The utility of Ki-67 as a prognostic biomarker in pulmonary neuroendocrine tumours: protocol for a systematic review and meta-analysis

INTRODUCTION: The omission of the immunohistochemical proliferation marker Ki-67 labelling index (henceforth, simply Ki-67) from the 2015 WHO classification system of pulmonary neuroendocrine tumours (Lung-NETs) as a prognostic and grading criterion remains controversial. This systematic review along with meta-analysis will be conducted to assess the prognostic/grading utility of Ki-67 in Lung-NETs.METHODS: This systematic review will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic search of MEDLINE Ovid, Embase, Scopus and the Cochrane Library will be performed from the inception of each database to 28 February 2019 for studies investigating any role of Ki-67 in Lung-NETs. Only full papers published in English detailing survival outcomes and HRs according to Ki-67 will be included. The primary endpoint will be establishing whether Ki-67 is a reliable marker in determining prognosis and thus assessing grade of Lung-NETs patients.ETHICS AND DISSEMINATION: Ethical approval will not be required as this is an academic review of published literature. Findings will be disseminated through the preparation of a manuscript for publication in a peer-reviewed journal as well as presentation at national and international conferences.PROSPERO REGISTRATION NUMBER: CRD42018093389.</p

Alterations in amino acid status in cats with feline dysautonomia

Feline dysautonomia (FD) is a multiple system neuropathy of unknown aetiology. An apparently identical disease occurs in horses (equine grass sickness, EGS), dogs, rabbits, hares, sheep, alpacas and llamas. Horses with acute EGS have a marked reduction in plasma concentrations of the sulphur amino acids (SAA) cyst(e)ine and methionine, which may reflect exposure to a neurotoxic xenobiotic. The aim of this study was to determine whether FD cats have alterations in amino acid profiles similar to those of EGS horses. Amino acids were quantified in plasma/serum from 14 FD cats, 5 healthy in-contact cats which shared housing and diet with the FD cats, and 6 healthy control cats which were housed separately from FD cats and which received a different diet. The adequacy of amino acids in the cats’ diet was assessed by determining the amino acid content of tinned and dry pelleted foods collected immediately after occurrences of FD. Compared with controls, FD cats had increased concentrations of many essential amino acids, with the exception of methionine which was significantly reduced, and reductions in most non-essential amino acids. In-contact cats also had inadequate methionine status. Artefactual loss of cysteine during analysis precluded assessment of the cyst(e)ine status. Food analysis indicated that the low methionine status was unlikely to be attributable to dietary inadequacy of methionine or cystine. Multi-mycotoxin screening identified low concentrations of several mycotoxins in dry food from all 3 premises. While this indicates fungal contamination of the food, none of these mycotoxins appears to induce the specific clinico-pathologic features which characterise FD and equivalent multiple system neuropathies in other species. Instead, we hypothesise that ingestion of another, as yet unidentified, dietary neurotoxic mycotoxin or xenobiotic, may cause both the characteristic disease pathology and the plasma SAA depletion

Newly qualified doctors' views about whether their medical school had trained them well: questionnaire surveys

A survey of newly qualified doctors in the UK in 2000/2001 found that 42% of them felt unprepared for their first year of employment in clinical posts. We report on how UK qualifiers' preparedness has changed since then, and on the impact of course changes upon preparedness. Methods Postal questionnaires were sent to all doctors who qualified from UK medical schools, in their first year of clinical work, in 2003 (n = 4257) and 2005 (n = 4784); and findings were compared with those in 2000/2001 (n = 5330). The response rates were 67% in 2000/2001, 65% in 2003, and 43% in 2005. The outcome measure was the percentage of doctors agreeing with the statement "My experience at medical school has prepared me well for the jobs I have undertaken so far". Results In the 2000/2001 survey 36.3% strongly agreed or agreed with the statement, as did 50.3% in the 2003 survey and 58.5% in 2005 (chi-squared test for linear trend: χ2 = 259.5; df = 1; p < 0.001). Substantial variation in preparedness between doctors from different medical schools, reported in the first survey, was still present in 2003 and 2005. Between 1998 and 2006 all UK medical schools updated their courses. Within each cohort a significantly higher percentage of the respondents from schools with updated courses felt well prepared. Conclusion UK medical schools are now training doctors who feel better prepared for work than in the past. Some of the improvement may be attributable to curricular change

'It gives you an understanding you can't get from any book.' The relationship between medical students' and doctors' personal illness experiences and their performance: a qualitative and quantitative study

Background: anecdotes abound about doctors' personal illness experiences and the effect they have on their empathy and care of patients. We formally investigated the relationship between doctors' and medical students' personal illness experiences, their examination results, preparedness for clinical practice, learning and professional attitudes and behaviour towards patients.Methods: newly-qualified UK doctors in 2005 (n = 2062/4784), and two cohorts of students at one London medical school (n = 640/749) participated in the quantitative arm of the study. 37 Consultants, 1 Specialist Registrar, 2 Clinical Skills Tutors and 25 newly-qualified doctors participated in the qualitative arm. Newly-qualified doctors and medical students reported their personal illness experiences in a questionnaire. Doctors' experiences were correlated with self-reported preparedness for their new clinical jobs. Students' experiences were correlated with their examination results, and self-reported anxiety and depression. Interviews with clinical teachers, newly-qualified doctors and senior doctors qualitatively investigated how personal illness experiences affect learning, professional attitudes, and behaviour.Results: 85.5% of newly-qualified doctors and 54.4% of medical students reported personal illness experiences. Newly-qualified doctors who had been ill felt less prepared for starting work (p &lt; 0.001), but those who had only experienced illness in a relative or friend felt more prepared (p = 0.02). Clinical medical students who had been ill were more anxious (p = 0.01) and had lower examination scores (p = 0.006). Doctors felt their personal illness experiences helped them empathise and communicate with patients. Medical students with more life experience were perceived as more mature, empathetic, and better learners; but illness at medical school was recognised to impede learning.Conclusion: the majority of the medical students and newly qualified doctors we studied reported personal illness experiences, and these experiences were associated with lower undergraduate examination results, higher anxiety, and lower preparedness. However reflection on such experiences may have improved professional attitudes such as empathy and compassion for patients. Future research is warranted in this area

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relaps

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse