Radiation exposure to comforters and carers during paediatric molecular radiotherapy.

BACKGROUND: To show whether the incidental radiation exposure received by comforters and carers of children undergoing molecular radiotherapy was kept as low as reasonably achievable and was within English national dose constraints. PROCEDURE: The radiation exposure of adult comforters and carers was routinely monitored with a whole body personal dose meter while the child was in hospital. Data were collected on iodine-131 meta-iodobenzylguanidine (131 I-mIBG), lutetium-177 DOTATATE (177 Lu-DOTATATE), and iodine-131 sodium iodide (131 I-NaI) treatments. RESULTS: Data were available for 50 treatments with high-administered activity double-infusion 131 I-mIBG and 12 single administrations; 15 177 Lu-DOTATATE treatments and 28 131 I-NaI administrations. The median age was 7 years (1-18). The median administered activity of: 131 I-mIBG was 16.2 GBq (6.8-59 GBq) for double infusion patients and 8.1 GBq (5.26-16.25 GBq) for single administrations; 177 Lu-DOTATATE was 7.2 GBq (2.5-7.5 GBq); and 131 I-NaI was 3 GBq for thyroid remnant ablation and 5.5 GBq for cancer therapy. The median number of comforters and carers for all administrations was 2 (range 1-9). The median exposure values for comforters and carers for high-administered activity 131 I-mIBG administrations was 302 µSv (0-5282 µSv); for single fraction 131 I-mIBG 163 µSv (3-3104 µSv); 177 Lu-DOTATATE 6 µSv (1-79 µSv); and 131 I-NaI 37 µSv (0-274 µSv). Only one of the comforters and carers exceeded the dose constraint of 5 mSv. CONCLUSIONS: Doses to comforters and carers were in all but one case within the dose constraint nationally recommended by the Health Protection Agency, now part of Public Health England. New evidence is presented which show that comforter and carer radiation exposure levels from paediatric molecular radiotherapy in routine clinical practice are acceptably low. Pediatr Blood Cancer 2015;62:235-239. © 2014 Wiley Periodicals, Inc.

Sentinel node imaging in breast cancer using superficial injections: technical details and observations.

INTRODUCTION: Sentinel lymph node (SLN) biopsy is the evolving standard of care for the management of early breast cancer. Accurate identification of the SLN is paramount for success of this procedure. Various techniques are described for SLN identification, but the superficial injection techniques, advocated by the UK National Training Programme (NEW START), are validated, reproducible and rapid. Pre-operative lymphoscintigraphy provides a road map for the surgeon and requires a reporting template. METHODS: As one of the NEW START training institutions in the UK practising this technique, we reviewed a mature series of 100 unselected, consecutive SLN lymphoscintigraphy procedures. We correlated the imaging, operative and pathology findings and have provided technical details of the technique and a template for reporting SLN lymphoscintigrams. RESULTS: The SLN localisation rate was 99% with one failed imaging. Seven patients required delayed imaging. The mean activity of the radiocolloid injected was 14.4MBq (range 8.3-23 MBq). The SLNs were visualised in the ipsilateral axilla in 98 images, intramammary in 3, and internal mammary in 1. A mean of 1.35 nodes were classified as 'True' SLNs on imaging criteria. Intra-operatively, a mean of 1.91 SLNs were excised. 32 of 116 hot and blue nodes, 7 of 15 only blue nodes, 13 of 47 only hot and 7 of 13 parasentinel nodes harboured metastases. CONCLUSION: The NEW START recommended, combined superficial injection techniques, have high localisation rates. Pre-operative sentinel node imaging is recommended and a template for reporting is provided.

A training simulator for sentinel node biopsy in breast cancer: a new standard.

BACKGROUND: Sentinel node biopsy is becoming the staging investigation of choice for early breast cancer. Optimal identification of the sentinel node requires the utilization of a radionuclide in combination with blue dye. Gamma probe guided surgery is a skill that is currently unfamiliar to many surgeons. Appropriate training within the surgical skills laboratory could play a major role in the widespread implementation of this technique, but no suitable model currently exists for this purpose. AIM: To develop a realistic phantom for the teaching and practice of the core new skills required of a surgeon to perform gamma probe guided sentinel node biopsy in breast cancer. METHODS: We describe the development of our sentinel node biopsy simulator which consists of a torso with its arm extended in an operating position. The replaceable breast and axilla are constructed from a thermoplastic elastomer gel, which has similar physical and radiation attenuation properties to that of human tissue. Radionuclide injection sites and radioactive sentinel nodes are simulated by hollow blue coloured PVC beads filled with Technetium-99m. The model allows demonstration and practice of injection techniques, imaging techniques and gamma probe guided removal of sentinel nodes. CONCLUSION: We believe that training for sentinel node biopsy should begin in the surgical skills laboratory. The model we have developed is able to provide an accurate simulation of all new practical skills required for accurate sentinel node identification. It is an important aid to training in the sentinel lymph node biopsy procedure for breast carcinoma.

