MDT practice determines treatment pathway for patients with advanced ovarian cancer: A multi-centre observational study.

OBJECTIVE: To investigate decision making for patients with advanced ovarian cancer as a possible explanation of geographical variation in treatment patterns. METHODS: We carried out a multi-centre observational study in multidisciplinary teams meetings for five major UK cancer centres. All patients presenting to five cancer centres with advanced ovarian cancer over a six-week period. The GO-MDT-MODe tool was used to provide a measure of participation and quality of case discussion for all cases of advanced ovarian cancer. MDT scores were correlated with surgical data extracted from national audit data. Data were recorded for overall MDT performance. RESULTS: A total of 870 case discussions, including 145 cases of advanced ovarian cancer, were observed. MDTs varied in structure, format and time allocation between centres. Cluster analysis showed significant variation in quality and participation of discussion between centres (p < 0.0025) and this correlated with the proportion of patients in the wider cancer alliance undergoing surgery. CONCLUSIONS: We have shown that at least part of the variation in practice seen in the UK correlates with different behaviours within MDTs. Increasing time for discussion and encouraging participation from all staff groups may increase proportions of patients undergoing optimal treatment regimens.

Evaluation of women referred to the two-week wait gynaecology clinic with suspected ovarian cancer.

OBJECTIVES: Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, making early diagnosis key. The two-week wait pathway aims to facilitate rapid referrals from primary to secondary care for suspected cancer thus increasing rates of early diagnosis. The objective of this study was to evaluate referrals made via the two-week wait pathway for suspected ovarian cancer. STUDY DESIGN: A retrospective analysis of 215 women referred on the two-week wait pathway to a tertiary centre in the United Kingdom with suspected ovarian cancer in 2018. RESULTS: Only 16% of women referred were subsequently diagnosed with gynaecological malignancy. Of those diagnosed with ovarian cancer, 78% had late stage disease at diagnosis. Pre-menopausal women made up 29% of those referred, but only 6% of those diagnosed with cancer. CONCLUSION: Despite its goal of increasing early stage diagnosis of cancer, the majority of women referred via the two-week wait pathway do not have cancer, and the majority of those who do are referred with late stage disease. These results highlight the need for an effective screening programme for ovarian cancer.

The impact of age and high-risk human papillomavirus (hrHPV) status on the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women with persistent hrHPV-positive, cytology-negative screening samples: a prospective cohort study.

OBJECTIVE: To establish the prevalence of high-grade cervical intraepithelial neoplasia (CIN2+) in women referred to colposcopy with persistent high-risk human papillomavirus (hrHPV) cytology-negative screening sample according to hrHPV genotype, age at referral and colposcopic performance. DESIGN: Prospective cohort study. SETTING: Single colposcopy clinic linked to a population-based screening programme. POPULATION: Women referred with persistent hrHPV cytology-negative routine screening samples. METHODS: Prospective study with descriptive statistics from a single colposcopy unit between June 2014 and July 2019. MAIN OUTCOME MEASURES: Prevalence of hrHPV genotypes and CIN2+, positive predictive value for colposcopic impression, and inadequate colposcopic examinations. RESULTS: A total of 3107 women were referred. Prevalence of CIN2+ was highest for persistent HPV16 infections (10.7%) compared with HPV18 (3.6%) or HPVO (4.7%). Prevalence of CIN2+ declined with age (25-34 years 14.2% to 55-64 years 1.1%) whereas the percentage of women with an inadequate colposcopic examination increased (25-34 years 0.9% to 55-64 years 29.5%). High-grade colposcopic impression fell over time during the study from 16.1 to 5.1%. The positive predictive value for colposcopic impression of CIN2+ was affected by hrHPV genotype (57.3% for HPV16 versus 32.1% for nonHPV16). The adjunctive use of electrical impedance spectroscopy detected an extra 42 cases of CIN2+, which was irrespective of hrHPV genotype. CONCLUSIONS: Primary hrHPV cervical screening increases detection of CIN2+; however, low specificity results in more women being referred to colposcopy with a low prevalence of CIN2+. Colposcopy performs poorly in some groups, particularly with HPVO infections and women over 50 years of age. An appropriate threshold for referral to colposcopy in primary hrHPV screening has not been established. TWEETABLE ABSTRACT: Low prevalence of CIN2+ in HPV-positive negative cytology samples. HPV genotype, age and prevalence of CIN2+ affect colposcopic performance.

