Implementing nitrous oxide cracking technology in the labour ward to reduce occupational exposure and environmental emissions: a quality improvement study.

Nitrous oxide, a potent greenhouse gas, is a common labour analgesic. One method which may reduce its carbon footprint is to 'crack' the exhaled gas into nitrogen and oxygen using catalytic destruction. In this quality improvement project, based on environmental monitoring and staff feedback, we assessed the impact of nitrous oxide cracking technology in the maternity setting. Mean ambient nitrous oxide levels were recorded during the final 30 minutes of uncomplicated labour in 36 cases and plotted on a run chart. Interventions were implemented in four stages, comprising: stage 1, baseline (12 cases); stage 2, cracking with nitrous oxide delivered and scavenged via a mouthpiece (eight cases); stage 3, cracking with nitrous oxide via a facemask with an air-filled cushion (eight cases); stage 4, cracking with nitrous oxide via a low-profile facemask, and enhanced coaching on the use of the technology (eight cases). The median ambient nitrous oxide levels were 71% lower than baseline in stage 2 and 81% lower in stage 4. Staff feedback was generally positive, though some found the technology to be cumbersome; successful implementation relies on effective staff engagement. Our results indicate that cracking technology can reduce ambient nitrous oxide levels in the obstetric setting, with potential for reductions in environmental impacts and occupational exposure.

Tetraspanins CD9 and CD151, epidermal growth factor receptor and cyclooxygenase-2 expression predict malignant progression in oral epithelial dysplasia.

BACKGROUND: Prognostic biomarkers aim to improve on the current inadequate method of histological assessment to identify patients with oral epithelial dysplasia at greatest risk of malignant transformation. We aimed to assess the prognostic ability of six protein biomarkers linked to the epidermal growth factor receptor (EGFR) pathway, including three tetraspanins, in a large multicentre oral dysplasia cohort. METHODS: One hundred and forty-eight cases with varying degrees of epithelial dysplasia underwent immunohistochemical assessment for CD9, CD151, CD82, EGFR, Her-2, and COX-2. Scoring was performed independently by two observers. Univariate analyses using both logistic and Cox regression models and a multivariate regression were performed. RESULTS: Malignant progression was significantly greater in those cases with decreased expression of CD9 (P=0.02), and increased expression of CD151 (P=0.02), EGFR (P=0.04), and COX-2 (P=0.003). Histological grade (P=0.0002) and morphology (P=0.03) were also prognostic, whereas smoking and alcohol were not. The optimal combination by backward-variable selection was of histological grade (hazard ratio (HR) 1.64; 95% CI 1.12, 2.40), COX-2 overexpression (HR 1.12; 1.02, 1.24) and CD9 underexpression (HR 0.88; 0.80, 0.97). CD82 and Her-2 demonstrated no prognostic ability. CONCLUSION: This is the first study of the expression and prognostic potential of the tetraspanins in oral dysplasia. A combination of certain biomarkers with clinical factors appeared to improve the accuracy of determining the risk of malignancy in individuals with oral dysplasia. These findings may also offer potential new therapeutic approaches for this condition.

Simulation-based training in obstetric anesthesia: an update.

In this update we explore the current applications of simulation in obstetric anesthesia, describe what is known regarding its impacts on care and consider the different settings in which simulation programs are required. We will introduce practical strategies, such as cognitive aids and communication tools, that can be applied in the obstetric setting and share ways in which a program might apply these tools. Finally, we provide a list of common obstetric emergencies essential for a program's curriculum and common teamwork pitfalls to address within a comprehensive obstetric anesthesia simulation program.

In Our Own Words: The Complex Sensory Experiences of Autistic Adults.