A new approach to pre-treatment assessment of the N0 neck in oral squamous cell carcinoma: the role of sentinel node biopsy and positron emission tomography.

OBJECTIVES: Pre-operative staging of the clinically N(0) neck in patients with oral squamous cell carcinoma is hindered by the relatively high false negative/positive rates of conventional imaging techniques. The aim of this study is to evaluate the utility of (18)F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) and sentinel lymph node (SLN) imaging and biopsy to determine the true disease status of the loco-regional lymphatics. METHODS: Nineteen patients with biopsy proven disease without palpable or radiological evidence of neck metastases underwent pre-operative (18)F-FDG PET and SLN imaging. All patients underwent whole-body FDG PET and a single view of the head and neck. SLN technique was performed using four peri-tumoural injections of (99m)Tc labeled albumin colloid each of 10 MBq. Dynamic and static imaging followed in the antero-posterior and lateral projections. At operation 1 ml of 2.5% Patent Blue Dye and a hand held gamma probe (Neoprobe 1500) were used in combination to identify and remove the SLN. Surgery then continued along conventional lines including a neck dissection. Histology of the resultant specimen was correlated with that of the SLN and pre-operative imaging. RESULTS: In all patients SLN harvesting was feasible. In 15/19 patients the SLN(s) and the residual neck dissection were -ve for tumour. In 3/19 patients the SLN(s) were +ve for tumour as were other neck nodes. In 1/19 patients the SLN was -ve but another single tumour +ve node was identified in the neck. This patient occurred early in our series with a SLN close to the primary tumour. (18)F-FDG PET failed to identify nodal disease in all four patients with histologically proven lymph node metastases. The size of these nodes ranged from 12 mm x 10 mm x 3 mm to 25 mm x 15 mm x 10 mm. CONCLUSION: SLN imaging and biopsy with probe and Patent Blue Dye guided harvest is feasible in patients with oral squamous cell carcinoma and can predict cervical nodal status. (18)F-FDG PET may be less useful.

Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules.

BACKGROUND: 4-Aminosalicylic acid has the potential for use in the treatment of diseases of the colon. AIM: To assess the feasibility of delivering 4-aminosalicylic acid directly to the colon using a hydroxypropylmethylcellulose capsule coated with a mixture of amylose, a polysaccharide metabolized by bacterial enzymes in the colon, and ethylcellulose. METHODS: Seven healthy male volunteers received, on three separate occasions, an uncoated or amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsule containing 4-aminosalicylic acid Na (550 mg), or an intravenous injection of 4-aminosalicylic acid Na (135 mg). The capsules were radiolabelled with 99mTc to allow their positions in the gastrointestinal tract to be followed using a gamma camera. Plasma and urine samples were collected and assayed for 4-aminosalicylic acid and metabolite concentrations. RESULTS: The uncoated capsules broke down within 10 min in the stomach, allowing rapid and complete absorption of the drug. The coated capsules remained intact in the upper gastrointestinal tract, and had a median gastric emptying time of 61 min (interquartile range, 77 min) and a median colon arrival time of 363 min (interquartile range, 185 min). For the coated capsules, only the metabolite was detected in the plasma and/or urine after the capsules had reached the colon. CONCLUSIONS: The specific coating protected the drug until the capsule reached the colon, where 4-aminosalicylic acid was slowly released and absorbed. Thus, such a formulation has the potential for use in the treatment of inflammatory bowel disease.

The role of dynamic imaging in sentinel lymph node biopsy in breast cancer.

The aim of this study was to evaluate the role of dynamic imaging in sentinel lymph node (SLN) biopsy in breast cancer. Patients with T1/T2, N0 invasive breast cancer underwent SLN localisation using intra-dermal injection of 15 MBq of 99mTc-nanocolloid. Gamma camera anterior-oblique dynamic imaging commenced simultaneously with tracer administration for 45 min, and was followed by anterior and lateral static imaging. Dynamic imaging data was reformatted into image files of different time-frames. Patterns of uptake were analysed using the sequences of dynamic frames and time-activity curve (TAC). SLN localisation was successful in 70/73 studies (96%) in 72 patients. Imaging information was present within the first 15 min of dynamic imaging in 67/70 studies (96%). Critical analysis of dynamic data helped to differentiate true SLN from secondary echelon nodes in eight studies and transient foci of radioactivity in six studies. In 17 studies, SLN contained metastatic disease. The detection of SLN metastasis was independent from the use of dynamic imaging. Dynamic imaging improves the interpretation of preoperative SLN imaging for breast cancer, but does not contribute significantly to the successful detection of SLN. Hence, preoperative dynamic imaging is not necessary in SLN biopsy for breast cancer.

