional, symptom, and global QL scores than before treatment. In patients who survived at least 2 years, QL scores returned to preoperative levels within 9 months, but patients who died within 2 years of surgery never regained their former QL. In both groups, dysphagia improved after surgery and the improvement was maintained until death or for the duration of the study. Patients undergoing palliative treatment reported gradual deterioration in most aspects of QL until death.Esophagectomy has a negative impact on QL; this effect is transient for patients who survive for 2 or more years. This finding should be considered when selecting patients for surgery.

OBJECTIVE: To retest the hypothesis that imprint cytology may be used to reliably diagnose parathyroid tissue and, if so, to ascertain whether accuracy in this technique may be easily attained. STUDY DESIGN: Imprint preparations from 15 parathyroid, 10 thyroid, 8 lymphoreticular and 2 adipose tissue specimens were assessed blindly by two pathologists, one of whom (pathologist B) had only limited experience with endocrine tissue imprint cytology. RESULTS: Both assessors consistently distinguished parathyroid and thyroid preparations from lymphoreticular and adipose tissue preparations. While there was occasional difficulty in distinguishing between parathyroid and thyroid preparations, this was usually attributable to the scanty nature of the preparations. No single cytologic feature allowed a distinction between parathyroid and thyroid tissue. However, by considering several relatively diagnostic features collectively, pathologist B showed an increase in specificity and sensitivity rates for distinguishing parathyroid from thyroid imprints from 82% to 100% and 57% to 83%, respectively. CONCLUSION: The high accuracy rates and rapid Table I Number (Percentage of Total Number of Preparations for Each Tissue Type) of Correct Imprint Cytology Diagnoses for Each Tissue Type, Assessor and Trial Tab. learning curve shown by imprint cytology in distinguishing between different neck or mediastinal tissue types, together with its time- and cost-cutting potential, support a role for the technique in the intraoperative diagnosis of parathyroid tissue.

There is a growing interest in assessing quality of life in patients with oesophageal cancer because it provides detailed information of the patients' perception of the benefits or harms of treatment. Yet few studies have prospectively measured quality of life using validated appropriate instruments. There are now several questionnaires for patients with cancer, although these are not sufficiently sensitive to small but clinically important changes in quality of life. It is therefore recommended that a disease-specific module is used in conjunction with generic measures. The European Organisation into Research and Treatment of Cancer (EORTC) QLQ-OES24 is currently completing an international validation study. It is used with the EORTC QLQ-C30 core instrument and is designed for patients undergoing potentially curative treatment or palliation of malignant dysphagia. Studies that have assessed quality of life after oesophagectomy have generally found that survivors do regain their former health. Little is known about the effect of neoadjuvant chemoradiation on patients' quality of life. Following endoscopic palliation of dysphagia, quality of life can be maintained and improvement of swallowing is seen. A validated appropriate assessment of quality of life should be included in future palliative trials and in studies of new treatments which may marginally influence survival but cause significant side effects.

Parathyroid cells express a plasma membrane calcium receptor (CaR), which is stimulated by a rise in extracellular calcium concentration ([Ca2+]ext). A decreased sensitivity to [Ca2+]ext occurs in adenomatous parathyroid cells in patients with primary hyperparathyroidism, but the underlying functional mechanism is not yet fully understood. This study explored whether CaR responsiveness is influenced by increasing the affinity of IP3 receptors--a major signalling component of other G-protein-coupled receptors. The sulphydryl reagent thimerosal was used to increase the responsiveness of IP3-receptors. Quantitative fluorescence microscopy in Fura-2-loaded cells was used to investigate the effects of thimerosal on the cytoplasmic calcium concentrations ([Ca2+]i) in human parathyroid cells and to compare its effects in a rat medullary thyroid carcinoma cell line (rMTC6-23) also expressing CaR. During incubation in Ca(2+)-free medium, thimerosal 5 microM induced a rapid sustained rise in [Ca2+]i in human parathyroid cells and no further [Ca2+]i increase appeared in response to the CaR agonist Gd3+ (100 microM). Thimerosal 1 microM induced only slow and minimal changes of basal [Ca2+]i and allowed a rapid response to Gd3+ 20 nM (a concentration without effect in control cells). The slope of the thimerosal-induced [Ca2+]i responses was steeper following exposure to CaR agonists. In the presence of 1 mM [Ca2+]ext, thimerosal (0.5 microM) induced a sharp increase in [Ca2+]i to a peak (within 60 s), followed either by return to basal [Ca2+]i or by a plateau of slightly higher amplitude. Similar results were obtained using rMTC6-23 cells. Thimerosal increases the responsiveness to CaR agonists through modulation of the sensitivity of the IP3 receptor in both parathyroid and rMTC6-23 cells.

