Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status.

BACKGROUND: There are relatively few articles addressing long-term follow-up in women with breast cancer at very young ages. METHODS: We have updated and extended our population-based analysis of breast cancer diagnosed at the age < or =30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested. Kaplan-Meier curves were generated to assess overall survival, contralateral breast cancer and other second primaries. RESULTS: Survival analysis of all 288 patients showed poor overall survival, although this improved from a 15-year survival of only 46% in those diagnosed between 1980 and 1989 to 58% in those diagnosed between 1990 and 1997 (P=0.05). Contralateral breast cancer rates were at a steady rate of 0.6 per 1000, although the rates in mutation carriers were approximately 2 per 1000. Altogether, 16 BRCA1, 9 BRCA2 and 6 TP53 mutations have now been found among the 115 cases on whom DNA analysis has been performed. BRCAPRO accurately predicted the number of carriers for BRCA1 and BRCA2 and was sensitive and specific at the 10 and 20% threshold, respectively. However, BRCAPRO did not seem to give any weight to DCIS, which accounted for two BRCA1 carriers and three TP53 carriers and overpredicted mutations at the high end of the spectrum, with only 6 of 11 (54%) with a >90% probability having identifiable BRCA1/2 mutations. INTERPRETATION: Rates of new primaries are predicted to some extent by mutation status. BRCAPRO is useful at determining those patients aged < or =30 years to be tested.

Addition of pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 testing.

BACKGROUND: Selection for genetic testing of BRCA1/BRCA2 is an important area of healthcare. Although testing costs for mutational analysis are falling, costs in North America remain in excess of US$3000 (UK price can be 690 pounds). Guidelines in most countries use a 10-20% threshold of detecting a mutation in BRCA1/2 combined within a family before mutational analysis is considered. A number of computer-based models have been developed. However, use of these models can be time consuming and difficult. The Manchester scoring system was developed in 2003 to simplify the selection process without losing accuracy. METHODS: In order to increase accuracy of prediction, breast pathology of the index case was incorporated into the Manchester scoring system based on 2156 samples from unrelated non-Jewish patients fully tested for BRCA1/2, and the scores were adapted accordingly. Results/ DISCUSSION: Data from breast pathology allowed adjustment of BRCA1 and combined BRCA1/2 scores alone. There was a lack of pathological homogeneity for BRCA2, therefore specific pathological correlates could not be identified. Upward adjustments in BRCA1 mutation prediction scores were made for grade 3 ductal cancers, oestrogen receptor (ER) and triple-negative tumours. Downward adjustments in the score were made for grade 1 tumours, lobular cancer, ductal carcinoma in situ and ER/HER2 positivity. Application of the updated scoring system led to four and nine more mutations in BRCA1 being identified at the 10% and 20% threshold, respectively. Furthermore, 65 and 58 fewer cases met the 10% and 20% threshold, respectively, for testing. Moreover, the adjusted score significantly improved the trade-off between sensitivity and specificity for BRCA1/2 prediction.

A British Ophthalmological Surveillance Unit study on serious ocular injuries from fireworks in the UK.

PURPOSE: We conducted a surveillance study to assess the nature, management, and visual outcomes of serious ocular injuries from fireworks in the UK. METHODS: New cases of serious ocular injuries from fireworks were prospectively ascertained through the monthly active surveillance system of the British Ophthalmological Surveillance Unit (BOSU). All ophthalmologists in the UK received a reporting card each month for a 2-year period commencing July 2004. They were asked to indicate any new cases of serious ocular injury from a firework, or to confirm that they had no new cases to report. Information on demographic detail, type of injury, management, and visual outcome was sought through an incident and 6-month follow-up questionnaire. RESULTS: Eighty-one per cent of the injuries occurred in October and November and 27% (13/47) of the patients were less than 18 years old. Twenty-six per cent (12/47) of patients had a penetrating injury, and ocular surgery was required in 53% (25/47) of cases. Eight patients (17%) required enucleation or evisceration and four (9%) required a cosmetic shell for phthisis. At 6-month follow-up, 53% (21/40) of cases had a visual acuity of 6/60 or worse. CONCLUSION: This prospective national survey confirms that firework injuries are an important cause of preventable visual disability particularly to young males. It is likely that such injuries occur year on year and as such represent an important public health concern in addition to the burden placed upon the health service.

Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity.

Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in 'pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset.

The NHS breast screening programme (pathology) EQA: experience in recent years relating to issues involved in individual performance appraisal.

