A comparison of intubating conditions in children following induction of anaesthesia with propofol and suxamethonium or propofol and remifentanil.

Sixty ASA 1 and 2 children aged between 2 and 16 years who required tracheal intubation as part of anaesthesia for elective surgery were studied. We evaluated intubating conditions, haemodynamic responses and duration of apnoea following propofol 4 mg.kg-1 combined with either remifentanil 1.25 microg.kg-1 (group R), or suxamethonium 1 mg.kg-1 (group S). Tracheal intubation was graded as excellent, good or poor according to ease of laryngoscopy, vocal cord position, coughing, and jaw relaxation and limb movement. Thirty of group S and 28 of group R children were successfully intubated on the first attempt. Overall, intubation conditions were excellent or good in 26/30 (87%) patients in group S and 20/30 (67%) in group R (p<0.05). Mean apnoea time was 190 s in group S, and 362 s in group R (p<0.001). Heart rate increased in response to suxamethonium (p<0.01) and both systolic and diastolic blood pressure decreased in the remifentanil group (p<0.01).

Radiation peak skin dose to risk stratify electrophysiological procedures for deterministic skin damage.

UNLABELLED: Ionising radiation is has the potential to cause harm both by increasing the probability future malignancy (stochastic mechanisms) and by direct physical injury (deterministic mechanisms). Several measures have been developed to quantify radiation exposure during a procedure and cardiologists usually refer to fluoroscopic screening time (FST). FST, however, has limitations for predicting deterministic injury which is directly dependant on peak skin dose (PSD). We compared FST to PSD for a range of interventional cardiac electrophysiology procedures. METHODS: All patients undergoing electrophysiology procedures during a 2-month period in our institution were studied. Demographic details, nature of procedure, FST and PSD were measured. The FST to PSD ratio was calculated and compared between patient and procedural factors. RESULTS: 67 procedures on patients (23 female) with body mass index (BMI) of 28 (SD 5) Kg/m2 were studied. Screening times ranged from 0.2 to 96.6 min (median 11.2). PSD ranged from <0.1 to 1108 mGy (median 141). There was a positive correlation between PSD to FST ratio and BMI (r = 0.59, p < 0.001). The PSD to FST ratio was higher in cardiac resynchronization therapy (CRT) devices than single or dual chamber ICDs (p = 0.002). CONCLUSION: FST is not a reliable predictor of deterministic skin injury and in high-risk procedures such as CRT devices and those on individuals of high BMI PSD should be measured.

Use of tissue microarray for interlaboratory validation of HER2 immunocytochemical and FISH testing.

AIMS: To evaluate the use of tissue microarray (TMA) technology as a validation tool for HER2 testing by both immunocytochemistry (ICC) and fluorescence in situ hybridisation (FISH) in the diagnostic setting. METHODS: TMA constructs from 57 cases of breast cancer were evaluated for HER2 (by ICC and FISH) by two centres. The results were compared. RESULTS: There was a high level of concordance for both ICC and FISH. In five "discrepant" cases only three would have had a potential impact on patient management. CONCLUSIONS: Validation of HER2 analysis in the clinical setting by ICC and FISH is essential. The use of TMAs provides for an economy of scale and would be practical in the setting of interlaboratory and intralaboratory validation. It is suggested that routine HER2 ICC and FISH should continue to be performed in laboratories on whole sections. Following this, TMAs would be constructed for all cases of breast cancer. ICC and FISH would be performed on these to validate the results. The TMAs would be available for circulation to other centres for validation purposes. The standardisation of testing between centres, the potential difficulty of minimum case numbers, and the workload issues surrounding validation would all be facilitated by this approach.

Radial intratumoral increase and correlation of microvessels and proliferation in solid breast carcinoma.

AIMS: To compare correlations between different morphometrically assessed measurements of tumour microvasculature and to identify those which show closest correlation with Ki67 and to examine radial intratumoral distribution of microvessels and proliferation. METHODS AND RESULTS: Immunohistochemically defined microvessels and Ki67+ cells were quantified in sequential fields of 0.12 mm2 (x600) in four transects in each of five tumours. The total number of vessels (TNV) correlated more closely with proliferative activity than the numbers of vessels with a discernible lumen (TLV) and TNV decreased towards the centre of the tumour whereas TLV did not. A higher proliferative index (PI) was found at the periphery of the tumours. Comparison between transects through subjectively identified microvessel hot-spots and non-hot-spot transects showed similar mean, median and peak vessel counts but showed a different distribution on chi2 analysis. CONCLUSIONS: TNV correlates most closely with PI in breast carcinomas. There is marked variation in microvessel density and PI between fields of 0.12 mm2 but there is a significant radial reduction in both from the edge towards the centre of tumours.

Effect of smoking and transdermal nicotine on colonic nicotinic acetylcholine receptors in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a disease largely of non-smokers, in which nicotine is of therapeutic value. The mode of action is unknown, but may involve nicotinic acetylcholine receptors (nAChRs) in the bowel wall. AIM: To investigate the presence of nAChRs in rectal mucosa, and the effect of smoking and nicotine on their expression. DESIGN: Prospective case-control study. METHODS: In situ hybridization (ISH) and immunocytochemistry (ICC) were used to show alpha3 nAChRs in colonic mucosa. Rectal mucosa was examined from controls (n=55) and patients with inactive UC (n=62), both smokers and non-smokers, by ICC, using two antibodies to show the density and distribution of receptors in the mucosa. Non-smokers with UC (n=43) were given transdermal nicotine or placebo patches for 6 months, and rectal biopsies, taken before and after treatment, were examined by ICC to show nAChRs. RESULTS: In normal colon, ISH and ICC showed alpha3 subunit in a wide variety of cells, including mucosal epithelium. In rectal biopsies, neither smoking nor nicotine influenced the expression of alpha3 immunoreactivity in epithelium, either in controls or UC. However, controls had a significantly greater density of immunodetectable mucosal epithelium alpha3 subunit, compared with UC patients. DISCUSSION: The presence of nAChRs in colonic epithelium may be pertinent to the beneficial effect of nicotine in UC, but since neither smoking nor nicotine treatment is associated with any change in the expression of epithelial alpha3 nAChRs, the effect may be due to functional changes in the receptor. The decreased number of alpha3 nAChRs in UC compared with controls may be related to an increased cell turnover in UC.

Effect of margins of excision on recurrence after local excision of ductal carcinoma in situ of the breast.

AIMS: To determine important factors influencing recurrence after local excision of duct carcinoma in situ (DCIS) of the breast. MATERIALS AND METHODS: The extent (size) in millimetres, classification (by cytonuclear grade (NHSBSP system), by extent of necrosis, and by the Van Nuys system), and excision margins of 115 cases of screen detected DCIS treated by local excision were measured. A prognostic index was calculated by the addition of the Van Nuys classification (low grade, 1; moderate grade, 2; high grade, 3), margin score (> or = 10 mm, 1; 1-9 mm, 2; < 1 mm, 3), and size score (< or = 15 mm, 1; 16-40 mm, 2; and > or = 41 mm, 3), giving a total score of 3-9. RESULTS: Classification using cytonuclear grade, extent of necrosis, or the Van Nuys system did not correlate significantly with recurrence. The excision margin (in millimetres) was associated with recurrence (p = 0.027) and if excision margin status was simplified using the scoring system (> or = 10 mm, 1; 1-9 mm, 2; < 1 mm, 3), the margin score was significantly associated with recurrence (p = 0.03). A prognostic index based on the Van Nuys score, margin status, and size was significantly associated with recurrence (p = 0.003). CONCLUSION: The results support the hypothesis that the margin of excision is the most important factor predicting the recurrence of DCIS after local excision.

The effect of fixation and processing on the sensitivity of oestrogen receptor assay by immunohistochemistry in breast carcinoma.

AIMS: To investigate the effect of different fixation and processing regimens on the assessment of oestrogen receptor (ER) by immunohistochemistry (IHC). METHODS: The ER results for 420 patients from seven different hospitals in which antigen retrieval and IHC were performed centrally were compared. The intensity of ER positivity was assessed semiquantitatively using the Quick score (range 0-7). The scoring profiles of cases from each different source (hospital) were compared to detect differences in the proportion of cases that were negative (Quick score = 0), moderately positive (Quick score = 1-5), and strongly positive (Quick score = 6-7). RESULTS: There were no significant differences (p = 0.3; kappa(2) test) in the proportion of cases in each category. CONCLUSIONS: None of the fixation or processing regimens had a significant adverse effect on the sensitivity of the ER assessment performed by automated immunohistochemistry.

Complex and extensive infective endocarditis: a novel surgical approach.

Endocarditis involving the central fibrous body of the heart requires carefully planned surgical intervention. We present a novel approach in a 65-year-old male with extensive endocarditis involving the aortic root, ventricular septum, central fibrous body together with mitral, aortic and tricuspid valves.