Autistic adults commonly experience sensory reactivity differences. Sensory hyperreactivity is frequently researched, whilst hyporeactivity and seeking, and experiences across domains, e.g., vision, are often neglected. Therefore, we aimed to understand more about the sensory experiences of autistic adults. We conducted a mixed-methods study, co-produced with stakeholders; recruiting 49 autistic adults who completed an online survey. Firstly, quantitative results and content analysis enhanced our understanding of sensory input/contexts associated with sensory hyperreactivity, hyporeactivity, and seeking across modalities. Secondly, thematic analysis developed themes relating to 'Outcomes', 'Control', 'Tolerance and management', and 'The role of other people', informing a theoretical model of sensory reactivity differences in autistic adults. These findings have implications for support services and improving quality of life for autistic adults.

Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer.

INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.

A pan-Canadian prospective study of young women with breast cancer: the rationale and protocol design for the RUBY study.

Introduction: The understanding of the biology and epidemiology of, and the optimal therapeutic strategies for, breast cancer (bca) in younger women is limited. We present the rationale, design, and initial recruitment of Reducing the Burden of Breast Cancer in Young Women (ruby), a unique national prospective cohort study designed to examine the diagnosis, treatment, quality of life, and outcomes from the time of diagnosis for young women with bca. Methods: Over a 4-year period at 33 sites across Canada, the ruby study will use a local and virtual recruitment model to enrol 1200 women with bca who are 40 years of age or younger at the time of diagnosis, before initiation of any treatment. At a minimum, comprehensive patient, tumour, and treatment data will be collected to evaluate recurrence and survival. Patients may opt to complete patient-reported questionnaires, to provide blood and tumour samples, and to be contacted for future research, forming the core dataset from which 4 subprojects evaluating genetics, lifestyle factors, fertility, and local management or delivery of care will be performed. Summary: The ruby study will be the most comprehensive repository of data, biospecimens, and patient-reported outcomes ever collected with respect to young women with bca from the time of diagnosis, enabling research unique to that population now and into the future. This research model could be used for other oncology settings in Canada.

Platelet-activating factor in the CNS.

Platelet-activating factor (PAF) is a phospholipid synthesized in a variety of cells throughout the body. Platelet-activating factor has been identified in the CNS and has a number of diverse physiological and pathological functions. It has been shown to be a modulator of many CNS processes, ranging from long-term potentiation (LTP) to neuronal differentiation. Excessive levels of PAF appear to play an important role in neuronal cell injury, such as that resulting from ischaemia, inflammation, human immunodeficiency syndrome (HIV) and meningitis. The beneficial effects of PAF receptor antagonists are many and give rise to possible therapeutic strategies for neurotrauma.

Adrenalectomy-induced neuronal degeneration.

The binding of glucocorticoids to CNS receptors results in the modulation of many processes, ranging from neurotransmission to cell birth and death. It is of no surprise, therefore, that the removal of these steroids following adrenalectomy disrupts a variety of physiological functions throughout the brain. It is the aim of this review to briefly describe the findings of research examining some of these glucocorticoid-mediated CNS effects; however, as many of these areas have been reviewed extensively by others, this review will focus on the recently described phenomenon, adrenalectomy-induced hippocampal cell death.

Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment.

We have investigated the ability of tamoxifen to regulate members of the transforming growth factor beta (TGF-beta) family in human breast cancers in vivo. Using immunohistochemical techniques, we find that 3 months of tamoxifen treatment causes a consistent induction of extracellular TGF-beta 1 in breast cancer biopsies, compared with matched pretreatment samples from the same patient. The induced TGF-beta is localized between and around stromal fibroblasts and appears to be derived from these cells. Lower levels of TGF-beta 1,-beta 2, and -beta 3 seen in epithelial cells were not altered by tamoxifen treatment. The increased stromal staining of TGF-beta 1 occurred in estrogen receptor-negative as well as estrogen receptor-positive tumors. These results provide in vivo evidence for a novel, estrogen receptor-independent mechanism of action for tamoxifen, involving the stromal induction of a potent growth inhibitor for epithelial cells.

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype.