A platform for x-ray Thomson scattering measurements of radiation hydrodynamics experiments on the NIF.

We present an experimental design for a radiation hydrodynamics experiment at the National Ignition Facility that measures the electron temperature of a shocked region using the x-ray Thomson scattering technique. Previous National Ignition Facility experiments indicate a reduction in Rayleigh-Taylor instability growth due to high energy fluxes, compared to the shocked energy flux, from radiation and electron heat conduction. In order to better quantify the effects of these energy fluxes, we modified the previous experiment to allow for non-collective x-ray Thomson scattering to measure the electron temperature. Photometric calculations combined with synthetic scattering spectra demonstrate an estimated noise.

Prevalence of high-grade cervical intraepithelial neoplasia in women with persistent high-risk HPV genotypes and negative cytology.

INTRODUCTION: Primary HPV screening will be implemented into the English Cervical Screening Programme by 2019. Its impact upon women referred to colposcopy, with negative cytology but persistently positive high-risk HPV (hrHPV), remains unreported from UK Sentinel sites. HPV primary screening was introduced in Sheffield, UK in April 2013; this paper reports its impact on the service. METHODS: A retrospective cohort study was performed from June 2014 to July 2016 at the Jessop Wing Colposcopy Unit, Sheffield. UK. Data were obtained from the pathology and colposcopy databases and cross-referenced with case-notes and pathology results for women referred with persistently positive hrHPV, cytology negative samples. Patient demographics, hrHPV genotype, biopsy rates, histological diagnoses, management, and outcomes were collected and baseline statistics performed. RESULTS: During the study 1076 women were seen. Most frequent hrHPV genotypes were: hrHPV other, 41%; and HPV16, 33%. The majority (72%) were found to have normal colposcopy; 28% had an abnormal colposcopic assessment (11% low-grade; 11% high-grade; 6% inadequate). The majority were discharged (83%) and only 5% underwent LLETZ. No cancers were detected. High-grade cervical intraepithelial neoplasia (CIN) was found in 7%; overall risk of CIN2 was 1/29; 1/30 for CIN3. Presence of HPV16 was associated with a significantly higher risk of high-grade CIN; 1/9. CONCLUSION: This is the first study to report results for women referred to colposcopy with cytology negative, persistently positive hrHPV. Disease prevalence is low, although women with HPV16 have a significantly higher likelihood of high-grade disease compared to other HPV subtypes.

Gas-free calibrated fMRI with a correction for vessel-size sensitivity.

Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology.

Early colposcopic reassurance and discharge to routine recall does not increase subsequent high-grade referral or treatment rates.

BACKGROUND: The Jessop Wing Colposcopy Unit identified that between 1st April 2014 and 31st March 2015 the number of women referred with high-grade dyskaryosis and the number of women undergoing treatment increased by 21% and 19%, respectively. There was concern that referral and treatment rates were increasing because we were now seeing women, previously discharged to routine recall with prior low-grade cytology hrHPV positive, re-enter the system for their second round of screening. The aim of this study was to assess the reasons for our significant increase in referral and treatment rates. METHODS: A retrospective cohort study performed between 1st April 2012 and 30th June 2015 at the Jessop Wing Colposcopy Unit, Sheffield, UK. RESULTS: During the study period, 1765 women underwent large loop excision of the transformation zone (LLETZ), of whom 1517 were referred with high-grade dyskaryosis. Fifty-six (4%) women undergoing treatment; and four untreated high-grade referrals were seen in the previous 3-5 years with low-grade cytology hrHPV positive and discharged to routine recall. There were no cases of invasive disease in the previously discharged groups. There was, however, a significantly higher likelihood of a negative LLETZ (P=.0066) in those women previously discharged to routine recall, and lower rates of CIN2 or worse identified. CONCLUSION: Prior discharge to routine recall does not have any major influence on treatment rates or high-grade referrals. The finding of no invasive disease; lower rates of CIN2 or worse; and a significantly higher likelihood of a negative LLETZ in those women previously discharged to routine recall is reassuring and further reinforces the safety of HPV triage pathways.