Comparison of core oestrogen receptor (ER) assay with excised tumour: intratumoral distribution of ER in breast carcinoma.

AIMS: The use of the H score (involving the assessment of intensity and distribution of positivity) on sections stained for the oestrogen receptor (ER) by immunocytochemistry (ICC) allows different samples to be compared and detailed correlations to be made between hormone receptor expression and morphology. This study assessed the reliability of core biopsy in predicting ER expression in the same tumour excised later at treatment. The distribution of ER within excised tumours was investigated. METHODS: The distribution of ER positivity was investigated in 51 diagnostic core biopsies and across the diameter of 51 subsequently excised tumours in a field by field (magnification, x40; field diameter, 0.4 mm) assessment using the semiquantitive H scoring system. RESULTS: The ER H score in diagnostic core biopsy was significantly higher (p = 0.05, paired rank test; overall mean, 130; n = 51) than the mean in the corresponding excised tumour (mean, 110; n = 51). There was a significant downward trend in ER positivity from the periphery of tumours towards the centre (p = 0.001). The reduction of ER positivity was 6 H score units (2%)/mm. If core biopsies were orientated with the tumour edge at one end no change in ER positivity with field number along the length of the core could be demonstrated. CONCLUSIONS: ER estimation in core biopsies correlated well with expression in tumours but ER expression was higher in the core biopsies than in the excised tumours. ER expression was higher at the periphery of tumours than at the centre. The higher ER expression in cores may reflect the higher chance of sampling the peripheral part of a tumour using a needle core.

Pericardial mesothelioma following mantle field radiotherapy.

A 49-year-old female was referred with recurrent pericardial effusion following mantle field radiotherapy for Hodgkin s lymphoma. She underwent video-assisted thoracoscopy and resection of a pericardial window. Intraoperatively she suffered a cardiac arrest and subsequently died in the early postoperative period despite maximal therapy. Pathological examination revealed extensive myocardial fibrosis and multiple nodules of pericardial mesothelioma. The latter has hitherto not been recognised following mediastinal radiation. The cardiac complications of mantle field radiotherapy are discussed.

Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs.

Fifty-six adult beagle dogs (28 male, 28 female) were orally administered thalidomide at 43, 200, or 1000 mg/kg/day for 53 weeks. Sixteen (2/sex/dose group) and 32 (4/sex/dose group) dogs were euthanized and necropsied after 26 and 53 weeks of dosing, respectively. The remaining 8 animals (2/sex/group; high-dose and control groups) were dosed for 53 weeks, euthanized, and necropsied at 58 weeks after a 5-week recovery period. There were no deaths during the study. The only observed clinical signs attributable to thalidomide administration were green-colored urine, white-colored fecal residue presumed to be unchanged thalidomide, enlarged and/or blue coloration of female mammary tissue, and prolonged estrus. There were no thalidomide-related changes in body weights, food consumption, electrocardiography, ophthalmoscopy, neurological function, and endocrine function. The mostly slight and/or transient variations observed in some hematology and blood chemistry values of dosed dogs were considered to be toxicologically insignificant and were supported by the lack of histopathologic correlates. The only gross finding attributable to thalidomide was a yellow-green discoloration of the femur, rib, and/or calvarium that was observed at each euthanization interval including recovery. There was no microscopic correlate for this finding. No thalidomide-related microscopic changes were seen in any of the organs and tissues at 26 weeks. Mammary duct dilatation and/or glandular hyperplasia observed in females at 53 and 58 weeks and hepatic bile pigment exhibited by high-dose males at 53 weeks were microscopic changes considered to be thalidomide-related. There was no gross and histopathologic evidence of any tumors. In summary, thalidomide at up to 1000 mg/kg/day for 53 weeks did not induce any major systemic toxicity or tumors in dogs. The NOAEL was 200 mg/kg/day.

Thyroid transcription factor-2 gene expression in benign and malignant thyroid lesions.

