Sentinel node biopsy for diagnosis of lymph node involvement in endometrial cancer.

BACKGROUND: Pelvic lymphadenectomy provides prognostic information for those diagnosed with endometrial (womb) cancer and provides information that may influence decisions regarding adjuvant treatment. However, studies have not shown a therapeutic benefit, and lymphadenectomy causes significant morbidity. The technique of sentinel lymph node biopsy (SLNB), allows the first draining node from a cancer to be identified and examined histologically for involvement with cancer cells. SLNB is commonly used in other cancers, including breast and vulval cancer. Different tracers, including colloid labelled with radioactive technetium-99, blue dyes, e.g. patent or methylene blue, and near infra-red fluorescent dyes, e.g. indocyanine green (ICG), have been used singly or in combination for detection of sentinel lymph nodes (SLN). OBJECTIVES: To assess the diagnostic accuracy of sentinel lymph node biopsy (SLNB) in the identification of pelvic lymph node involvement in women with endometrial cancer, presumed to be at an early stage prior to surgery, including consideration of the detection rate. SEARCH METHODS: We searched MEDLINE (1946 to July 2019), Embase (1974 to July 2019) and the relevant Cochrane trial registers. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of tracers for SLN assessment (involving the identification of a SLN plus histological examination) against a reference standard of histological examination of removed pelvic +/- para-aortic lymph nodes following systematic pelvic +/- para-aortic lymphadenectomy (PLND/PPALND) in women with endometrial cancer, where there were sufficient data for the construction of two-by-two tables. DATA COLLECTION AND ANALYSIS: Two review authors (a combination of HN, JM, NW, RG, and WH) independently screened titles and abstracts for relevance, classified studies for inclusion/exclusion and extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We calculated the detection rate as the arithmetic mean of the total number of SLNs detected out of the total number of women included in the included studies with the woman as the unit of analysis, used univariate meta-analytical methods to estimate pooled sensitivity estimates, and summarised the results using GRADE. MAIN RESULTS: The search revealed 6259 unique records after removal of duplicates. After screening 232 studies in full text, we found 73 potentially includable records (for 52 studies), although we were only able to extract 2x2 table data for 33 studies, including 2237 women (46 records) for inclusion in the review, despite writing to trial authors for additional information. We found 11 studies that analysed results for blue dye alone, four studies for technetium-99m alone, 12 studies that used a combination of blue dye and technetium-99m, nine studies that used indocyanine green (ICG) and near infra-red immunofluorescence, and one study that used a combination of ICG and technetium-99m. Overall, the methodological reporting in most of the studies was poor, which resulted in a very large proportion of 'unclear risk of bias' ratings. Overall, the mean SLN detection rate was 86.9% (95% CI 82.9% to 90.8%; 2237 women; 33 studies; moderate-certainty evidence). In studies that reported bilateral detection the mean rate was 65.4% (95% CI 57.8% to 73.0%) . When considered according to which tracer was used, the SLN detection rate ranged from 77.8% (95% CI 70.0% to 85.6%) for blue dye alone (559 women; 11 studies; low-certainty evidence) to 100% for ICG and technetium-99m (32 women; 1 study; very low-certainty evidence). The rates of positive lymph nodes ranged from 5.2% to 34.4% with a mean of 20.1% (95% CI 17.7% to 22.3%). The pooled sensitivity of SLNB was 91.8% (95% CI 86.5% to 95.1%; total 2237 women, of whom 409 had SLN involvement; moderate-certainty evidence). The sensitivity for of SLNB for the different tracers were: blue dye alone 95.2% (95% CI 77.2% to 99.2%; 559 women; 11 studies; low-certainty evidence); Technetium-99m alone 90.5% (95% CI 67.7% to 97.7%; 257 women; 4 studies; low-certainty evidence); technetium-99m and blue dye 91.9% (95% CI 74.4% to 97.8%; 548 women; 12 studies; low-certainty evidence); ICG alone 92.5% (95% CI 81.8% to 97.1%; 953 women; 9 studies; moderate-certainty evidence); ICG and blue dye 90.5% (95% CI 63.2.6% to 98.1%; 215 women; 2 studies; low-certainty evidence); and ICG and technetium-99m 100% (95% CI 63% to 100%; 32 women; 1 study; very low-certainty evidence). Meta-regression analyses found that the sensitivities did not differ between the different tracers used, between studies with a majority of women with FIGO stage 1A versus 1B or above; between studies assessing the pelvic lymph node basin alone versus the pelvic and para-aortic lymph node basin; or between studies that used subserosal alone versus subserosal and cervical injection. It should be noted that a false-positive result cannot occur, as the histological examination of the SLN is unchanged by the results from any additional nodes removed at systematic lymphadenectomy. AUTHORS' CONCLUSIONS: The diagnostic test accuracy for SLNB using either ICG alone or a combination of a dye (blue or ICG) and technetium-99m is probably good, with high sensitivity, where a SLN could be detected. Detection rates with ICG or a combination of dye (ICG or blue) and technetium-99m may be higher. The value of a SLNB approach in a treatment pathway, over adjuvant treatment decisions based on uterine factors and molecular profiling, requires examination in a high-quality intervention study.

Editor's Choice - Trends in Lower Extremity Amputation Incidence in European Union 15+ Countries 1990-2017.

