Results of a national training programme in sentinel lymph node biopsy for breast cancer.

BACKGROUND: New Start, a structured, validated, multidisciplinary training programme in sentinel lymph node biopsy (SLNB), was established to allow the introduction and rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice across the UK. METHODS: Multidisciplinary teams attended a theory/skills laboratory course, following which they performed 30 consecutive SLNBs, either concurrently with their standard axillary staging procedure (training model A) or as stand-alone SLNB (training model B). SLNB was performed according to a standard protocol using the combined technique of isotope ((99m) Tc-labelled albumin colloid) and blue dye. An accredited New Start trainer mentored the first five procedures in the participant's hospital, or all 30 if stand-alone. Validation standards for model A and B were a localization rate of at least 90 per cent. In addition, for model A only, in which a minimum of ten patients were required to be node-positive, a false-negative rate (FNR) of 10 per cent or less was required. RESULTS: From October 2004 to December 2008, 210 SLNB-naive surgeons, in 103 centres, performed 6685 SLNB procedures. The overall sentinel lymph node (SLN) localization rate was 98·9 (95 per cent confidence interval 98·6 to 99·1) per cent (6610 of 6685) and the FNR 9·1 (7·9 to 10·5) per cent (160 of 1757). The FNR was related to nodal yield, ranging from 14·8 per cent for one node and declining to 9·7, 6·6, 4·7 and 4·1 per cent for two, three, four and more than four SLNs respectively. No learning curve was identified for localization or FNR. CONCLUSION: The programme successfully trained a wide range of UK breast teams to perform safe SLNB and suggested that a standard injection protocol and structured multidisciplinary training can abolish learning curves.

Ultra-Widefield OCT Angiography.

Optical Coherence Tomography Angiography (OCTA), a functional extension of OCT, has the potential to replace most invasive fluorescein angiography (FA) exams in ophthalmology. So far, OCTA's field of view is however still lacking behind fluorescence fundus photography techniques. This is problematic, because many retinal diseases manifest at an early stage by changes of the peripheral retinal capillary network. It is therefore desirable to expand OCTA's field of view to match that of ultra-widefield fundus cameras. We present a custom developed clinical high-speed swept-source OCT (SS-OCT) system operating at an acquisition rate 8-16 times faster than today's state-of-the-art commercially available OCTA devices. Its speed allows us to capture ultra-wide fields of view of up to 90 degrees with an unprecedented sampling density and hence extraordinary resolution by merging two single shot scans with 60 degrees in diameter. To further enhance the visual appearance of the angiograms, we developed for the first time a three-dimensional deep learning based algorithm for denoising volumetric OCTA data sets. We showcase its imaging performance and clinical usability by presenting images of patients suffering from diabetic retinopathy.

Impact of the COVID-19 Pandemic on Outcomes for Patients with Lung Cancer Receiving Curative-intent Radiotherapy in the UK.

AIMS: Previous work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre's usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19-27). We present the impact of these changes on patient outcomes. MATERIALS AND METHODS: The COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression. RESULTS: Patient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I-II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661). CONCLUSION: This study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations.

Overestimation of carboplatin doses is avoided by radionuclide GFR measurement.

BACKGROUND: Glomerular filtration rate (GFR) is used in the calculation of carboplatin dose. Glomerular filtration rate is measured using a radioisotope method (radionuclide GFR (rGFR)), however, estimation equations are available (estimated GFR (eGFR)). Our aim was to assess the accuracy of three eGFR equations and the subsequent carboplatin dose in an oncology population. PATIENTS AND METHODS: Patients referred for an rGFR over a 3-year period were selected; eGFR was calculated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault (CG) equations. Carboplatin doses were calculated for those patients who had received carboplatin chemotherapy. Bias, precision and accuracy were examined. RESULTS: Two hundred and eighty-eight studies met the inclusion/exclusion criteria. Paired t-tests showed significant differences for all three equations between rGFR and eGFR with biases of 12.3 (MDRD), 13.6 (CKD-EPI) and 7.7 ml min(-1) per 1.73 m(2) (CG). An overestimation in carboplatin dose was seen in 81%, 87% and 66% of studies using the MDRD, CKD-EPI and CG equations, respectively. CONCLUSION: The MDRD and CKD-EPI equations performed poorly compared with the reference standard rGFR; the CG equation showed smaller bias and higher accuracy in our oncology population. On the basis of our results we recommend that the rGFR should be used for accurate carboplatin chemotherapy dosing and where unavailable the use of the CG equation is preferred.