Sex differences in amino acids lost via sweating could lead to differential susceptibilities to disturbances in nitrogen balance and collagen turnover.

Fluid collected during sweating is enriched with amino acids derived from the skin's natural moisturising factors and has been termed "faux" sweat. Little is known about sex differences in sweat amino acid composition or whether faux sweat amino acid losses affect nitrogen balance. Faux sweat collected by healthy adults (n = 47) after exercise, and at rest by chronic fatigue patients, was analysed for amino acid composition. Healthy females had higher total amino acid concentrations in sweat (10.5 ± 1.2 mM) compared with healthy males (6.9 ± 0.9 mM). Females had higher levels of 13 amino acids in sweat including serine, alanine and glycine. Higher hydroxyproline and proline levels suggested greater collagen turnover in females. Modelling indicated that with conservative levels of exercise, amino acid losses in females via faux sweat were triple than those predicted for urine, whereas in males they were double. It was concluded that females were more susceptible to key amino acid loss during exercise and/or hot conditions. Females reporting chronic fatigue had higher levels of methionine in faux sweat than healthy females. Males reporting chronic fatigue had higher levels of numerous amino acids in faux sweat compared to healthy males. Higher amino acid loss in faux sweat associated with chronic fatigue could contribute to a hypometabolic state. Depending on activity levels, climatic conditions and gender, amino acid losses in sweat and skin leachate could influence daily protein turnover where periods of continuously high turnover could lead to a negative net nitrogen balance.

Descriptive data on cardiovascular and metabolic risk factors in ambulatory and non-ambulatory adults with cerebral palsy.

Forty-two participants with cerebral palsy were recruited for a study examining traditional and novel indicators of cardiovascular risk (McPhee et al., 2015 [1]). Data pertaining to the prevalence of obesity, smoking, hypertension, and metabolic risk are provided. These data are presented along with the scoring methods used in evaluation of the study participants. Percentages are included for comparative purposes with the existing literature.

Effects of collecting serial tracheal aspirate and bronchoalveolar lavage samples on the cytological findings of subsequent fluid samples in healthy Standardbred horses.

OBJECTIVE: To evaluate the effect of collecting serial tracheal aspirate (TA) and bronchoalveolar lavage (BAL) samples on the cytological findings of subsequent fluid samples obtained from horses without clinical signs of respiratory disease. STUDY DESIGN: Experimental. STUDY POPULATION: Six healthy Standardbred horses. METHODS: Endoscopically-guided TA samples, and BAL samples collected using the blind field technique were obtained from the six horses on days 1, 2, 3, 4, 5, 12, and 17. On day 17, horses were sampled three times: at baseline and at 2.5 h and 4 h apart. The differential cytology of the fluid samples collected at each time point was expressed as percentages and compared statistically. RESULTS: There was a significant increase in neutrophil percentage in the TA samples taken at day 17 (at 2.5 h but not at 4 h apart). There was no significant change in the neutrophil percentages in the TA samples when repeated samples were taken ≥ 24 h apart. There was no significant change in the neutrophil percentages in the BAL fluid at any collection point. There were inconsistent changes in the percentages of lymphocytes and macrophages in the BAL fluid over time, but these remained within normal reference ranges and were considered clinically insignificant. CONCLUSIONS: Serial TA and BAL samples can be taken at 24 h intervals without affecting the cytological findings of subsequent fluid samples collected using the techniques described.