OBJECTIVE: Lower extremity amputation (LEA) carries significant mortality, morbidity, and health economic burden. In the Western world, it most commonly results from complications of peripheral arterial occlusive disease (PAOD) or diabetic foot disease. The incidence of PAOD has declined in Europe, the United States, and parts of Australasia. The present study aimed to assess trends in LEA incidence in European Union (EU15+) countries for the years 1990-2017. METHODS: This was an observational study using data obtained from the 2017 Global Burden of Disease (GBD) Study. Age standardised incidence rates (ASIRs) for LEA (stratified into toe amputation, and LEA proximal to toes) were extracted from the GBD Results Tool (http://ghdx.healthdata.org/gbd-results-tool) for EU15+ countries for each of the years 1990-2017. Trends were analysed using Joinpoint regression analysis. RESULTS: Between 1990 and 2017, variable trends in the incidence of LEA were observed in EU15+ countries. For LEAs proximal to toes, increasing trends were observed in six of 19 countries and decreasing trends in nine of 19 countries, with four countries showing varying trends between sexes. For toe amputation, increasing trends were observed in eight of 19 countries and decreasing trends in eight of 19 countries for both sexes, with three countries showing varying trends between sexes. Australia had the highest ASIRs for both sexes in all LEAs at all time points, with steadily increasing trends. The USA observed the greatest reduction in all LEAs in both sexes over the time period analysed (LEAs proximal to toes: female patients -22.93%, male patients -29.76%; toe amputation: female patients -29.93%, male patients -32.67%). The greatest overall increase in incidence was observed in Australia. CONCLUSION: Variable trends in LEA incidence were observed across EU15+ countries. These trends do not reflect previously observed reductions in incidence of PAOD over the same time period.

Type 1 diabetes mellitus disease burden in high health expenditure countries between 1990 and 2019.

OBJECTIVE: This observational study assesses trends in type 1 diabetes mellitus (T1DM) disease burden across the 19 countries of the European Union (EU) 15+ between 1990 and 2019. METHODS: The Global Burden of Disease Study database was used to gather T1DM age-standardised incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability-adjusted life-year (DALY) rates per 100,000 for each EU15+ country (1990 - 2019). Joinpoint regression analysis was used to describe the trends. RESULTS: From 1990 to 2019, T1DM ASIRs and ASPRs increased globally except for females in Finland (-2.9% and -9.4%), the largest increase in ASPR for males and females was observed in France (+144.4% and +137.5% respectively). All had reductions in ASMRs for males and females, with the largest observed in Spain (-56.7% and -79.0% respectively). Trends in DALYs were variable across countries, with increases in DALYs noted in 14/19 for males, and 9/19 for females. Denmark, Finland, Norway, Netherlands, and Sweden had a reduction in DALYs for both males and females. CONCLUSIONS: Mortality from T1DM is reducing across EU15+ countries, despite concomitant increases in incidence and prevalence rates. Trends in DALYs are variable across countries, reflecting differential trends in the disease burden across countries with similarly high health expenditure.

Trends in type 2 diabetes mellitus disease burden in European Union countries between 1990 and 2019.

This observational study aimed to assess trends in type 2 diabetes mellitus (T2DM) disease burden in European Union countries for the years 1990-2019. Sex specific T2DM age-standardised prevalence (ASPRs), mortality (ASMRs) and disability-adjusted life-year rates (DALYs) per 100,000 population were extracted from the Global Burden of Disease (GBD) Study online results tool for each EU country (inclusive of the United Kingdom), for the years 1990-2019. Trends were analysed using Joinpoint regression analysis. Between 1990 and 2019, increases in T2DM ASPRs were observed for all EU countries. The highest relative increases in ASPRs were observed in Luxembourg (males + 269.1%, females + 219.2%), Ireland (males + 191.9%, females + 165.7%) and the UK (males + 128.6%, females + 114.6%). Mortality trends were less uniform across EU countries, however a general trend towards reducing T2DM mortality was observed, with ASMRs decreasing over the 30-year period studied in 16/28 countries for males and in 24/28 countries for females. The UK observed the highest relative decrease in ASMRs for males (- 46.9%). For females, the largest relative decrease in ASMRs was in Cyprus (- 67.6%). DALYs increased in 25/28 countries for males and in 17/28 countries for females between 1990 and 2019. DALYs were higher in males than females in all EU countries in 2019. T2DM prevalence rates have increased across EU countries over the last 30 years. Mortality from T2DM has generally decreased in EU countries, however trends were more variable than those observed for prevalence. Primary prevention strategies should continue to be a focus for preventing T2DM in at risk groups in EU countries.

Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.

The 'National Finals Revision Day' Teaching Strategy: A Cost-Effective Way to Pass Medical School 'Finals' and Upskill Junior Doctors.

Courses to help medical students pass 'Finals' already exist but are typically expensive or can only be attended by a limited number of students. We describe the success of 'The National Finals Revision Day' (NFRD) course, which we believe is sustainable and unique in terms of its combined scale and cost (£10 per person). The course was organised and taught by 12 junior doctors. In total, 300 students attended from 55% of UK medical schools. Attendees found the course both relevant (96.4%) and cost-effective (97%), whilst the 11 medical and surgical talks were of a high standard (90.1%). The organising committee felt confident to organise their own teaching course in the future with 100% having already run a course themselves since the NFRD course. The NFRD course was also used by 11/12 (91.7%) of the organising committee to achieve their Annual Review of Competency Progression (ARCP) and 12/12 (100%) of the organising committee to obtain jobs on training programmes in the UK. We provide guidance about how to organise similar large-scale events for those interested. Moving forward, the teaching course will be run at: (i) multiple times; (ii) multiple UK venues; (iii) run over two days to cover more medical and surgical topics; and (iv) include the option of attending via video link.