BACKGROUND: The original role of the National Health Service breast screening programme (pathology) external quality assessment (EQA) scheme was educational; it aimed to raise standards, reinforce use of common terminology, and assess the consistency of pathology reporting of breast disease in the UK. AIMS/METHODS: To examine the performance (scores) of pathologists participating in the scheme in recent years. The scheme has evolved to help identify poor performers, reliant upon setting an acceptable cutpoint. Therefore, the effects of different cutpoint strategies were evaluated and implications discussed. RESULTS/CONCLUSIONS: Pathologists who joined the scheme improved over time, particularly those who did less well initially. There was no obvious association between performance and the number of breast cancer cases reported each year. This is not unexpected because the EQA does not measure expertise, but was established to demonstrate a common level of performance (conformity to consensus) for routine cases, rather than the ability to diagnose unusual/difficult cases. A new method of establishing cutpoints using interquartile ranges is proposed. The findings also suggest that EQA can alter a pathologist's practice: those who leave the scheme (for whatever reason) have, on average, marginally lower scores. Consequently, with the cutpoint methodology currently used (which is common to several EQA schemes) there is the potential for the cutpoint to drift upwards. In future, individuals previously deemed competent could subsequently be erroneously labelled as poor performers. Due consideration should be given to this issue with future development of schemes.

Impact of a national external quality assessment scheme for breast pathology in the UK.

BACKGROUND: This article presents the results and observed effects of the UK National Health Service Breast Screening Programme (NHSBSP) external quality assurance scheme in breast histopathology. AIMS/METHODS: The major objectives were to monitor and improve the consistency of diagnoses made by pathologists and the quality of prognostic information in pathology reports. The scheme is based on a twice yearly circulation of 12 cases to over 600 registered participants. The level of agreement was generally measured using kappa statistics. RESULTS: Four main situations were encountered with respect to diagnostic consistency, namely: (1) where consistency is naturally very high-this included diagnosing in situ and invasive carcinomas (and certain distinctive subtypes) and uncomplicated benign lesions; (2) where the level of consistency was low but could be improved by making guidelines more detailed and explicit-this included histological grading; (3) where consistency could be improved but only by changing the system of classification-this included classification of ductal carcinoma in situ; and (4) where no improvement in consistency could be achieved-this included diagnosing atypical hyperplasia and reporting vascular invasion. Size measurements were more consistent for invasive than in situ carcinomas. Even in cases where there is a high level of agreement on tumour size, a few widely outlying measurements were encountered, for which no explanation is readily forthcoming. CONCLUSIONS: These results broadly confirm the robustness of the systems of breast disease diagnosis and classification adopted by the NHSBSP, and also identify areas where improvement or new approaches are required.

The rising cost of glaucoma drugs in Ireland 1996-2003.

BACKGROUND: Glaucoma affects approximately 2% of the population in developed countries and is estimated to affect 67 million people worldwide. The authors investigated the effect of the introduction of new medications on the volume and cost of drugs for glaucoma in two countries, Northern Ireland (NI, population approximately 1.7 million) and the Republic of Ireland (ROI, population approximately 3.9 million) in the 8 years from 1996 to 2003. They also looked at the surgical rates for glaucoma within the same time period for the two countries. METHODS: A retrospective analysis was performed of drug costs, prescribing data, and operation rates for glaucoma in Ireland from January 1996 to December 2003. Information regarding costs and volume were obtained for each type of glaucoma drug and these were then grouped into the glaucoma treatment subsections as found in the British National Formulary. The drug information was obtained from the Central Services Agency in NI and IMS Health in the ROI and included both public and private prescriptions. The information on surgical rates for glaucoma was obtained from the Department of Health and Social Services in NI and the Hospital In-patient Enquiry (HIPE) data national files in the ROI. RESULTS: There was a 30% increase in prescription items for glaucoma in NI and a 59% increase in the ROI from 1996 to 2003. The costs increased more rapidly than the number of items: 227% in the ROI and 78% in NI from January 1996 to December 2003. In the ROI, there was an average 19% year on year increase in costs. In NI, new drugs accounted for 40% of the quantity of prescription items for glaucoma and 63% of the market cost in 2003. In the ROI new drugs accounted for 57% of the quantity and 77% of the market cost for glaucoma in 2003; prostaglandin analogue drugs alone accounted for 53% of the cost. The number of trabeculectomies performed decreased by more than 60% in both countries. CONCLUSION: Volume and cost of glaucoma drugs increased dramatically in both NI and the ROI from 1996 to 2003, probably the result of a combination of changing demographics and a changing approach towards the management of patients with glaucoma and ocular hypertension. In 2003 in the ROI, prostaglandin analogues were the most commonly prescribed class of drug for patients with glaucoma and/or ocular hypertension causing a profound rise in drug expenditure.

