Enhancing clinical decision support with genomic tools in breast cancer: A Scottish perspective.

INTRODUCTION: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice. MATERIALS & METHODS: Pan-Scotland study between August 2018-August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. RESULTS: Chemotherapy treatment was strongly influenced by the RS (p < 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p < 0.001). Increasing grade was also associated with high RS (OR 3.81, p < 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p < 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis. CONCLUSIONS: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland. It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate.

Variation in chemotherapy prescribing rates and mortality in early breast cancer over two decades: a national data linkage study.

BACKGROUND: Regional variation in clinical practice may identify differences in care, reveal inequity in access, and explain inequality in outcomes. The study aim was to measure geographical variation in Scotland for adjuvant chemotherapy use and mortality in early-stage breast cancer. PATIENTS AND METHODS: In this retrospective cohort study using population cancer registry-based data linkage, patients with surgically treated early breast cancer between 2001 and 2018 were identified from the Scottish Cancer Registry. Geographical regions considered were based on NHS Scotland organisational structure including 14 territorial Health Boards as well as three regional Cancer Networks. Regional variation in the proportion receiving chemotherapy, breast cancer mortality and all-cause mortality was investigated. Inter-regional comparisons of chemotherapy use were adjusted for differences in case mix using logistic regression. Comparison of breast cancer-specific mortality and all-cause mortality used regression with a parametric survival model. Time trends were assessed using moving average plots. RESULTS: Chemotherapy use ranged from 35% to 46% of patients across Health Boards without adjustment. Variation reduced between 2001 and 2018. Following adjustment for clinical case mix, variation between cancer networks was within 3 percentage points, but up to 10 percentage points from the national average in some Health Boards. Differences in breast cancer mortality and all-cause mortality between cancer networks were modest, with hazard ratios of between 0.933 (95% confidence interval 0.893-0.975) and 1.041 (1.002-1.082) compared with the national average. Survival improved over the time period studied. CONCLUSION: With adequate case mix adjustment, variation in adjuvant chemotherapy use for early breast cancer in Scotland is small, with a trend towards greater convergence in practice and improved mortality outcomes in more recent cohorts. This suggests very limited regional inequity in access and convergence of clinical practice towards risk-stratified treatment recommendations. Outliers require assessment to understand the reasons for variance.

Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas.

BACKGROUND: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy. METHODS: Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations. RESULTS: We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin. CONCLUSIONS: In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.

Early clinical experience with the Anaconda re-deployable endograft in 106 patients with abdominal aortic aneurism: the west of Scotland Anaconda registry.

Endovascular repair of abdominal aortic aneurysm is a common procedure and not without complications. The aim of this study was to evaluate the early results of the Anaconda endograft (Vascutek Ltd., Inchinnan, Scotland, UK) in 106 patients in three hospitals in the west of Scotland. A prospective registry of 106 consecutive patients undergoing endoluminal repair of their abdominal aortic aneurysms using the Anaconda device was set up to record the clinical outcomes, with a mean follow-up of two years. There was no 30-day perioperative mortality in the 106 patients. Only type II endoleaks were detected on serial computed tomography scanning at follow-up. Technical success was achieved in 99% (105/106) in this study; one patient was converted to open surgical repair. Two cases of proximal device migration (>1 cm) were detected at one month and 19 months, respectively, with no associated endoleak or sac enlargement. Five cases of endograft limb thrombosis were noted in this study. Our early clinical experience with the Anaconda endograft compares favourably with other commercially available endografts in the treatment of abdominal aortic aneurysms. The main advantages of this device are that it is re-deployable and that it has a magnetic wire system which makes it easy to implant.