Thyroid transcription factor-2 (TTF-2) is a recently cloned thyroid-specific gene and is central to the development and differentiation of the thyroid follicular cell. Information regarding transcript levels in normal and diseased adult human thyroids is lacking. We have investigated TTF-2 gene expression in various thyroid pathologies and assessed its potential in preoperative diagnosis of thyroid nodular disease, which is a common clinical problem. We have used reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH) and detected TTF-2 transcripts in 60% of 125 samples of adult human thyroids tested by RT-PCR (64% of 35) or ISH (59% of 90). In normal thyroid tissues TTF-2 transcript levels are low, 18 of 36 were weakly positive and 18 of 36 negative when tested by ISH. In the benign lesions, TTF-2 transcripts were detected either by RT-PCR or ISH in 8 of 8 Graves disease; 3 of 7 Hashimoto's; 2 of 2 follicular hyperplasia; 15 of 21 follicular adenoma; 11 of 13 multinodular goiters and 0 of 1 hyalinizing trabecular adenoma. In the malignant thyroid lesions, TTF-2 transcripts were detected in 8 of 18 follicular cancers; 0 of 2 anaplastic carcinoma, and 11 of 17 papillary cancers. Compared with normal thyroids, transcripts were more abundant in 24% of thyroid lesions tested by ISH. In conclusion, we report for the first time on TTF-2 gene expression in normal and diseased adult human thyroids.

Consistency in the observation of features used to classify duct carcinoma in situ (DCIS) of the breast.

AIM: To determine interobserver and intra-observer agreement in the assessment of cytological grade and intraduct necrosis in pure duct carcinoma in situ (DCIS) of the breast. METHODS: Sixty unselected cases with illustrated diagnostic criteria were circulated to 19 practising histopathologists. RESULTS: Overall agreement was moderate for cytological grade in three categories: 71% agreement; weighted kappa (kappa w), 0.36; intraduct necrosis in three categories (absent, present, extensive): 76% agreement; kappa w, 0.57; and the Van Nuys classification system: 73% agreement; kappa w, 0.48. Agreement was no better among observers participating in the National External Quality Assurance Programme. Intra-observer agreement for cytological assessment (69.6% agreement; kappa w, 0.52) and intraduct necrosis (68.3% agreement; kappa w, 0.48) was moderate, suggesting that individual variation rather than precision of criteria contributes to the lack of agreement. CONCLUSIONS: Moderate agreement on observations can be achieved by non-specialist pathologists, with better agreement on necrosis than cytological grade. There was evidence of consistent individual bias towards over or under scoring cytological grade, which could be corrected with adequate and prompt feedback.

Electrophysiological mapping and ablation of intra-atrial reentry tachycardia after Fontan surgery with the use of a noncontact mapping system.

BACKGROUND: Atrial tachyarrhythmias are a complication of Fontan surgery. Conventional electrophysiological mapping and ablation techniques are limited by the complex anatomic and surgical substrate and a high arrhythmia recurrence rate. This study investigates the use of noncontact mapping to identify arrhythmia circuits and guide ablation in Fontan patients. METHODS AND RESULTS: Eleven arrhythmias were recorded in 6 patients. Noncontact mapping improved recognition of the anatomic and surgical substrate and identified exit sites from zones of slow conduction in all clinical arrhythmias. Radiofrequency linear lesions were targeted across these critical zones in 5 patients. One patient underwent surgical cryotherapy. Although immediate success was achieved in 3 of 5 patients with radiofrequency ablation, 2 patients had a recurrence after a mean of 6.4 months of follow-up. The patient who underwent cryoablation remains free of arrhythmias. CONCLUSIONS: Noncontact mapping can identify arrhythmia circuits in the Fontan atrium and guide placement of ablation lesions. Arrhythmia recurrence is high, possibly because of inadequate lesion creation rather than inaccurate mapping and lesion targeting.

Role of octreotide on release of intact 1-84 parathyroid hormone from human parathyroid cells.

BACKGROUND: Octreotide has been shown to lower urinary calcium in primary hyperparathyroidism although the mechanism remains unclear. This study examined the effect of octreotide on parathyroid hormone (PTH) secretion from human parathyroid cells in culture and as isolated cells. Additionally in situ hybridization was performed for somatostatin receptor messenger RNA (mRNA) and immunocytochemistry for somatostatin in eight parathyroid adenomas. METHODS: Tissue from three hyperplastic glands and three adenomas was studied as dispersed cell suspensions. Incubation was in buffers containing high (2.0 mmol/l) and low (0.5 mmol/l) calcium concentrations, with or without octreotide 200 ng/ml. Cells were also seeded into tissue culture wells for 24 h to allow receptors to regenerate. Supernatant was removed at regular intervals and PTH levels were estimated using a two-site chemiluminescent assay. RESULTS: Mean(s.e.m.) PTH secretion at 90 min in hyperplastic cells was 445(75) pmol/l in low calcium and 160(42) pmol/l in high calcium (P< 0.02), and in adenoma cells was 170(21) pmol/l in low calcium and 137(27) pmol/l in high calcium (P=0.37). There was no significant difference in secretion of PTH from cells incubated with octreotide either in culture or as dispersed cells. In situ hybridization failed to demonstrate any mRNA for the somatostatin receptors and no somatostatin was detected in any cells with immunocytochemistry. CONCLUSION: Somatostatin has no direct action on PTH production and release from human parathyroid cells and is unlikely to be of any therapeutic value in the treatment of hyperparathyroidism.