PURPOSE: To assess the results of treatment with the purine analog 2'deoxycoformycin (pentostatin [DCF]) in patients with postthymic T-cell malignancies. PATIENTS AND METHODS: One hundred forty-five patients with postthymic T-cell malignancies were given DCF intravenously at 4 mg/m2/wk for the first 4 weeks and then every 2 weeks until maximal response; the last 30 patients received weekly injections until maximal response. RESULTS: The overall response rate was 32% (complete responses [CRs] plus partial responses [PRs]), with marked variation according to diagnosis. The best responses occurred in patients with Sézary syndrome (62%) and T-prolymphocytic leukemia (T-PLL) (45%), with CRs in three of 16 Sézary syndrome and five of 55 T-PLL patients. In contrast, no responses (NRs) were documented in 13 patients with other types of cutaneous T-cell lymphoma, including five mycosis fungoides. Two of five patients with large granular lymphocyte (LGL) leukemia had a CR and two of four with Sézary cell leukaemia had a PR. A low response rate was observed in 27 patients with peripheral T-non-Hodgkin's lymphoma (T-NHL) (19%) and in 25 with adult T-cell leukemia/lymphoma (ATLL) (12%). The latter included two CRs and one PR. Toxicity was low and DCF was generally well tolerated. No significant differences were observed when results were analyzed according to previous treatment. Disease subtype was the most important factor to influence results. CONCLUSION: We conclude that DCF is effective as a single agent in T-PLL, Sézary syndrome, and LGL leukemia, but has low activity in other T-cell disorders.

LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial.

PURPOSE: The purpose of this randomized trial was to compare the efficacy of eight cycles of chlorambucil, vincristine, procarbazine, and prednisone (LOPP) with four cycles of LOPP that alternate with four cycles of etoposide, vinblastine, Adriamycin (doxorubicin; Familitalia Carlo Erba, Ltd, UK), and prednisone (EVAP) in patients with advanced Hodgkin's disease. PATIENTS AND METHODS: Between June 1983 and December 1989, 594 patients were entered onto the study. Of the 594, 295 patients were allocated to receive LOPP, and 299 were allocated to receive LOPP/EVAP. RESULTS: The complete remission (CR) rates were 57% and 64%, respectively, after initial chemotherapy (difference not significant [NS]), and 65% and 75%, respectively, after the subsequent administration of radiotherapy to residual masses (P less than .01). The procedure associated mortality in the LOPP and LOPP/EVAP arms was 1% and 3%, respectively. The actuarial CR relapse-free survival was significantly greater in the LOPP/EVAP arm (P less than .001) as was the overall survival (P less than .05). The CR relapse-free rate, disease-free survival (DFS) rate, and overall survival rate at 5 years were 52%, 32%, and 66%, respectively, in the LOPP arm, compared with 72%, 47%, and 75% in the LOPP/EVAP arm, respectively. CONCLUSION: These results indicate that LOPP and EVAP is superior to LOPP alone as initial treatment for advanced Hodgkin's disease.

Marginal zone B-cell lymphoma: A clinical comparison of nodal and mucosa-associated lymphoid tissue types. Non-Hodgkin's Lymphoma Classification Project.

PURPOSE: In the International Lymphoma Study Group classification of lymphoma, extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) type is listed as a distinctive entity. However, nodal MZL is listed as a provisional entity because of questions as to whether it is truly a disease or just an advanced stage of MALT-type MZL. To resolve the issue of whether primary nodal MZL without involvement of mucosal sites exists and whether it is clinically different from extranodal MALT-type lymphoma, we compared the clinical features of these two lymphomas. PATIENTS AND METHODS: Five expert hematopathologists reached a consensus diagnosis of MZL in 93 patients. Seventy-three were classified as having MALT-type MZL because of involvement of a mucosal site at the time of diagnosis, and 20 were classified as having nodal MZL because of involvement of lymph nodes without involvement of a mucosal site. RESULTS: A comparison of the clinical features of nodal MZL and MALT-type MZL showed that more patients with nodal MZL presented with advanced-stage disease (71% v 34%; P =. 02), peripheral lymphadenopathy (100% v 8%; P <.001), and para-aortic lymphadenopathy (56% v 14%; P <.001) than those with MALT-type MZL. However, fewer patients with nodal MZL had a large mass (> or = 5 cm) than those with MALT-type MZL (31% v 68%; P =.03). The 5-year overall survival of patients with nodal MZL was lower than that for patients with MALT-type MZL (56% v 81%; P =.09), with a similar result for failure-free survival (28% v 65%; P =.01). Comparisons of patients with International Prognostic Index scores of 0 to 3 showed that those with nodal MZL had lower 5-year overall survival (52% v 88%; P =.025) and failure-free survival (30% v 75%; P =.007) rates than those with MALT-type MZL. CONCLUSION: Nodal MZL seems to be a distinctive disease entity rather than an advanced stage of MALT-type MZL because the clinical presentations and survival outcomes are different in these two types of MZL. Clinically, nodal MZL is similar to other low-grade, node-based B-cell lymphomas, such as follicular and small lymphocytic lymphomas.

Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.

BACKGROUND: Neither chemotherapy with a single-alkylating agent nor aggressive combination chemotherapy cures advanced stage low-grade non-Hodgkin lymphomas, even when combined with radiotherapy. Our aim was to compare administration of immediate chlorambucil treatment with a policy of delaying chlorambucil until clinical progression necessitated its use, in asymptomatic patients with advanced-stage, low-grade non-Hodgkin lymphoma. METHODS: 309 patients with asymptomatic, advanced-stage, low-grade non-Hodgkin lymphomas were recruited from 44 UK centres between Feb 1, 1981, and July 31, 1990. 158 patients were randomised to receive immediate systemic therapy with oral chlorambucil 10 mg per day continuously. The remaining 151 were randomised to an initial policy of observation, with systemic therapy delayed until disease progression. In both groups, local radiotherapy to symptomatic nodes was allowed. FINDINGS: Median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the two groups (median overall survival for oral chlorambucil 5.9 [range 0-17.8] years and for observation 6.7 [0.5-18.9] years, p=0.84; median cause-specific survival 9 [0-17.8] years and 9.1 [0.67-18.9] years, respectively p=0.44). In a multivariate analysis, age younger than 60 years, erythrocyte sedimentation rate (ESR) 20 mm/h or less, and stage III disease, conferred significant advantages in both overall survival (p<0.0001, 0.03, and 0.03, respectively) and cause-specific survival (p=0.002, 0.008, and 0.001, respectively). In the observation group, at 10 years' follow-up, 19 patients were alive and had not received chemotherapy. The actuarial chance of not needing chemotherapy (non-lymphoma deaths censored) at 10 years was 19% (40% if older than 70 years). INTERPRETATION: An initial policy of watchful waiting in patients with asymptomatic, advanced stage low-grade non-Hodgkin lymphoma is appropriate, especially in patients older than age 70 years.

Surgical pathological second opinion in thyroid malignancy: impact on patients' management and prognosis.

OBJECTIVES: To evaluate the effect of inter-institutional surgical pathology review of thyroid cancer on patients' treatment and prognosis. METHODS: All cases referred to the Institute of Pathology at Leeds for thyroid pathology review between January 2001 and March 2003 were included. The referring pathologists reports were compared to those produced in the MDT meeting by the expert pathologist. Whenever there was disagreement a third expert opinion was sought who was blinded for both diagnoses. Effects on management and prognosis were evaluated if there was disagreement. RESULTS: Of the 66 patients reviewed, 12 (18%) had a different pathological diagnosis (kappa=0.33). Two had their diagnosis changed from malignant to benign and a further two from benign to malignant. Eight patients had their prognosis downgraded and four upgraded after histopathological review. Five patients had their management affected by the new pathological diagnosis. CONCLUSION: A second opinion of surgical pathology for thyroid tumours can result in major therapeutic and prognostic modifications. All cases of suspected thyroid cancers should be reviewed in a multidisciplinary meeting supported by pathologist with experience in thyroid pathology.

Intermediate filament-ubiquitin diseases: implications for cell sanitization.