Sphingosine kinase 1 knockdown reduces insulin synthesis and secretion in a rat insulinoma cell line.

To evaluate the role of sphingosine kinase 1 (SphK1) in insulin secretion, we used stable transfection to knock down the expression of the Sphk1 gene in the rat insulinoma INS-1 832/13 cell line. Cell lines with lowered Sphk1 mRNA expression and SphK1 enzyme activity (SK11 and SK14) exhibited lowered glucose- and 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) plus glutamine-stimulated insulin release and low insulin content associated with decreases in the mRNA of the insulin 1 gene. Overexpression of the rat or human Sphk1 cDNA restored insulin secretion and total insulin content in the SK11 cell line, but not in the SK14 cell line. The Sphk1 cDNA-transfected SK14 cell line expressed significantly less SphK1 activity than the Sphk1 cDNA-transfected SK11 cells suggesting that the shRNA targeting SK14 was more effective in silencing the exogenous rat Sphk1 mRNA. The results indicate that SphK1 activity is important for insulin synthesis and secretion.

Neuromagnetic imaging of movement-related cortical oscillations in children and adults: age predicts post-movement beta rebound.

We measured visually-cued motor responses in two developmentally separate groups of children and compared these responses to a group of adults. We hypothesized that if post-movement beta rebound (PMBR) depends on developmentally sensitive processes, PMBR will be greatest in adults and progressively decrease in children performing a basic motor task as a function of age. Twenty children (10 young children 4-6 years; 10 adolescent children 11-13 years) and 10 adults all had MEG recorded during separate recordings of right and left index finger movements. Beta band (15-30 Hz) event-related desynchronization (ERD) of bi-lateral sensorimotor areas was observed to increase significantly from both contralateral and ipsilateral MI with age. Movement-related gamma synchrony (60-90 Hz) was also observed from contralateral MI for each age group. However, PMBR was significantly reduced in the 4-6 year group and, while more prominent, remained significantly diminished in the adolescent (11-13 year) age group as compared to adults. PMBR measures were weak or absent in the youngest children tested and appear maximally from bilateral MI in adults. Thus PMBR may reflect an age-dependent inhibitory process of the primary motor cortex which comes on-line with normal development. Previous studies have shown PMBR may be observed from MI following a variety of movement-related tasks in adult participants - however, the origin and purpose of the PMBR is unclear. The current study shows that the expected PMBR from MI observed from adults is increasingly diminished in adolescent and young children respectively. A reduction in PMBR from children may reflect reduced motor cortical inhibition. Relatively less motor inhibition may facilitate neuronal plasticity and promote motor learning in children.

Effect of lipopolysaccharide infusion on gene expression of inflammatory cytokines in normal horses in vivo.

Horses are exquisitely sensitive to bacterial endotoxin and endotoxaemia is common in colic cases. In this study, gene expression of inflammatory cytokines was characterised in the blood of healthy horses following i.v. administration of lipopolysaccharide (LPS). Six horses received an LPS infusion and 6 controls received an equivalent volume of saline. Gene expression of genes encoding interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, and tumour necrosis factor-alpha (TNF-alpha) was quantified by real-time PCR. Gene expression of all inflammatory cytokines was upregulated following administration of LPS. Interleukin-1alpha, IL-1beta, IL-8 and TNF-alpha gene expression peaked at 60 min, while IL-6 expression peaked at 90 min post LPS infusion. Interleukin-1beta and IL-6 messenger RNA expression levels were above the baseline values 3 h post LPS infusion, whereas IL-1alpha, IL-8 and TNF-alpha expression levels returned to baseline values by 3 h after LPS infusion. It was concluded that LPS infusion upregulated gene expression of inflammatory cytokines in the blood of healthy horses.

Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes.