Epstein-Barr virus, B cell lymphoproliferative disease, and SCID mice: modeling T cell immunotherapy in vivo.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) arises in up to 10% of organ transplant recipients and is fatal in ∼50% of cases. PTLD can be modeled in SCID mice using EBV+ve human B lymphoblastoid cell lines (BLCLs), and the current study investigated intraperitoneal (ip) inoculation of such animals in experiments which assessed the effect of EBV-specific cytotoxic T lymphocytes (CTLs) and cytokines on PTLD growth. Ip transfer of one dose of autologous CTLs, or CD8-enriched T cells, into ip BLCL-inoculated animals significantly delayed tumor development (P = 0.001) and prevented tumor formation in a significant proportion (40%) of mice (P = 0.001). A combination of interleukin (IL)2, 7, and 15 conditioning of CTLs prior to ip injection significantly delayed ip BLCL-derived tumor formation in vivo when compared to CTLs expanded in vitro using only IL2 (P = 0.04) and prevented tumor outgrowth in a significant proportion (60%) of mice (P = 0.02). Daily ip IL2 dosing of ip CTL-inoculated mice significantly delayed tumor development in vivo (P = 0.004) and prevented tumor outgrowth in a significant proportion (78%) of mice (P = 0.02) when compared to animals dosed with vehicle only. In SCID mice, autologous CTLs, and CD8-enriched T cells, have significant capacity to hinder development of PTLD-like tumors. Whilst studies are needed to delineate the role of cytokine conditioning and CD4-enriched T cells, the results suggest that IL2 plays a key role in supporting CTL funtion in vivo.

Immunization information systems progress - United States, 2005.

Immunization registries are confidential, computerized information systems that collect and consolidate vaccination data from multiple health-care providers, generate reminder and recall notifications, and assess vaccination coverage within a defined geographic area. A registry with added capabilities, such as vaccine management, adverse event reporting, lifespan vaccination histories, and linkages with electronic data sources, is called an immunization information system (IIS). This report summarizes data from CDC's 2005 Immunization Information System Annual Report (IISAR), a survey of grantees in 50 states, five cities, and the District of Columbia (DC) that receive funding under section 317b of the Public Health Service Act. These data indicated that approximately 56% of U.S. children aged <6 years participated in an IIS, an increase from 48% in 2004. Moreover, 75% percent of public vaccination provider sites and 44% of private vaccination provider sites submitted vaccination data to an IIS during July-December 2005. These findings underscore the need to increase the number of participating children, from the current 13 million to approximately 21 million, to assure 95% participation of children aged <6 years and improve the effectiveness of U.S. immunization programs.

Variability in concentrations of potentially toxic elements in urban parks from six European cities.

Use of a harmonised sampling regime has allowed comparison of concentrations of copper, chromium, nickel, lead and zinc in six urban parks located in different European cities differing markedly in their climate and industrial history. Wide concentrations ranges were found for copper, lead and zinc at most sites, but for chromium and nickel a wide range was only seen in the Italian park, where levels were also considerably greater than in other soils. As might be expected, the soils from older cities with a legacy of heavy manufacturing industry (Glasgow, Torino) were richest in potentially toxic elements (PTEs); soils from Ljubljana, Sevilla and Uppsala had intermediate metal contents, and soils from the most recently established park, in the least industrialised city (Aveiro), displayed lowest concentrations. When principal component analysis was applied to the data, associations were revealed between pH and organic carbon content; and between all five PTEs. When pH and organic carbon content were excluded from the PCA, a distinction became clear between copper, lead and zinc (the "urban" metals) on the one hand, and chromium and nickel on the other. Similar results were obtained for the surface (0-10 cm depth) and sub-surface (10-20 cm depth) samples. Comparisons with target or limit concentrations were limited by the existence of different legislation in different countries and the fact that few guidelines deal specifically with public-access urban soils intended for recreational use.

Colorectal stenting for colonic obstruction: the indications, complications, effectiveness and outcome--5 year review.