Changes in the Management of Patients having Radical Radiotherapy for Lung Cancer during the First Wave of the COVID-19 Pandemic in the UK.

AIMS: In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020. MATERIALS AND METHODS: Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression. RESULTS: In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease. CONCLUSIONS: The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes.

Significant differences when using MDRD for GFR estimation compared to radionuclide measured clearance.

OBJECTIVES: To evaluate Estimated Glomerular Filtration Rate (eGFR), using the Modification of Diet in Renal Disease equation, and compare with radionuclide GFR (rGFR) in a Radiology setting to assess renal function prior to contrast administration. METHODS: Five hundred and sixteen retrospective rGFR studies from a mixed referral population were selected and the eGFR calculated. Regression and Bland-Altman analysis was performed. The percentage of rGFR and eGFR studies below 30 ml/min/1.73 m² and 60 ml/min/1.73 m² were calculated; these are important thresholds for classifying renal insufficiency. RESULTS: A significant correlation between eGFR and rGFR (R² = 0.62, p < 0.0001) and significant differences in the medians (p < 0.0001) were found. eGFR overestimated rGFR with a bias (mean difference) of 10.8 ml/min/1.73 m² over the whole range of rGFR. Studies with an rGFR of under 30 ml/min/1.73 m² had a mean bias of 4.6 ml/min/1.73 m² (difference range -5.9 to 26.3 ml/min/1.73 m²). The bias over the range 30 to 60 ml/min/1.73 m² was 13.2 ml/min/1.73 m² (difference range -16.8 to 88.3 ml/min/1.73 m²). In 25.4% of studies, eGFR was less than 60 ml/min/1.73 m² compared with 40.5% of rGFR studies. CONCLUSIONS: Awareness of the bias between eGFR and rGFR is important when assessing Radiology patients for risks of nephrotoxicity and Nephrogenic Systemic Fibrosis from contrast medium.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

Acetylcholine binding to Torpedo electroplax: relationship to acetylcholine receptors.

Binding of [(3)H]acetylcholine to a particulate fraction of Torpedo electroplax was measured by equilibrium dialysis. Two high-affinity sites present on phospholipoproteins bound acetylcholine reversibly, and binding was blocked by nicotinic drugs. Characteristics of this binding suggest that these phospholipoproteins may be acetylcholine receptors.

Differential expression of HLA-DQ alleles in peripheral blood mononuclear cells: alleles associated with susceptibility to and protection from autoimmune type 1 diabetes.

Differential expression of human leucocyte antigen (HLA) class II genes has been postulated to influence the risk of developing autoimmune disease. In this study, we investigated the relationship between the level of mRNA expression of DQA1 and DQB1 alleles in peripheral blood mononuclear cells and the influence of the alleles on susceptibility to type 1 diabetes (T1D). Transcripts from pairs of DQA1 and DQB1 alleles were quantified in 59 DQ-heterozygous individuals (29 patients with T1D and 30 healthy control subjects). Luciferase reporter gene assays were used to investigate the relative promoter activities of the alleles associated with high and low risk of disease. DQA1*0301 and the DQB1*06 group of alleles (*0601, *0602, *0603 and *0604) were generally overexpressed in comparison to other alleles. In contrast, mRNA for DQB1*0201/*0202 was generally less abundant than other DQB1 transcripts. These data correlated well with the relative promoter activities observed for the diabetes-associated alleles; the strongest promoters were those derived from DQA1*0301 and DQB1*0602, while a 700-bp fragment derived from the DQB1*0201 promoter showed the lowest activity of the DQB1 constructs. There was no simple correlation between the level of expression of specific DQ alleles and their influence on the risk of diabetes. The functional relevance of our findings and their implications for the pathogenesis of autoimmunity remain to be determined.