AIMS/HYPOTHESIS: Glucose-stimulated insulin secretion is defective in patients with type 2 diabetes. We sought to acquire new information about enzymes of glucose metabolism, with an emphasis on mitochondrial enzymes, by comparing pancreatic islets of type 2 diabetes patients with those of non-diabetic controls. METHODS: Expression of genes encoding 13 metabolic enzymes was estimated with microarrays and activities of up to nine metabolic enzymes were measured. RESULTS: The activities of the mitochondrial enzymes, glycerol phosphate dehydrogenase, pyruvate carboxylase (PC) and succinyl-CoA:3-ketoacid-CoA transferase (SCOT) were decreased by 73%, 65% and 92%, respectively, in the diabetic compared with the non-diabetic islets. ATP citrate lyase, a cytosolic enzyme of the mitochondrial citrate pyruvate shuttle, was decreased 57%. Activities of propionyl-CoA carboxylase, NADP-isocitrate dehydrogenase, cytosolic malic enzyme, aspartate aminotransferase and malate dehydrogenase were not significantly different from those of the control. The low activities of PC and SCOT were confirmed with western blots, which showed that their protein levels were low. The correlation of relative mRNA signals with enzyme activities was good in four instances, moderate in four instances and poor in one instance. In diabetic islets, the mRNA signal of the islet cell-enriched transcription factor musculoaponeurotic fibrosarcoma oncogene homologue A, which regulates expression of islet genes, including the PC gene, was decreased to 54% of the control level. PC activity and protein levels in the non-diabetic islets were significantly lower than in islets from non-diabetic rodents. CONCLUSIONS/INTERPRETATION: Low levels of certain islet metabolic enzymes, especially mitochondrial enzymes, are associated with human type 2 diabetes.

Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics.

The olfactory epithelium constitutes the sole source of regenerating neural cells that can be obtained from a living human. As such, primary cultures derived from human olfactory epithelial biopsies can be utilized to study neurobiological characteristics of individuals under different conditions and disease states. Here, using such human cultures, we report in vitro generation of cells that exhibit a complex neuronal phenotype, encompassing receptors and signaling pathways pertinent to both olfaction and other aspects of CNS function. Using in situ hybridization, we demonstrate for the first time the native expression of olfactory receptors in cultured cells derived from human olfactory epithelial tissue. We further establish the presence and function of olfactory transduction molecules in these cells using immunocytochemistry, calcium imaging and molecular methods. Western blot analysis revealed the expression of neurotransmitter receptors for dopamine (D2R), 5-HT (5HT2C) and NMDA subtypes 1 and 2A/2B. Stimulation with dopamine or 5-HT enhanced receptor G protein activation in a subtype specific manner, based on 35S-guanosine triphosphate incorporation assay. Functional characteristics of the cultured cells are demonstrated through enhanced tyrosine phosphorylation of NMDAR 2A/2B and recruitment of signaling partners in response to NMDA stimulation. The array of neuronal characteristics observed here establishes that proliferating cells derived from the human olfactory epithelium differentiate in vitro to express functional and molecular attributes of mature olfactory neurons. These cultured neural cells exhibit neurotransmitter pathways important in a number of neuropsychiatric disorders. Their ready availability from living humans thus provides a new tool to link functional and molecular features of neural cells with clinical characteristics of individual living patients.

Improving patient survival with the colorectal cancer multi-disciplinary team.