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.

In reviewing articles or books, influential judgments are made about the scientific worth and value of colleagues’ written work. This should be done with a more than adequate background knowledge and a desire to be fair and just. Hippocrates correctly tells us that experience alone is fallacious and any reviewer must also agree that “judgement is difficult.” From the perspective of the journal using referee comments to decide upon the fate of a paper or deciding whether to publish a book review, other criteria must obtain. One hundred years ago the editorial columns of the New York Medical Journal were “controlled by the desire to promote the welfare, honour and advancement of the science of medicine, as viewed from a standpoint looking to the best interests of the profession. Nothing is admitted to its columns that has not some bearing on medicine, or is not possessed of some practical value.” These parameters have probably changed little since 1892 and apply equally to specific surgical disciplines.

There has been concern about the number of interval cancers which have been detected within the National Breast Screening Programme. A series of 134 women presenting with interval cancers was studied by prospective audit and the rate and radiological classification of the tumours determined. The cancers were classified as true (67), false-negative (22), unclassifiable (28), occult (12), and minimal sign (5). The interval cancer rate did not achieve the new National Guidelines in either the first 2 years or the 3rd interval year. The false-negative cancers presented mainly in the 1st interval year, whereas the true cancers were predominantly confined to the 2nd and 3rd years. These data suggest that alterations to the screening programme may be beneficial. It may be, however, that the programme is still on the learning curve and this should be taken into account when interpreting these data.

The 4th year of the Avon breast screening programme comprises two distinct groups: those called for screening for the first time (prevalent group) and those who were initially screened 3 years earlier (incident group). The cancer detection rate, stage of disease and rate of interval cancers in these patients have been compared. For the prevalent groups of year 1 and year 4 there was no statistically significant difference in the cancer detection rate, proportion of small tumours or node positivity. For the prevalent and incident groups of year 4, there was no statistically significant difference in the cancer detection rate or proportion of small tumours. There were significantly fewer node-positive tumours in the incident group (5/45 vs 8/23; P < 0.05). Fifty-six interval cancers presented in the 3-year period between years 1 and 4 of screening; 28 (50%) after 24 months. The screening programme may result in tumours being detected at an earlier stage, but this may be offset by the high rate of interval cancers. This suggests that the time between screens may need to be reduced to 2 years.

There is controversy as to the value of the radiological or pathological estimation of surgical clearance of microcalcifying breast lesions. An important part of this issue has been addressed by coordinated three-dimensional radiographic and histological examination of a prospective consecutive series of 40 benign and malignant mammographically detected lesions in surgical breast biopsy specimens containing microcalcifications, including 20 cases of ductal carcinoma in situ. They were radiographed from four viewpoints by means of rotation in a radiolucent tetrahedral container. The planes of histological examination were then chosen to correspond to the radiographic view showing the minimum separation of the edge of the specimen and the outermost microcalcification. There was a close correlation (Spearman ranked) between the least tetrahedral radiographic distance and the corresponding histological distance separating the surgical margin of excision. There were, however, incompatible Wilcoxon signed ranking orders when comparing the least tetrahedral distance or the histological distance with all four single radiographic views, including the conventional specimen radiographic view. Two-dimensional specimen mammography and standardized histological examination are suboptimal and may thus have contributed to confusion as to the value of determining adequate surgical excision of ductal carcinoma in situ of the breast. Although labour-intensive, use of four-view radiography and choice of the appropriate plane of histological examination give a better correlation of the radiographic estimates of surgical clearance with histology than single-view specimen radiography and arbitrary histological sectioning.

Quality of life (QOL) assessments in patients with oesophageal cancer should provide clinically meaningful data that can assist management decision making. This study describes the development of a specific module for oesophageal cancer to use with the European Organisation into Research and Treatment of Cancer (EORTC) QOL questionnaire, the EORTC QLQ-C30. Relevant QOL issues were generated from a literature search and interviews with patients and oesophageal cancer specialists. Issues were formulated into items compatible with those of the EORTC QLQ-C30. The provisional module was pretested in patients from the United Kingdom, Spain and Sweden. The resulting module, the QLQ-OES 24, includes 24 items conceptualised as containing six scales and five single items. The addition of an oesophageal cancer-specific module to the core questionnaire should improve the sensitivity and specificity of the core instrument to allow detection of even small benefits accrued from new treatment modalities.