Dental abnormalities in rats after a single large dose of cyclophosphamide.

Delayed drug-related mortality in rats treated with a single high dose (75 mg/kg) of cyclophosphamide complicated experiments using this drug treatment. We observed that this delayed mortality was due to dental abnormalities including broken teeth, absent teeth, extra long teeth, and/or supernumerary teeth. These dental abnormalities developed about 140 days after treatment and, if left untreated, interfered with eating. Eventually, the untreated rats starved. Clipping their long teeth and feeding the rats powdered chow eliminated the deaths. Researchers should be aware that high doses of cyclophosphamide may result in dental abnormalities several months after the treatment.

Recovery in rats after spinal cord injury.

Previous studies from this laboratory have shown evidence of regeneration of long descending spinal motor tracts in rats after spinal cord transection and treatment to modify the animals' immune response. In this study, less extensive surgical lesions were combined with the most favorable drug treatment (75 mg per kilogram of cyclophosphamide in a single dose) in an effort to improve the prospects for regeneration. Less than complete spinal cord transections in the rat were frequently followed by clinical and electrophysiologic evidence of return of function. Such return of function appears to depend on a reorganization of the nervous system that results in the use of the few remaining fibers to transmit motor information rather than on regeneration. Immunosuppressive treatment had no effect on these results.

Moving segments region of interest attenuator for x-ray fluoroscopy.

Region of interest (ROI) imaging has previously been proposed as a means of reducing x-ray fluoroscopy radiation dose. Previous ROI attenuators made of partially attenuating metal plates change beam quality, which may lead to uncertainty in image restoration procedures. The design and construction of a prototype moving segments ROI attenuator (MS-ROI), which maintains beam quality across the whole field of view is described. The x-ray beam intensity is halved by 36 lead segments which are rapidly rotated between the x-ray tube and patient, with a central hole projecting a circular ROI at full intensity. Image processing techniques with automatic detection of the ROI boundary were used to homogenize image brightness across the whole image. Images restored using these techniques were judged to be visually acceptable, with a good match between pixel values inside and outside the ROI. Image contrast within the ROI was improved by 18% due to reduced scatter and veiling glare from the periphery. The introduction of the MS-ROI attenuator also results in a 48% increase in statistical noise in the area outside the ROI, with no significant change in object contrast. The patient entrance dose measured using the dose area product (DAP) method was reduced by 53.4% under manual exposure control, with the dose to operators reduced by 48.4% under automatic brightness control. Further work is needed to determine whether the attenuator can be used with pulsed fluoroscopy, and to reduce vibrational effects on the ROI boundary. The MS-ROI attenuator provides a more constant ratio of central-to-peripheral image intensity, and maintains uniform beam quality and image contrast across the whole image in comparison to simple metal plate attenuators.

A new rapid assay of oestrogens in pregnancy urine using the substrate native fluorescence.

A simple and rapid method is described for the quantitative determinations of free and conjugated oestrogens in pregnancy urine. The oestrogens are precipitated with ammonium sulphate and freed from non-oestrogenic compounds by solvent extraction. The conjugated oestrogens are hydrolysed by a beta-glucuronidase from Escherichia coli, and the total free oestrogens are extracted into ether and their fluorescence intensity at 310 nm in this solvent is determined. The method is rapid and precise for oestrogen levels at concentrations greater than 2 mug/ml (7 mumol/1). It is proposed that this method, which measures oestradiol and oestriol levels, be applied routinely to monitor feto-placental function in pregnancy. It offers advantages over other currently used assays in that less manipulative and technical skill is required to give a high level of precision and accuracy. An accurate estimate can be produced within 30-60 min of receipt of a 24-h uring specimen. Two variations of the method are also described. In one the ammonium sulphate precipitation step is omitted so as to give an even quicker assay procedure which determines conjugated oestrogens in the urine, and in the other oestriol only is determined.

