Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer.

AIMS: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

Differentiated Thyroid Cancer in Children: A UK Multicentre Review and Review of the Literature.

AIMS: To obtain an overview of the management and outcomes of children aged 18 years or younger diagnosed with differentiated thyroid carcinoma of follicular cell origin across the UK, by collecting and analysing data from the limited number of centres treating these patients. This multicentre data might provide a more realistic perspective than single-institution series. MATERIALS AND METHODS: Six centres submitted data extracted from historical records on patients aged 18 years or younger, diagnosed between 1964 and 2017. The univariate and multivariable Cox proportional hazard model was used to identify potential predictors of progression-free survival, using national data as a control. RESULTS: Data on 166 patients were available for analysis. Females (74%) were predominant, and the age ranged from 3 to 19 years at diagnosis, mean 14.1 years. Nodal metastases were present in 51%; 12% had distant metastases. After surgery, 95% received radioactive iodine (39% on more than one occasion) and 4% received external beam radiotherapy. With a median follow-up duration of 5 years, 69% are alive with no evidence of disease; 20% are alive with a raised thyroglobulin level as the only evidence of residual disease; 6% have residual structural disease detectable on imaging; 2% have died, from cerebral metastases. CONCLUSION: Despite most patients having advanced disease at presentation, outcomes are very good. A national prospective registry should allow systematic collection of good-quality data and may facilitate research to further improve outcomes.

Can We Discharge Dynamically Risk-Stratified Low-Risk (Excellent Response to Treatment) Thyroid Cancer Patients After 5 Years of Follow-Up?

AIMS: The 2014 British Thyroid Association thyroid cancer guidelines recommend lifelong follow-up of thyroid cancer patients. This is probably unnecessary, can cause patient anxiety, is time consuming and places significant demand on National Health Service resources. It has been suggested that low-risk differentiated thyroid cancer (DTC) patients could be discharged to primary care once they are 5 years from diagnosis and treatment. The aim of this study was to investigate the potential safety of this practice. MATERIALS AND METHODS: In total, 756 patients with dynamically risk-stratified (DRS) low-risk/excellent response to treatment DTC treated over 2001-2013 in the Leeds region were followed after diagnostic surgery and the recurrence rate calculated. RESULTS: The median follow-up time was nearly 10 years (5-17 years). Radiological recurrence occurred in 13/756 (1.7%) patients and was always preceded by raised thyroglobulin/ thyroglobulin antibody levels. In all 13 patients elevation of thyroglobulin occurred within 5 years of diagnosis. Two additional patients were found to have rising thyroglobulin at almost 9 and 10.5 years from diagnosis, although to date radiological recurrence has not been detected. Assuming these two patients developed recurrence with longer duration of follow-up, then 0.26% (2/756) of patients would not have their recurrence discovered within 5 years of diagnosis. To detect 100% of patients with a putative recurrence in our cohort would require 10.5 years of follow-up. Four patients had transiently raised thyroglobulin, which became undetectable within 2 years (in three patients), without any treatment and radiological recurrence was not discovered. CONCLUSION: Discharge of DRS low-risk DTC patients to primary care after 5 years of secondary care follow-up is reasonable, accepting that late recurrence may occur in a very small minority of individuals (0.26%, ∼1:400). A more cautious approach would be to continue monitoring for 10 years, although the frequency of assessments could be reduced with increasing duration of follow-up.

How did we do? An investigation into the suitability of patient questionnaires (PREMs and PROMs) in three primary care oral surgery practices.

Introduction With the expansion of oral surgery services into the primary care sector there is a need to monitor the quality of the care provided. The Guide for Commissioning Oral Surgery and Oral Medicine proposed a set of questions to be used as patient related experience and outcome measures (PREMs and PROMs).Aim The British Association of Oral Surgeons (BAOS) primary care group (which includes the authors) were tasked by the Chief Dental Officer for England to test the suitability of these PREMs and PROMs.Method The questions as published in the commissioning guide were piloted in primary care oral surgery practices and patient feedback was sought. The authors then proposed and implemented an amended series of questions that they felt would be more practical as generic templates for oral surgery services.Results Our data demonstrates that the revised questions have produced data that is easy to interpret and attracted a greater number of feedback comments from patients.Discussion and conclusion The revised questionnaires incorporate the NHS Friends and Family Test as the collection of this data is normally a contractual requirement for providers of NHS services. They also use questions from other validated healthcare satisfaction survey tools. The use of Likert scales provides a richer data set which makes the interpretation of data easier and highlights areas for improvement. It is important to note that the data provided by PREMs and PROMs is subject to a number of biases and should be used for local quality improvement and longitudinal analysis of outcome data rather than comparison between providers.

An investigation into the variability of primary care oral surgery contracts and tariffs in England and Wales (2014/2015).

Primary care oral surgery services vary markedly throughout the country but until now there has been a paucity of data on these services. The British Association of Oral Surgeons (BAOS) primary care group (the authors) were tasked to gather data around primary care oral surgery contracts and tariffs and provide evidence-based recommendations on the commissioning of these services. Following a freedom of information (FOI) request, data were obtained for 27 English local area teams and seven Welsh local health boards. The data demonstrated both regional and national variability with respect to primary care oral surgery contracts, concerning both contract type and level of remuneration. These differences are discussed and the authors make recommendations for standardising oral surgery contracts and tariffs.