Conscious sedation and analgesia for oocyte retrieval during in vitro fertilisation procedures.

BACKGROUND: Various methods of sedation and analgesia have been used for pain relief during oocyte recovery in IVF/ICSI procedures. The choice of agents has also been influenced by quality of analgesia as well as by concern about possible detrimental effects on reproductive outcome. OBJECTIVES: To assess the efficacy of conscious sedation and analgesia versus alternative methods on pregnancy outcomes and pain relief in patients undergoing transvaginal oocyte retrieval. SEARCH STRATEGY: We searched the Specialised Register of the Menstrual Disorders and Subfertility Group, The Central Register of Controlled Trials (CENTRAL) , MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), the National Research Register, and Current Controlled Trials. There was no language restriction. All references in the identified trials and background papers were checked and authors contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials comparing conscious sedation and analgesia versus alternative methods for pain relief during oocyte recovery were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently scanned abstracts of the reports identified by electronic searching to identify relevant papers, extracted data and assessed trial quality. Interventions were classified and analysed under broad categories/strategies of pain relief comparing conscious sedation/analgesia with alternative methods and administration protocols. MAIN RESULTS: Our search strategy identified 390 potentially eligible reports and 12 papers met our inclusion criteria. There were no significant differences in clinical pregnancy rates per woman and patient satisfaction between the methods compared. Women's perception of pain showed conflicting results. Due to considerable heterogeneity, in terms of types and dosages of sedation or analgesia used, and tools used to assess the principal outcomes of pain and satisfaction, a meta-analysis of all the studies was not attempted. Of the three trials which compared the effect of conventional medical analgesia plus paracervical block versus electro-acupuncture plus paracervical block, there was no significant difference in clinical pregnancy rates per woman in the two groups (OR 1.01; 95% CI 0.73 to 1.4). For intra-operative pain score as measured by visual analogue scale (VAS), there was a significant difference (WMD -4.95; 95% CI -7.84 to -2.07), favouring conventional medical analgesia plus paracervical block . There was also a significant difference in intra-operative pain by VAS between patient-controlled sedation and physician-administered sedation (WMD 5.98; 95% CI 1.63 to 10.33), favouring physician -administered sedation. However, as different types and dosages of sedative and analgesic agents were used in these trials, these data should be interpreted with caution. For the rest of the trials, a descriptive summary of the outcomes was presented. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effect of different methods of pain relief when compared with conscious sedation and analgesia used during oocyte recovery. In this review, no one particular pain relief method or delivery system appeared to be better than the other. In future, greater consensus is needed to determine both the tools used to evaluate pain and the timing of pain evaluation during and after the procedure. Pain assessment using both subjective and objective measures may merit consideration. In addition, future trials should include intra- and post-operative adverse respiratory and cardiovascular events as outcomes.

Management and outcome of sight-threatening diabetic retinopathy in pregnancy.

AIMS: To report the management and outcomes of sight-threatening diabetic retinopathy in pregnancy. METHODS: A retrospective review of 8 diabetic females who developed pregnancy related sight-threatening diabetic retinopathy requiring treatment over a 12-year period. RESULTS: In total, 16 eyes of eight patients were included in this series. The mean age of the patients at presentation was 30.75 years +/-3.8 SD and the mean duration of diabetes was 21.0 years +/-5.1 SD. The mean follow-up period was 46.75 months +/-47.2 SD. A total of 87.5% of patients showed progression of diabetic retinopathy during pregnancy, 71% of which were in the sight-threatening proliferative category. In the postpartum period, 81% of patients continued to progress to proliferative diabetic retinopathy, requiring panretinal photocoagulation and multiple other surgical procedures. In all, 69% of eyes retained visual acuity equal to or better than 0.3 logMAR units (6/12). CONCLUSION: Sight-threatening diabetic retinopathy in pregnancy is a rare disease, but it can have devastating consequences for mother and child. Laser photocoagulation should be considered for pregnant women with severe preproliferative diabetic retinopathy. Proliferative diabetic retinopathy may not regress postpartum. Close followup should be extended in the postpartum period in this group of patients until the retinopathy is stabilised. The presence of combined rhegmatogenous and tractional retinal detachment and neovascular glaucoma were associated with the worst outcome.