PIP: A simple and rapid method for the measurement of free and conjugated estrogens during pregnancy is described. The method can give an accurate estimation within 30-60 minutes when estrogen concentrations are greater than 2 mcg/ml. Conjugated estrogens are hydrolysed by a beta-glucuronidase from Escherichia coli and free estrogens are extracted into ether and their fluorescence intensity at 310 nm is determined. The method has application in the routine monitoring of feto-placental function in pregnancy. 2 variations of the method, 1 which eliminates the ammonium sulphate precipitation step, are described.

A phantom and a procedure to obtain variable-object-contrast test images in gamma camera emission computed tomography (SPECT).

The value of test objects with a range of object contrast has been widely recognized for the testing of medical imaging equipment. A simple phantom is described, which, together with a data processing procedure, provides variable-contrast rod objects in gamma camera emission computed tomography (SPECT). There is only one compartment to fill with radioisotope, and data from hot rods, cold rods and a uniform section are available for analysis. The rod object contrast varies from 100% to 0%, with nine contrast steps used in this analysis. The measured image contrast in the transaxial slices is shown to be sensitive to variations in the system spatial resolution. With only one compartment to fill with radioisotope, this procedure is applicable for routine checking or optimization of gamma camera SPECT systems.

Performance assessment of a slat gamma camera collimator for 511 keV imaging.

The physical performance of a prototype slat collimator is described for gamma camera planar imaging at 511 keV. Measurements were made of sensitivity, spatial resolution and a septal penetration index at 511 keV. These measurements were repeated with a commercial parallel hole collimator designed for 511 keV imaging. The slat collimator sensitivity was 22.9 times that of the parallel hole collimator with 10 cm tissue equivalent scatter material, and 16.8 times the parallel hole collimator sensitivity in air. Spatial resolution was also better for the slat collimator than the parallel hole collimator (FWHM at 10 cm in air 17.9 mm and 21.2 mm respectively). Septal penetration was compared by a single value for the counts at 120 mm from the point source profile peak, expressed as a percentage of the peak counts, showing less penetration for the slat collimator than the parallel hole collimator (1.9% versus 3.6% respectively). In conclusion, these results show that the slat collimator may have advantages over the parallel hole collimator for 511 keV imaging, though the greater complexity of operation of the slat collimator and potential sources of artefact in slat collimator imaging are recognized.

The addition of computer simulated noise to investigate radiation dose and image quality in images with spatial correlation of statistical noise: an example application to X-ray CT of the brain.

This study validates a method to add spatially correlated statistical noise to an image, applied to transaxial X-ray CT images of the head to simulate exposure reduction by up to 50%. 23 patients undergoing routine head CT had three additional slices acquired for validation purposes, two at the same clinical 420 mAs exposure and one at 300 mAs. Images at the level of the cerebrospinal fluid filled ventricles gave readings of noise from a single image, with subtraction of image pairs to obtain noise readings from non-uniform tissue regions. The spatial correlation of the noise was determined and added to the acquired 420 mAs image to simulate images at 340 mAs, 300 mAs, 260 mAs and 210 mAs. Two radiologists assessed the images, finding little difference between the 300 mAs simulated and acquired images. The presence of periventricular low density lesions (PVLD) was used as an example of the effect of simulated dose reduction on diagnostic accuracy, and visualization of the internal capsule was used as a measure of image quality. Diagnostic accuracy for the diagnosis of PVLD did not fall significantly even down to 210 mAs, though visualization of the internal capsule was poorer at lower exposure. Further work is needed to investigate means of measuring statistical noise without the need for uniform tissue areas, or image pairs. This technique has been shown to allow sufficiently accurate simulation of dose reduction and image quality degradation, even when the statistical noise is spatially correlated.