The molecular pathology of chronic degenerative disease is not understood. Generally there must be two related, but opposing, processes: the direct deleterious effects of the pathogenic insult which can be chemical or viral and a cellular cytoprotective response to the insult. We have recently shown that there is a previously unsuspected link between the intracellular inclusions seen in some major chronic degenerative diseases: the inclusions contain ubiquitin immunoreactivity. The conditions include Parkinson's disease, motor neurone disease, Alzheimer's disease and alcoholic liver disease as well as astrocytomas and a myopathy. Protein ubiquitination is considered a signal for extra-lysosomal protein degradation although ubiquitin-protein conjugation may have several other important functions. Intermediate filaments are a component of some of the inclusions in diseased cells; we have previously reported that they are involved in protein sequestration for degradation by lysosomally mediated autophagy. Therefore, intermediate-filament-containing ubiquitinated inclusions may be hallmarks of cellular attempts to eliminate pathogenic insults by activating protein degradation mechanisms. Ubiquitinated inclusions could also be a hallmark of viral infections: they are in polio-virus-infected anterior horn neurones and Epstein-Barr-transformed lymphoblastoid cells. Some of the clinical observations can be reproduced experimentally in tissue culture cells. The implications of the combined clinical and experimental observations for cell sanitization and protein catabolism will be discussed.

Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen.

The expression of the bcl-2 proto-oncogene, which is associated with prolonged cell survival and prevention of programmed cell death, was investigated in human primary breast carcinomas prior to and following endocrine therapy with the anti-oestrogen, tamoxifen. Using the BCL-2-100 antibody, a 26-kD protein was detected by western immunoblot in the cytosols of oestrogen receptor (ER)+ve human breast cancers. In a cross-sectional study, the immunohistochemical expression of Bcl-2 was observed in 32% of invasive breast cancers, but in 65% of tumours treated with tamoxifen (P = 0.009). There was a significant association of Bcl-2 with ER status, with 64% of untreated and 88% of tamoxifen-treated Bcl-2-positive tumours being ER+ve. A significantly lower Ki-67 score was found in tamoxifen-treated tumours which were Bcl-2-positive compared with Bcl-2-negative (9.3 versus 24.6%, P = 0.01). In a separate series of sequential Trucut biopsies from 18 patients, the frequency of Bcl-2 expression was increased in ER+ve tumours from 3/12 to 8/11 following tamoxifen (P = 0.04). This was also associated with a significant reduction in mean Ki-67 score from 32 to 12% (P = 0.0004). The observations from this study clearly indicate that Bcl-2 in human breast cancer is associated with ER status, and that expression is enhanced in ER+ve tumours following tamoxifen, in association with reduced cell proliferation.

Suprahyoid Hodgkin's disease stage IA.

From 1973 to 1987, 71 patients (age greater than or equal to 16 years) with stage IA supradiaphragmatic Hodgkin's disease were treated with radiotherapy alone. 23 patients (20, clinical stage; 3, pathological stage) had disease localised to the suprahyoid region of the neck (upper deep cervical, 11; submandibular, 6; submandibular and upper deep cervical, 5; submental, 1). The age range was 17 to 64 (median 33). The male to female ratio was 2.8:1. The histological types were: lymphocyte predominant, 11; nodular sclerosis grade I, 8; mixed cellularity, 4. The 5 and 10 year cause-specific survival was 100% with a disease-free survival of 90% at 5 and 10 years. The proportion of patients with suprahyoid Hodgkin's disease IA was constant over the 15-year period. This only became apparent when the histology of patients with suprahyoid non-Hodgkin's lymphoma stage IA was reviewed.

Stage-specific serine and metallo-proteinase release by adult and larval Trichostrongylus vitrinus.

Proteinases were released in a stage-specific manner during in vitro culture by 4th larval stage and adult Trichostrongylus vitrinus. Substrate gel analyses and inhibitor studies revealed the presence of serine and metallo-proteinases, active over a broad pH range, which degraded proteins such as fibrinogen, plasminogen and fibronectin but not immunoglobulin. The adult proteinases were partially inhibited (43%) by immunoglobulin from immune lamb lymph compared to controls, indicating their relevance to parasite immunobiology in vivo.