INTRODUCTION: Currently self-expanding metallic stents are being used for palliation and acute decompression of colonic obstruction. The aim of this study is to review our experience of using these metallic stents over a 5-year period. MATERIALS AND METHODS: Case records of 102 patients who had colorectal stenting between 1998 and 2004 were reviewed retrospectively. The indications for colorectal stenting, efficacy of the procedure in relieving the obstruction, complications and clinical outcome were analysed. RESULTS: Ninety-nine patients had malignant disease and in three patients a benign cause of obstruction was demonstrated. All procedures were performed during normal working hours. Stenting was technically successful in 87 patients (85%). A single stent was placed in 80 patients. Seven patients required two stents. Of the successful cases, 67 had stents placed by fluoroscopy alone and 20 by a combined fluoroscopy/endoscopy procedure. Four percent had early complications (within 30 days) which included four perforations. There were late complications (over 30 days) in 9% which included five stent migrations, two blocked stents and one colovesical fistula. Ninety percent (n=76) of the successful patients needed no further radiological or surgical intervention later. Survival ranged from 14 days to 2 years. CONCLUSION: Colorectal stenting when technically successful is an effective procedure for both preoperative and palliative decompression of colonic obstruction.

Mercury in urban soils: a comparison of local spatial variability in six European cities.

The objective of this study was to quantify and assess for the first time the variability of total mercury in urban soils at a European level, using a systematic sampling strategy and a common methodology. We report results from a comparison between soil samples from Aveiro (Portugal), Glasgow (Scotland), Ljubljana (Slovenia), Sevilla (Spain), Torino (Italy) and Uppsala (Sweden). At least 25 sampling points (in about 4-5 ha) from a park in each city were sampled at two depths (0-10 and 10-20 cm). Total mercury was determined by pyrolysis atomic absorption spectrometry with gold amalgamation. The quality of results was monitored using certified reference materials (BCR 142R and BCR 141R). Measured total mercury contents varied from 0.015 to 6.3 mg kg(-1). The lowest median values were found in Aveiro, for both surface (0-10 cm) and sub-surface (10-20 cm) samples (0.055 and 0.054 mg kg(-1), respectively). The highest median mercury contents in soil samples were found in samples from Glasgow (1.2 and 1.3 mg kg(-1), for surface and sub-surface samples, respectively). High variability of mercury concentrations was observed, both within each park and between cities. This variability reflecting contributions from natural background, previous anthropogenic activities and differences in the ages of cities and land use, local environmental conditions as well as the influence of their location within the urban area. Short-range variability of mercury concentrations was found to be up to an order of magnitude over the distance of only a few 10 m.

Anaesthetic implications of uterine artery embolisation in management of massive obstetric haemorrhage.

The latest triennial report on maternal deaths has recommended the consideration of uterine artery embolisation in management of cases of massive obstetric haemorrhage. We have been using interventional radiology to manage both expected and unanticipated postpartum bleeding in our centre. Three case reports are presented to highlight the value of this technique and issues relating to the anaesthetic and postoperative management of these patients are discussed.

Rupture of tuberculous spinal abscess resulting in tuberculous empyema and chylothorax.

STUDY DESIGN: Case report with a review of scientific literature. OBJECTIVE: To describe the course of tuberculous spinal disease (Pott's disease) complicated by pyogenic and tuberculous empyema, and chylothorax as there has been an increase in the numbers of notified cases of tuberculosis in the UK(1). To the best of our knowledge, a similar case has not been reported previously in the UK, although there has been a report of bilateral chylothorax associated with Pott's disease. SETTING: A national spinal injuries unit in a Scottish university teaching hospital. METHODS: Review of literature on the chemotherapy of spinal tuberculosis and the role of streptokinase in the treatment of empyema and the relation between spinal tuberculosis, empyema and chylothorax. RESULTS: Although spinal tuberculosis was recognised and treated appropriately with chemotherapy, the patient sustained pleural involvement with later development of both empyema and chylothorax. CONCLUSION: The case highlights the difficulties in the treatment of tuberculosis of the spine inspite of the presence of fully sensitive organisms and early institution of appropriate chemotherapy. In the absence of surgical debridement, the duration and dosage of chemotherapy as practised in the initial period may have to be prolonged into the continuation phase. The thoracic duct can be damaged either because of extension of the tuberculosis itself or because of instillation of intrapleural streptokinase for treatment of pleural empyema leading to chylothorax. There is a need for randomised trials of intrapleural streptokinase treatment in tuberculous empyema.