Inter-observer reproducibility of quantitative radionuclide colonic transit imaging.

The colonic transit of an indium-111 enteric coated capsule was imaged with a gamma camera over a period of 3 days. The geometric centre of activity in the colon was calculated from regions drawn over four segments of the colon, plus a fifth segment as the estimated passed stool activity. Fifteen healthy subjects were scanned and the results analysed. The images were analysed by two observers to assess reproducibility of the geometric centre quantitative index (correlation, r = 0.985). In conclusion, although it can be difficult to identify the anatomical segments of the colon from the gamma camera images, by following a protocol with clear guidelines for ROI placement, good inter-observer reproducibility can be obtained.

Regional indices of relative hepatic arterial perfusion from dynamic liver scintigraphy: the variability of indices and the use of parametric imaging.

Regional indices of relative arterial hepatic perfusion have been studied in 21 control subjects following dynamic radiocolloid scintigraphy of the liver (DLS). Three different indices have been calculated: the hepatic perfusion index (HPI); the hepatic arterial ratio (HAR) and the mesenteric fraction (MF). Three regions were defined in the upper, mid and lower right hepatic lobes and the three indices were calculated for each region. There was reasonable agreement between regional values of the same index with inter-regional correlation coefficients above 0.7 and standard errors in straight line fits of less than 0.093. There were significant regional differences for (1-MF) and HPI indices, but not for HAR. The index (1-MF) was calculated for each pixel and presented as a parametric image in 16 control subjects. The parametric images indicated the raised regional arterial indices due to overlying lung, right kidney and aorta. Parametric images may be of value to show the hepatic area free of significant overlying tissue and therefore available for analysis by DLS. However, the results suggest that the observed variability of single pixel indices limit the potential of parametric imaging for the localization of small focal lesions.

A general software package for the handling of medical images.

PICS (portable imaging computer software), is a software system designed for handling and processing a variety of types of medical image. It has been designed to satisfy the following criteria: (a) the software should be portable between different items of hardware with minimal alteration; (b) there should be a simple operator interface to enable use by inexperienced users, while avoiding the need for experienced users to be directed through tedious menu trees; (c) the programming environment should enable simple integration of new data handling protocols. To meet these requirements the software was written in FORTRAN using structured subroutine organization. The software has basic image handling and processing facilities and contains a comprehensive set of nuclear medicine clinical protocols. Other facilities include alignment of images from different modalities with display of superimposed images and ability to handle, analyse and display three-dimensional data sets. Data transfer programs have been written to capture data from gamma camera, CT, MRI, ultrasound and radiographs by converting the images to a common data format. The system provides a hospital with a central digital image handling resource, enabling investigation of the value of digital image processing in potential clinical applications.

Hot or not? The 10% rule in sentinel lymph node biopsy for malignant melanoma revisited.

BACKGROUND: The surgeon needs a practical rule to follow when deciding whether to excise a lymph node during sentinel node biopsy (SLNB). The "10% rule" dictates that all nodes with a radiation count of greater than 10% of the hottest node and all blue nodes should be removed, and this study observes the effects of following this rule in SLNB in melanoma. METHODS: We reviewed the records of 665 patients with primary melanoma who underwent sentinel lymph node over a 5-year period (2007-2011). RESULTS: 2064 nodes were identified in 898 nodal basins in 665 patients. 141 (21%) patients had at least one positive sentinel node. 105 positive nodal basins were identified in which more than one sentinel node was removed. In 18 of these, a less radioactive node was positive for tumour when the most radioactive node was negative. Of 175 positive nodes 157 (90%) contained blue dye staining. For cases in which the positive sentinel node was not the hottest node, the positive node had apparent blue dye staining in all 18 cases (100%), and was the second hottest node in the basin. CONCLUSION: In this series removing just the hottest node and all blue nodes would not have missed a single positive basin and would have resulted in a 38% reduction in the number of nodes removed compared to those taken following the 10% rule, without changing the staging in any patient.