OBJECTIVE: There is little information on the impact of the colorectal multi-disciplinary team (MDT) in the United Kingdom. Our single operator presented his patients before and after the inception of an MDT meeting in June 2002. The aim of this study was to assess the effect of this on his patients' survival, and trends in the use of adjuvant chemotherapy. METHOD: Data were collected on all patients (n = 310) undergoing colectomy for colorectal cancer by one surgeon. Excluding patients with Dukes A stage, the pre-MDT cohort from January 1997 to May 2002 was 176 and the post-MDT cohort from June 2002 to December 2005 was 134. Three-year survival rates were calculated using Kaplan-Meier life table analysis. Prognostic factors were analysed using Cox-proportional hazard regression, and chemotherapy data analysed using the chi-squared test. Independent prognostic indicators of chemotherapy prescription were examined using binary logistic testing. RESULTS: MDT status was shown to be an independent predictor of survival on hazard regression analysis (P = 0.044). A significantly greater number of patients were prescribed adjuvant chemotherapy in the post-MDT cohort (P = 0.0002). MDT status was shown to be a significant prognostic indicator of chemotherapy prescription (P < 0.0001). Three-year survival for Dukes C patients was 58% in the pre-MDT group, and 66% in the post-MDT group (P = 0.023). CONCLUSION: There was a significant increase in patients undergoing adjuvant postoperative chemotherapy after the inception of the MDT. This was associated with a significant survival benefit in patients with Dukes C disease. The data suggest that the MDT process has resulted in an increase in the prescription of adjuvant chemotherapy, with 3-year survival being greater after its inception.

Role of PGL-I of M. leprae in TNF-alpha production by in vitro whole blood assay.

Phenolic glycolipid-I (PGL-I) is known to be a major antigen of Mycobacterium leprae. We have studied the influence of PGL-I on the production of Tumour Necrosis Factor alpha (TNF-alpha) using the in vitro whole blood assay. Armadillo-derived M. leprae (ADML) are thought to be depleted of PGL-I during the purification process. M. leprae obtained from mouse foot pad material (MFPML) has been subjected to a less rigorous purification process; their PGL-I coating is therefore believed to be more intact than that of ADML. PGL-I or ADML alone induced the secretion of minimal levels of TNF-alpha in whole blood assay; when added in combination, higher levels of this cytokine were observed. The highest TNF-alpha response was seen following stimulation with MFPML. MFP material not infected with ML did not elicit any response. The difference in TNF-alpha response shown by ADML and MFPML was postulated to be largely due to the presence of higher levels of PGL-I in MFPML. This increase in TNF-alpha production suggests that PGL-I may play a significant role in the induction of TNF-alpha during natural infection.

Diagnostic challenges in extrauterine epithelioid trophoblastic tumours: a report of two cases.

INTRODUCTION: Epithelioid trophoblastic tumour (ETT) is a rare condition with a paucity of cases reported in the literature. CASE REPORTS: We present two unusual cases of ETT. Both patients presented with markedly elevated hCG levels; one case presented with a mass in the gallbladder, the other with extensive metastases; and both patients died from disease. DISCUSSION: To gain a greater understanding of the nature and progression of this disease, reporting of cases in the literature should be thorough and contain detailed information on patient clinicopathological characteristics and treatment. To enable identification of prognostic factors, long-term follow up must also be reported because recurrence can be both late and complex.

Abdominal actinomycosis.

Abdominal actinomycosis has been recognised for over 150 years yet remains largely unknown to most clinicians. It's varied presentations are usually considered to represent malignancy rather than an infective process - and was once described as 'the most misdiagnosed disease'. Actinomyces are gram positive bacilli of the Actinomycetales genus, and A. israelii is responsible for the majority of human disease. They are normal commensal inhabitants of the human bronchial and gastrointestinal tracts and seem to only cause pathological infection after preceding mucosal breakdown. Patients who have undergone appendicectomy, have had a missed perforated appendicitis or women with a history of intrauterine contraceptive device use are at an increased risk. Florid abscess formation with fistulation, abundant granulation and dense surrounding fibrosis are common. Diagnosis prior to, or even during, surgery is rare and the findings are usually mistaken for acute inflammatory pathologies or malignancy. The treatment of choice is prolonged antibiotic therapy, usually with penicillin to which the organisms remain exquisitely sensitive, although delayed recurrence is possible. This review outlines the historical background of actinomyceal infection and considers the epidemiology, pathophysiology and clinical features of abdominal actinomycosis.