Mediastinal chest sump tubes following cardiac surgery: an unconventional method.

The practice of using conventional mediastinal chest tubes (MCTs) connected to a closed collection device is commonplace in cardiovascular surgery care settings. The MCT collection device requires a closed system to maintain a negative intrathoracic pressure with the goal of preventing inadvertent trapping of air and blood within the mediastinal space. Despite the proposed integrity of the closed system, there is no guarantee that the suction's negative pressure will prevent cardiac tamponade. In addition, it has been postulated that the required negative intrathoracic suction may potentiate mediastinal tissue damage. This clinical paper will describe the use of multi-lumen MCTs open to atmosphere following surgical repair for congenital heart defects. It is postulated that open MCTs may potentially reduce the risks of cardiac tamponade and mediastinal tissue damage. Through case presentation, the mechanics of open MCTs, nursing care, and possible complications will be delineated.

Continuous venous hemodiafiltration with trisodium citrate anticoagulation in cardiac surgery patients.

Despite advances in perioperative organ protection during cardiovascular surgery, acute renal failure remains a serious complication. The purpose of this clinical article is to describe the role of continuous renal replacement therapy (CRRT) in proactive maintenance of fluid and electrolyte balance and treatment of acute renal failure in patients following cardiovascular surgery. Implications for nursing practice, education, and future research will be delineated using a case study of a patient who required mechanical circulatory support and CRRT. The complexity of the patient's care was compounded by the need to alter conventional anticoagulation therapy to trisodium citrate.

Purification and characterization of pyruvate kinase from Schizosaccharomyces pombe: evidence for an unusual quaternary structure.

Earlier attempts to purify and characterize nonrecombinant pyruvate kinase from Schizosaccharomyces pombe proved difficult due to problems associated with the instability of the protein. The enzyme has been overexpressed in Saccharomyces cerevisiae strain AH22, permitting studies to determine the conditions required to stabilize the enzyme during purification. Recombinant S. pombe pyruvate kinase was purified by a combination of ion-exchange chromatography and gel filtration. The purified enzyme showed sigmoidal kinetics with respect to PEP; in the presence of FBP, the kinetics were restored to Michaelis-Menten behavior. With respect to ADP, the Hill coefficient was not affected by FBP. Determination of the molecular mass of the purified enzyme by ultracentrifugation showed that it behaved as a dimer-tetramer system with a Kd of approximately 1 microM.

Isotype-specific antibody responses to the surface-exposed antigens of adult and larval stages of Dictyocaulus viviparus in infected and vaccinated calves.

The antibody responses to the surface-exposed antigens of living larval and adult Dictyocaulus viviparus were measured by quantitative immunofluorescence using sera from calves infected with, or vaccinated against, the parasite. In infected animals, the surface of the sheath of the third-stage larvae (L3) (retained cuticle of second-stage larvae (L2)) proved highly immunogenic despite the fact that it is thought to be shed prior to parasite penetration of the host intestine. When responses to the surface of exsheathed larvae (L3 cuticle) were measured, a high level of heterophile IgM antibody was detected in the serum of animals that had not been previously exposed to the parasite and, following infection, a specific IgG response was detected against the exsheathed L3 surface. The antibody response, however, was less marked than that observed against the intact L3 sheath. Responses of patently infected animals to the adult surface showed an initial IgM response that was superseded with time by IgG1 and IgG2 responses. Vaccinated animals showed only low level responses to the surfaces of the L3 sheath, L3 cuticle and adult stages following immunisation with two doses of irradiated larvae. The immunised animals produced a strong antibody response to the larval surface antigens following challenge with infective larvae but they failed to produce antibody to the surface of adult parasites. These results show that the surfaces of all the stages of D. viviparus examined are immunogenic in infected calves and, depending on the developmental stage, infection regime, or time of infection, high levels of parasite-specific IgG1 or IgM are stimulated. It has previously been shown that significant levels of protective immunity can be obtained in naive animals following passive transfer of serum from infected calves. Thus, the antibody responses detected in the work reported here may be of relevance in protective immunity against dictyocaulosis.