Optimal nuclear medicine support in sentinel node detection.

The correct identification of sentinel lymph nodes (SLNs) is paramount if this technique is to become the standard of care in the management of early disease in surgical oncology. Despite the apparent attraction and ease of this approach, a detailed understanding of its different technical components is vital. High sensitivity, reproducibility, and accuracy levels must be achieved in the identification and discrimination of the SLN if the extent and place of the standard lymph node diagnostic dissections can be challenged. This article reviews the technology and methodology and gives indications of the possible progress to be achieved.

The effect of polyethylene glycol 400 on gastrointestinal transit: implications for the formulation of poorly-water soluble drugs.

PURPOSE: To assess the effect of polyethylene glycol 400 (PEG 400), a pharmaceutical excipient frequently employed to enhance the solubility and bioavailability of poorly water-soluble drugs, on the gastrointestinal transit of liquid and pellet preparations in human subjects using gamma scintigraphy. METHODS: Ten, healthy male volunteers each received, on separate occasions, a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). Non-disintegrating pellets of size 1.4-1.7 mm. encapsulated within a hard gelatin capsule, were simultaneously administered on both occasions to act as a marker for solid dosage form transit. The liquid and pellet preparations were radiolabelled with 111In and 99mTc respectively thus enabling their positions within the gastrointestinal tract to be followed using a gamma camera. RESULTS: Rapid liquid emptying from the stomach was observed, with no significant difference noted in the gastric residence times of the two preparations. Caecum arrival times for the liquid preparations were significantly different by virtue of their differential rates of transit through the small intestine. The mean small intestinal liquid transit time for the control preparation was 236 min whereas the corresponding value for the PEG 400-containing test preparation was 153 min. This 35% reduction in transit time was attributed to the presence of PEG 400. Pellet transit was largely unaffected by the presence of PEG 400. CONCLUSIONS: These findings clearly demonstrate that PEG 400 has a marked accelerating effect on small intestinal liquid transit, which in turn has implications for the formulation of poorly water-soluble drugs with PEG 400.

Radiation safety of the sentinel lymph node technique in breast cancer.

Many publications attest to the potential of the sentinel lymph node technique in advancing the clinical management of melanoma and, more recently, breast cancer. Whilst not yet universally regarded as the standard of care, the technique is gaining wide acceptance. Use of a radiolabelled colloidal tracer is central to optimising sensitivity, and this brings with it the need to address radiation safety issues relating to the use of radioactive materials in the operating theatre and pathology laboratory, and the generation of radioactive waste. The radiation dose to the patient should also be determined if the professional is to reassure the patient by placing this in its proper context. For the purpose of this investigation, biodistribution data were obtained from patient studies to quantify the migration of tracer beyond the injection site, thereby permitting a detailed assessment of the internal dosimetry of the tracer and the resulting radiation dose to the patient. Uptake of tracer in the sentinel nodes, reticulo-endothelial system and circulating blood was investigated. The radiation dose to surgical staff was recorded using whole-body monitors and extremity dosimeters worn at the fingers. Clinical waste in the operating theatre was monitored and the radioactive content of significantly contaminated items determined. The radiation dose to pathology staff was estimated from knowledge of the radioactive content of the specimens obtained and a study of work practices. Migration of tracer was found to be minimal, with greater than 95% retention at the injection site. The effective dose resulting to the patient was 2.1x10(-2) mSv/MBq, with a mean breast dose of 7.2x10(-1) mGy/MBq. A mean whole-body dose of 0.34 microSv was received by surgical staff per procedure, with a mean finger dose of 0.09 mSv (90 microSv). Radiation doses received by pathology staff will be predominantly below measurable levels and are likely to be negligible unless primary specimens from a large number of studies are analysed promptly upon their excision. At operation, surgical swabs can become significantly contaminated and have been found to contain up to 22% of the administered activity, dependent upon the surgical procedure performed. It is concluded that moderate activities of technetium-99m labelled tracer are administered to the patient, and the radiation risk to the patient is consequently low relative to that from many other medical exposures. The radiation doses to staff groups involved in all aspects of the technique are low, and under normal circumstances and levels of workload, routine radiation monitoring will not be required. Standard biohazard precautions prevent direct intake of radioactive contamination. Radioactive waste is created in the operating theatre, and may be generated in the pathology laboratory if specimens are not routinely stored until fully decayed. This will require special handling if the disposal of radioactive material is not permitted.