Evidence of effectiveness of clinical audit in improving histopathology reporting standards of mastectomy specimens.

AIM: To assess the effectiveness of clinical audit in improving standards in histopathological reporting of mastectomy specimens. METHODS: Reports on mastectomy specimens containing tumour issued by non-specialist histopathologists in 1990, 1992, 1994, and 1996 were scored for their information content. There were 10 reports evaluated from each year. Before 1990 no reporting guidelines had been formulated within the department. The audits in 1992 and 1994 were performed after agreed written guidelines (including the establishment of six essential pieces of information), and in 1996 the specimens were reported using a proforma. RESULTS: There was a significant increase in information after the introduction of written guidelines but there was a reduction in information over time. In 1990 none of the 10 reports included all six pieces of mandatory information; in 1992 four of the reports contained all mandatory information; in 1994 only one report contained all mandatory information. The introduction of a proforma for reporting resulted in further significant improvement with all 10 reports in 1996 containing all mandatory information. CONCLUSIONS: Successive rounds of audit increases the standard of reporting in histopathology. There is a need for continuing monitoring of standards as these may deteriorate over time. Reporting complex specimens on a proforma has a significant beneficial effect on information content.

Preliminary single center clinical experience of the use of a new implantable cardioverter defibrillator.

We report a single center's preliminary clinical experience of the Sentinel (Angeion, Minneapolis, MN) implantable cardioverter defibrillator (ICD), which employs novel technologies that offer the potential for significant reduction in ICD size. Thirty-three patients have received Sentinel ICDs with a mean follow-up of 450 (range 150-1023) days. Device shock therapy has been used to defibrillate/cardiovert 43 spontaneous episodes of malignant ventricular arrhythmia and 510 episodes of hemodynamically well tolerated ventricular arrhythmia have been pace-terminated (pace-termination failed in 6 episodes with subsequent delivery of appropriate shock therapy). There has been no arrhythmic death in this patient population. There have been 9 inappropriate shocks in 6 patients (in 2 patients for atrial fibrillation which had satisfied the algorithm detection criteria for high zone ventricular arrhythmia, in 3 for sinus tachycardia [rate greater than 180 beats per min] and in 1 due to device capacitor malfunction). Device replacement has been required for component malfunction in 3 patients. There have been no other major complications. Follow-up time to date is short and longterm device efficacy and performance remain unproven. However, our early clinical experience suggests that the innovations used to manufacture the Sentinel ICD have facilitated reduction in ICD size without compromising therapeutic efficacy.

The clinical behavior of breast carcinoma is probably determined at the preinvasive stage (ductal carcinoma in situ).

BACKGROUND: Mammography has greatly increased the number of women diagnosed with ductal carcinoma in situ (DCIS) of the breast. New classifications of DCIS recently have been proposed. In this study, these classifications were applied to DCIS associated with invasive tumors and correlated with patient prognosis. METHODS: Three hundred cases of infiltrating ductal carcinoma of the breast in which there was associated DCIS in the surrounding breast were studied. The DCIS was classified as well, moderately, or poorly differentiated, according to two recently published systems using the cytonuclear features of the malignant cells (Holland classification) and cytology and the presence of necrosis (Van Nuys classification). RESULTS: The differentiation of DCIS was significantly correlated with the grade of the invasive carcinoma (P < 0.0001), the Nottingham prognostic index (P < 0.0001), and the clinical outcomes of the patients (P < 0.0001). CONCLUSIONS: These findings indicate that a model in which there is increasing in situ dysplasia before the development of stromal invasion is incorrect for breast carcinoma. Rather, in most cases, well-differentiated DCIS probably gives rise to low grade invasive breast carcinoma with a better long term clinical outcome. These data suggest that many of the important prognostic biologic and genetic characteristics of breast carcinoma are already established in the neoplastic clones of malignant cells at the preinvasive stage of the disease.