Epidemiological aspects of lungworm infections of goats in Morocco.

The results of a survey of lungworm infections in goats in the Middle Atlas and Rabat areas in Morocco during 1990-1992 are reported. Five species were recorded: Dictyocaulus filaria, Protostrongylus rufescens, Cystocaulus ocreatus, Muellerius capillaris and Neostrongylus linearis. The parasitological profile of protostrongylid species was represented by Muellerius (69-78%), Protostrongylus (16-25%) and Cystocaulus (5-6%) in the Rabat and Middle Atlas areas. Neostrongylus was virtually non-existent (under 1%) in both regions. Multigeneric infection involving several species of lungworms reached 54% in Rabat and 88% in Middle Atlas. Dictyocaulus infection of goats does not appear to be a serious problem. Infection rates of 40% and 50%, and average worm burdens of three and five worms per kid and adult goat were recorded in autumn in the Rabat area. A similar pattern was noted in Middle Atlas. In contrast, the incidence of small lungworm infections in goats is widespread at levels likely to be of economic significance. The level of infection was considerably higher than the Dictyocaulus infection and the infection rate was virtually 100% in both age groups in the two areas. The overall worm burdens averaged 77.03 +/- 22.6 parasites per adult goat and 44.16 +/- 16.3 per kid in the Rabat area, whereas the corresponding figures in Middle Atlas were 51.48 +/- 16.65 and 34.06 +/- 2.69 worms. The periods of high risk of infection by small lungworms were autumn, early winter and late spring-early summer. However, the heaviest infection by adult worms and the highest larval excretion were observed in late autumn and winter when molluscs were heavily infected. The periparturient period seemed to exert a positive influence on protostrongylid larval production. The output of first stage larvae (L1) of lungworms was significantly higher in goats than in sheep. Thus, goats may play a greater role in pasture contamination. The epidemiological factors influencing the seasonal fluctuations of lungworms are discussed and a timetable of recommended treatments is suggested.

Stage-specific surface antigens of the cattle lungworm Dictyocaulus viviparus.

Immunofluorescence on live Dictyocaulus viviparus parasites revealed a significant antibody response by vaccinated and patently infected bovine hosts to the sheath of infective larvae (L3), a structure which is generally thought to be shed from the parasite surface prior to invasion of host tissue. In contrast, surface-exposed antigens of the adult, egg and pulmonary L1 stages were recognized only by serum antibody from calves exposed to a patient lungworm infection. Radioiodination of sheathed L3 identified a restricted set of components while a more complex pattern of labelled material was observed with adult parasites. Many more components of adult worms were labelled by the Bolton-Hunter than by the Iodogen reagent, probably reflecting the more penetrative labelling propensities of the former. Stage-specificity of surface-associated antigens of adult parasites was demonstrated by their immunoprecipitation by antibody from patently-infected, but not from vaccinated, calves. There was no in vitro release of the major iodinatable surface-associated antigens of adult parasites not any binding of antibody raised against adult excretory-secretory (ES) products to the surface of living adult worms, suggesting that surface components do not contribute to adult ES products in this species. Antibody responses to the surface of adults, L1 and eggs were specific to patently-infected animals and may provide a useful indicator of exposure to patent infection.