Clinical evaluation of technetium-99m-L,L-ethylenedicysteine in patients with chronic renal failure.

UNLABELLED: Technetium-99m-L,L-ethylenedicysteine (99mTc-L,L-EC), a new renal radiopharmaceutical, has been shown to have similar excretion characteristics but a higher plasma clearance than 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) in normal volunteers and patients with obstructive nephropathy. This study evaluated 99mTc-L,L-EC in patients with chronic renal failure. METHODS: The clearance of 99mTc-L,L-EC was compared with that of 125l-hippuran in 26 patients with varying degrees of chronic renal impairment (serum creatine 168-1163 mumol/liter). All 26 patients also were imaged with 99mTc-L,L-EC (70-80 MBq). Fifteen patients had further imaging with 99mTc-MAG3 (100 MBq) the following day. RESULTS: A subjective analysis of the 99mTc-L,L-EC images revealed that all were of acceptable quality regardless of creatinine level. In the 15 patients who were imaged with both 99mTc-L,L-EC and 99mTc-MAG3, general image quality and target-to-background ratios were similar. Time-activity curves and mean parenchymal transit times obtained with the two agents were almost identical. Plasma clearance values (mean +/- s.d.) of 99mTc-L,L-EC and 125l-hippuran were 81 +/- 68 ml/min and 114 +/- 104 ml/min, respectively. Mean 99mTc-L,L-EC clearance was 71% of the mean 125l-hippuran value. CONCLUSION: Technetium-99m-L,L-EC provides equally high-quality images to 99mTc-MAG3 in patients with chronic renal failure. Technetium-99m-L,L-EC clearance more closely resembles that of hippuran than does 99mTc-MAG3 clearance. These features together with its ease of preparation make 99mTc-L,L-EC an attractive alternative to 99mTc-MAG3 in patients with chronic renal failure.

A reappraisal of current methods for the assessment of planar gamma camera performance.

This study reappraises the acquisition parameters defined by three current protocols for the specification of planar gamma camera performance. These are the manufacturer Standards of the National Electrical Manufacturers' Association [1] and the International Electrotechnical Commission [2], and the user-orientated protocol of the UK Department of Health (DoH, formerly DHSS) Gamma Camera Performance Assessment Group [3]. The study looks specifically at three major planar performance characteristics: intrinsic non-uniformity, intrinsic spatial resolution and intrinsic non-linearity (spatial distortion). Acquisition parameters specified for these characteristics are investigated by testing a range of values for each parameter around those figures currently advocated by the three protocols. Those acquisition parameters which may be relaxed without loss of data integrity are identified and the adoption of revised parameters for some measurements within the DoH assessment protocol is suggested. Reviewing the data obtained, observations are made regarding the accuracy of some tests performed regularly for quality control purposes. The feasibility and advantages of incorporating some suitably modified DoH performance assessment tests within a routine quality assurance protocol for the gamma camera are also discussed.

Intraoperative localization of recurrent medullary carcinoma of the thyroid using indium-111 pentetreotide and a nuclear surgical probe.

A patient with recurrent medullary thyroid cancer in the neck in whom previous surgery for recurrence had been undertaken with only partial success had the diseased tissue localized preoperatively by indium-111 pentetreotide. Scanning with technetium-99m V dimercaptosuccinic acid and iodine-123 metaiodobenzylguanidine failed to localize the tumor. Utilization of a nuclear surgical probe after preoperative 111In pentetreotide allowed accurate surgical localization of the tumour tissue.

Preoperative imaging of colorectal cancers. Targeting the epithelial membrane antigen with a radiation-labeled monoclonal antibody.