Management of endophthalmitis with retained intraocular foreign body.

AIMS: To assess the impact of primary injection of intravitreal antibiotics and delayed pars plana vitrectomy with removal of intraocular foreign body (IOFB) in patients with clinical features of bacterial endophthalmitis and retained IOFB. METHODS: Retrospective review of all patients with clinical features of infective endophthalmitis and a retained IOFB who had immediate injection of intravitreal antibiotics and delayed pars plana vitrectomy with removal of IOFB in two vitreo-retinal centres during 1995-2001. Nine patients were identified and minimum follow-up was 3 months. RESULTS: Four of the nine patients had a final visual outcome of 6/18 or better. One patient developed total retinal detachment. CONCLUSIONS: The current series suggests that immediate injection of intravitreal antibiotics with delayed removal of IOFB in eyes with clinical features of infective endophthalmitis and a retained IOFB is a possible alternative to immediate removal of IOFB. This management may be associated with preservation of the eye and restoration of useful visual acuity.

Serious eye and adnexal injuries from fireworks in Northern Ireland before and after lifting of the firework ban--an ophthalmology unit's experience.

BACKGROUND/AIMS: To report serious fireworks-related eye and adnexal injuries presenting to the Department of Ophthalmology in the Royal Victoria Hospital, Belfast. To assess the effect of lifting of the legislative ban on fireworks in Northern Ireland in 1996. METHOD: Twelve year retrospective review from 1990 to 2001 inclusive of all ocular and adnexal injuries from fireworks requiring hospitalisation to the ophthalmology department. RESULTS: Twenty three patients with 23 injured eyes were reported. Six were female. The mean age was 18 years (+/- 13 SD). Six patients presented between the years 1990 and 1995. The remaining 17 patients presented between 1996 and 2001. Nearly half of the patients required ophthalmic surgical procedures. Thirty-six percent of patients had a final visual acuity of 6/60 or less. Superficial trauma not requiring hospitalisation was not included. CONCLUSION: Removal of the legislative ban on fireworks in 1996 has had a significant effect on the incidence of eye injuries. These injuries are potentially preventable with stricter control on the availability of fireworks and a greater awareness of the ocular risks they pose.

Penetrating ocular injuries from fish-hooks.

PURPOSE: To report four cases of penetrating ocular injuries from fish-hooks. METHODS: The case records of four patients who attended the ophthalmology department with ocular fish-hook injuries were reviewed. RESULTS: Individuals were male, between the ages of 9 and 67. All cases had anterior segment involvement and the hooks were extracted by backing them out through the primary incision. Final visual outcomes were 6/12 or better. CONCLUSIONS: These results suggest that a good visual outcome can be achieved with the less published back-out method of fish-hook extraction. Obviously the technique of choice used for removal of the hook will vary depending on the case and perhaps more important than the method of hook extraction is the need for prompt surgical repair.

Mechanism underlying diuretic effect of L-NAME at a subpressor dose.

The diuretic effects of nitric oxide (NO) synthase inhibitors administered at subpressor dose in rats are controversial, and the tubular segments involved are not known. In the present study, we examined the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subpressor dose on renal interstitial NO and cGMP activity and on renal tubular segmental reabsorption of fluid in the rat. Intravenous infusion of L-NAME at 1 microg. kg(-1). min(-1) in Sprague-Dawley rats (N = 8), which did not alter mean arterial pressure or glomerular filtration rate, significantly increased urine flow rate (U(v); from 78.2 +/- 12.7 to 117.1 +/- 14.9 microl/min, P < 0.05). Paradoxically, this effect of L-NAME was concomitant with significant increases in nitrite/nitrate (from 10.79 +/- 1.20 to 16.50 +/- 2.60 microM, P < 0.05) and cGMP (from 0.65 +/- 0.09 to 0.98 +/- 0.18 nM, P < 0.05) concentrations in renal cortical microdialysate as well as the nitrite/nitrate concentration in the medullary microdialysate. Micropuncture studies in the superficial nephron revealed that L-NAME significantly increased the flow rate (from 8.3 +/- 0.9 to 12.2 +/- 1.2 nl/min, P < 0.05) and fractional delivery of fluid to the distal tubule, but not those in the late proximal tubule. In conclusion, L-NAME, at the subpressor dose used in this study, increased renal nitrate/nitrite and cGMP and inhibited fluid reabsorption in tubular segments between the late proximal tubule and the distal tubule of superficial nephrons.