Ten Year Experience of Radioiodine Dosimetry: is it Useful in the Management of Metastatic Differentiated Thyroid Cancer?

AIMS: When a fixed activity of radioiodine is given for differentiated thyroid cancer (DTC), absorbed doses of radioiodine can vary widely and are not usually measured. Leeds Cancer Centre has routinely used a form of lesion-specific dosimetry for radioiodine patients. This study investigated if the results of dosimetry influenced treatment decisions for patients with advanced DTC. MATERIALS AND METHODS: Since 2005, patients with regionally advanced/metastatic DTC, who underwent radioiodine treatment together with dosimetry, were included in this study. Patients were excluded if their radioiodine post-treatment scan showed no abnormal uptake. Dosimetry was calculated using images taken 2, 3 and 7 days post-radioiodine. Regions of interest were drawn around lesions that required dosimetry and a time-dose activity curve was created. The total cumulative activity was equal to the area under the curve. Each patient's results were prospectively assessed by their oncologist regarding the usefulness of dosimetry in making management decisions. RESULTS: Thirty patients were studied and underwent 102 admissions of radioiodine between them. Dosimetry was carried out during 83 of 102 admissions. An absorbed dose of >20 Gy was taken as significant from dosimetry calculations, following which further radioiodine was considered. In 80% of patients, dosimetry was found to be useful when making treatment decisions. Only on 1/19 admissions did dosimetry calculate a minimum dose above 20 Gy in patients who had a total of four or more admissions for radioiodine. Ten per cent (3/30) had a complete response to radioiodine, both biochemically and radiologically, with a median follow-up of 6.7 months. Thirty-three per cent had a partial response/stable disease to radioiodine. The remainder had progressive disease. The decision to discontinue radioiodine therapy was often based on dosimetry and thyroglobulin results. Dosimetry was very useful for patients with thyroglobulin antibodies. CONCLUSION: Only 10% had a complete response. Therefore, a significant number of patients became refractory to radioiodine during a course of repeat admissions for treatment. Dosimetry (often together with thyroglobulin and anatomical scans) helped to identify these patients to avoid further futile radioiodine therapy.

Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale.

Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.

Assessing the use of the Index of Sedation Need in oral surgery.

OBJECTIVE: This article evaluates the use of the Index of Sedation Need in oral surgery. DESIGN: Service evaluation and audit. SETTING: Oral surgery department of a London dental teaching hospital. SUBJECTS (MATERIALS) AND METHODS: Patients attending for oral surgery procedures with sedation which had been arranged without reference to the IOSN tool completed the IOSN and a patient questionnaire. Operators completed a similar questionnaire. The IOSN was calculated and the questionnaire responses analysed using SPSS. RESULTS: 56% of the patients in this study (n = 105) were receiving sedation appropriately according to the IOSN tool. When the questionnaire responses were analysed depending on sedation need, no statistical difference was found using Fisher's exact test or Pearson Chi-Square (p <0.05). Fifty percent of patients who had no need for sedation according to the IOSN tool were considered by the operator to have been untreatable without it. CONCLUSION: This study raises questions over the validity and reliability of the IOSN tool as a method of defining sedation need.

A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR.

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/µl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).

Increasing the yield of recombinant thyroid-stimulating hormone-stimulated 2-(18-fluoride)-flu-2-deoxy-D-glucose positron emission tomography-CT in patients with differentiated thyroid carcinoma.

OBJECTIVE: The aim of this study was to assess the accuracy of recombinant thyroid-stimulating hormone (rTSH)-stimulated 2-(18-fluoride)-flu-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET)-CT in detecting recurrence in patients with differentiated thyroid cancer. METHODS: Consecutive (18)F-FDG PET-CT scans performed with rTSH stimulation between 2007 and 2010 in patients with a history of papillary or follicular thyroid carcinoma were reviewed. PET-CT findings were correlated with thyroglobulin levels, and histological, clinical and radiological follow-up. RESULTS: 58 rTSH PET-CT scans were performed in 47 patients with a previous thyroidectomy and radioiodine ablation. The only indication for PET-CT was a raised thyroglobulin level in 46 of 58 scans, with the remainder for characterisation of equivocal radiology or staging. 25 (43%) of PET-CT scans were positive for recurrent disease. Histological correlation was available for 21 (36%) scans. The overall sensitivity, specificity, positive predictive value and negative predictive value were 69%, 76%, 72% and 73%, respectively. Median unstimulated thyroglobulin in true-positive scans was 33 µg l(-1) and 2.2 µg l(-1) in the remainder (p=0.12). 4 of 35 (11%) patients with unstimulated thyroglobulin levels <10 µg l(-1) had true-positive scans. Median stimulated thyroglobulin in true-positive scans was 320 µg l(-1), and 10 µg l(-1) in the remainder (p=0.046), with no positive scans with a stimulated thyroglobulin <8 µg l(-1). PET-CT directly influenced patient management in 17/58 (29%) scans. CONCLUSION: rTSH PET-CT is a useful imaging technique for detecting disease recurrence in patients with iodine-resistant differentiated thyroid cancer. Low stimulated thyroglobulin levels are potentially useful in identifying patients unlikely to benefit from a PET-CT scan.