The epithelial membrane antigen (EMA) is expressed by the majority of colorectal cancers but has not previously been investigated as a target for radiation-labeled monoclonal antibodies (MoAb) in the imaging of patients with colorectal cancer. A rat IgG2a MoAb that recognizes EMA, ICR2, was labeled with Indium-111 (100 megabecquerel per milligram [MBq/mg]MoAb) using the bicyclic anhydride of the chelating agent diethylene triamine pentacetic acid (ccDTPA) and was administered intravenously to 22 patients known to have or thought to have colorectal cancer. Daily gamma camera imaging was performed for 3 days during the time between the administration of the radiation-labeled antibody and surgical procedure. At operation, the biopsies were done of the tumors and the normal colon, and the uptake of radiation-labeled MoAb was measured in a gamma well-counter. Immunocytochemistry for EMA expression also was done on resected tumors. Independent unblinded and blinded reporting was done on all scans. The sensitivity of 111In-ICR2 for detecting cancers preoperatively was 80% and 60%, respectively, on unblinded and blinded reporting, and the corresponding specificity 20% and 60%. The low unblinded specificity was attributable to a false-positive localization in severely dysplastic benign tumors (n = 2) and inflammatory tissue (n = 2). Liver metastases present in three patients were cold relative to normal liver. Lymph node metastases were localized in 1 of 6 patients preoperatively. The mean absolute uptake of 111In-ICR2 in tumor tissue was 7.75 +/- 3.77 x 10(-3) percent of injected dose per gram, and the ratio to normal colon was 2.10 +/- 0.92:1. On immunohistochemistry, EMA was expressed by 16 of the 17 primary cancers, both dysplastic adenomas, and all nodal metastatic deposits. EMA-negative tumors (1 cancer + 1 colonic lipoma) had negative antibody scans, and patients whose tumor was negative or only focally positive for EMA expression had lower tumor/normal colon ratios of radioactivity (1.30 +/- 0.26 versus 2.45 +/- 0.65, P = 0.005) on gamma well-counting of excised specimens. These results suggest a possible role for 111In-ICR2 in the detection of colorectal cancer and metastases but not its liver deposits.

Intraoperative localization of colorectal cancers using radiolabelled monoclonal antibodies.

Radiation detectors may allow the intraoperative localization of small cancer deposits following administration of radiolabelled tumour-associated antibodies. This technique was evaluated in 16 patients with colorectal tumours (14 cancers, one adenoma, one lipoma) with the 111In-labelled monoclonal antibody (MAb) ICR2 which recognizes the tumour-associated epithelial membrane antigen (EMA). At operation counting was carried out (3 x 20 s per site) using a hand-held radiation probe over the primary lesions and any palpable lymph nodes in the mesocolon. The tumour to normal colon (T/NC) ratio of counts recorded at operation was more than 1.5:1 in eight of the 14 patients with cancer (mean(s.d.), 1.54(0.41):1) and 0.91:1 and 1.06:1 respectively in the two patients with benign tumours. Node to normal colon ratios were higher in lymph nodes containing metastases. The uptake of radiolabelled antibody (T/NC ratio) was higher in EMA-expressing cancers than in those not expressing the target antigen (mean(s.d.), 2.45(0.65):1 versus 1.40(0.20):1, P = 0.019). An abdominal tumour model was also developed. Radioactively filled containers of 0.5-10 ml representing tumour deposits were suspended in a tank of 111In solution representing the background activity found in normal tissues. The ratio of radioactivity in the 'tumour' to that of background varied from 2:1 to 8:1. The 'tumour' was considered to be detectable if the mean counts recorded over the 'tumour' exceeded the mean of counts recorded over background by three standard deviations. At a ratio of 2:1 only 'tumours' greater than 5 ml could be detected with a sodium iodide probe and those over 10 ml could be detected with a cadmium telluride (CdTe) probe. At a ratio of 8:1, 'tumours' of 0.5 ml could be detected with either probe. At all ratios and counting periods the NaI probe was more sensitive than the CdTe.

Evaluation of a technique for the intraoperative detection of a radiolabelled monoclonal antibody against colorectal cancer.

Occult tumour deposits may be localised at operation with a radiation detecting probe following the administration of a radiolabelled monoclonal antibody (MoAb) recognising a tumour-associated antigen. We have recently evaluated the clinical usefulness of this technique in detecting primary colorectal tumours targetted with an indium-111 MoAb. In the present study the physical characteristics of the two detector systems used were investigated; a sodium iodide [NaI(Tl)] scintillation detector and a cadmium telluride (CdTe) semiconductor probe. Limitations of the technique in use have been examined by testing the statistical significance of tumour detection using an abdominal phantom based on the currently available clinical biodistribution data for tumour uptake of radiolabelled MoAbs. The effect of tumour volume, antibody uptake, collimation and counting conditions was examined. Results indicate that tumours of 10 ml volume may be detected with the NaI(Tl) probe at the lowest levels of radiolabelled antibody uptake currently reported in the literature but that at higher published levels, lesions as small as 1 ml may be identified with both detector systems. Detector sensitivity and limited antibody specificity restrict the usefulness of the technique, although moderate improvements in tumour uptake may allow the detection of tumour deposits not clinically apparent. The statistical significance criterion used for this study could be an accurate and reliable indicator for tumour detection in vivo.