Role of plasma renin activity and the renal nerves in the natriuresis of L-NMMA infusion in rats.

The objective of this study was to determine the effect of N(G)-monomethyl-L-arginine (L-NMMA) infusion on plasma renin activity (PRA) in the presence or absence of the renal nerves in normotensive Wistar-Kyoto (WKY) rats and Okamoto spontaneously hypertensive rats (SHR). All rats were unilaterally nephrectomized two weeks before the acute experiment. On the day of the experiment, acute renal denervation (Dnx) of the remaining kidney was performed in one group of WKY rats (Dnx-WKY; n= 10) and one group of SHRs (Dnx-SHR: n=7). The renal nerves were left intact in a group of WKY rats (Inn-WKY; n=8) and SHRs (Inn-SHR; n=9). After a control clearance period, L-NMMA was administered i.v. (15 mg/kg bolus followed by 500 microg/kg/min infusion) and another clearance period of 20 min was taken. In all experimental groups L-NMMA infusion resulted in a significant natriuresis. L-NMMA infusion increased fractional excretion of sodium (FE(Na)) to a greater extent in the Inn-SHR than in the Inn-WKY (delta FE(Na) = 5.23+/-0.87% vs delta FE(Na) = 2.87+/-0.73% respectively; P=0.05), PRA did not change in the SHR with the infusion of L-NMMA. However, in the Inn-WKY group, the natriuresis of L-NMMA infusion was associated with a tendency for lower PRA levels as compared to a group of time control Inn-WKY rats. In Dnx-WKY, the natriuresis of L-NMMA infusion (delta FE(Na) = 4.60+/-0.52%) was associated with a significantly lower level of PRA (4.26+/-1.18 ng AI/ml/hr) as compared to a group of time control Dnx-WKY rats (9.83+/-1.32 ng AI/ml/hr; P<0.05). In the Dnx-SHR, the natriuretic response to L-NMMA infusion was significantly attenuated by renal denervation (delta FE(Na) = 2.36+/-0.34%) and PRA was unchanged. In conclusion, the natriuretic effect of systemic inhibition of nitric oxide (NO) synthesis was associated with decreased PRA in the Dnx-WKY suggesting that a potential interaction exists between NO and the renal nerves in the modulation of PRA in the normotensive WKY rat. Whereas, the natriuretic effect of L-NMMA infusion in the SHR in the presence and absence of the renal nerves, were independent of changes in PRA.

Intrarenal serotonin, dopamine, and phosphate handling in remnant kidneys.

BACKGROUND: Serotonin (5-HT) and dopamine (DA) are intrarenal autocrine/paracrine substances that regulate phosphate reabsorption. The present studies explored intrarenal serotonin and DA metabolism and the implications for phosphate homeostasis in rats with remnant kidneys, a model for renal failure. METHODS: The intrarenal productions of serotonin and DA were determined from measurements of renal interstitial fluid (microdialysate) and urine in rats with remnant or intact kidneys. In clearance studies, the effects of infusion of methiothepin, a serotonin receptor antagonist, or gludopa, a renal selective DA precursor, on phosphate and sodium excretion were determined in rats with a remnant or intact kidneys. RESULTS: Renal interstitial serotonin (5-HT, 3.4 +/- 0.9 pg/min) was fourfold higher than DA (0.6 +/- 0.1 pg/min) in remnant kidneys. Conversely, urinary excretion of serotonin was fourfold less than DA in rats with a remnant kidney (5-HT 0.4 +/- 0.02 vs. DA 1.5 +/- 0.1 ng/min). Infusion of methiothepin or gludopa significantly increased the fractional excretion of phosphate (FE(Pi)) in rats with a remnant kidney from 54 +/- 3 to 67 +/- 7% (P < 0.05) and from 36 +/- 10% to 51 +/- 13% (P < 0.05), respectively. CONCLUSION: We conclude that serotonin preferentially accumulates in the renal interstitium, whereas DA exits primarily via the tubular lumen. Phosphate excretion is increased by both the acute infusion of the serotonin receptor antagonist and the infusion of gludopa, suggesting that both serotonin and DA modulate phosphate excretion in rats with remnant kidneys.