Hybrid intraoperative imaging techniques in radioguided surgery: present clinical applications and future outlook.

PURPOSE: This review aims to summarise the hybrid modality radioguidance techniques currently in clinical use and development, and to discuss possible future avenues of research. Due to the novelty of these approaches, evidence of their clinical relevance does not yet exist. The purpose of this review is to inform nuclear medicine practitioners of current cutting edge research in radioguided surgery which may enter standard clinical practice within the next 5-10 years. Hybrid imaging is of growing importance to nuclear medicine diagnostics, but it is only with recent advances in technology that hybrid modalities are being investigated for use during radioguided surgery. These modalities aim to overcome some of the difficulties of surgical imaging while maintaining many benefits, or providing entirely new information unavailable to surgeons with traditional radioguidance. METHODS: A literature review was carried out using online reference databases (Scopus, PubMed). Review articles obtained using this technique were citation mined to obtain further references. RESULTS: In total, 2367 papers were returned, with 425 suitable for further assessment. 60 papers directly related to hybrid intraoperative imaging in radioguided surgery are reported on. Of these papers, 25 described the clinical use of hybrid imaging, 22 described the development of new hybrid probes and tracers, and 13 described the development of hybrid technologies for future clinical use. Hybrid gamma-NIR fluorescence was found to be the most common clinical technique, with 35 papers associated with these modalities. Other hybrid combinations include gamma-bright field imaging, gamma-ultrasound imaging, gamma-ß imaging and ß-OCT imaging. The combination of preoperative and intraoperative images is also discussed. CONCLUSION: Hybrid imaging offers new possibilities for assisting clinicians and surgeons in localising the site of uptake in procedures such as in sentinel node detection.

Investigation of an SFOV hybrid gamma camera for thyroid imaging.

The Hybrid Compact Gamma Camera (HCGC) is a small field of view (SFOV) portable hybrid gamma-optical camera intended for small organ imaging at the patient bedside. In this study, a thyroid phantom was used to determine the suitability of the HCGC for clinical thyroid imaging through comparison with large field of view (LFOV) system performance. A direct comparison with LFOV contrast performance showed that the lower sensitivity of the HCGC had a detrimental effect on image quality. Despite this, the contrast of HCGC images exceeded those of the LFOV cameras for some image features particularly when a high-resolution pinhole collimator was used. A clinical simulation showed that thyroid morphology was visible in a 5 min integrated image acquisition with an expected dependency on the activity within the thyroid. The first clinical use of the HCGC for imaging thyroid uptake of (123)I is also presented. Measurements indicate that the HCGC has promising utility in thyroid imaging, particularly as its small size allows it to be brought into closer proximity with a patient. Future development of the energy response of the HCGC is expected to further improve image detectability.

Measurement of gastric meal and secretion volumes using magnetic resonance imaging.

MRI can assess multiple gastric functions without ionizing radiation. However, time consuming image acquisition and analysis of gastric volume data, plus confounding of gastric emptying measurements by gastric secretions mixed with the test meal have limited its use to research centres. This study presents an MRI acquisition protocol and analysis algorithm suitable for the clinical measurement of gastric volume and secretion volume. Reproducibility of gastric volume measurements was assessed using data from 10 healthy volunteers following a liquid test meal with rapid MRI acquisition within one breath-hold and semi-automated analysis. Dilution of the ingested meal with gastric secretion was estimated using a respiratory-triggered T1 mapping protocol. Accuracy of the secretion volume measurements was assessed using data from 24 healthy volunteers following a mixed (liquid/solid) test meal with MRI meal volumes compared to data acquired using gamma scintigraphy (GS) on the same subjects studied on a separate study day. The mean ± SD coefficient of variance between 3 observers for both total gastric contents (including meal, secretions and air) and just the gastric contents (meal and secretion only) was 3 ± 2% at large gastric volumes (>200 ml). Mean ± SD secretion volumes post meal ingestion were 64 ± 51 ml and 110 ± 40 ml at 15 and 75 min, respectively. Comparison with GS meal volumes, showed that MRI meal only volume (after correction for secretion volume) were similar to GS, with a linear regression gradient ± std err of 1.06 ± 0.10 and intercept -11 ± 24 ml. In conclusion, (i) rapid volume acquisition and respiratory triggered T1 mapping removed the requirement to image during prolonged breath-holds (ii) semi-automatic analysis greatly reduced the time required to derive measurements and (iii) correction for secretion volumes provided accurate assessment of gastric meal volumes and emptying. Together these features provide the scientific basis of a protocol which would be suitable in clinical practice.

A scheme for assessing the performance characteristics of small field-of-view gamma cameras.

Existing protocols for assessing the performance characteristics of large field-of-view (LFOV) gamma cameras can be inappropriate and require modification for use with small field-of-view (SFOV) gamma camera systems. This communication proposes a generic scheme suitable for evaluating the performance characteristics of SFOV gamma cameras, based on modifications to the standard procedures of NEMA NU1-2007. Key differences in methodology between tests for LFOV and SFOV gamma cameras are highlighted along with the rationale for these changes. It is envisaged that this scheme will provide more appropriate methods for equipment characterisation, ensuring quality and consistency for all SFOV cameras.

Characterisation of a high resolution small field of view portable gamma camera.

A handheld, high-resolution small field of view (SFOV) pinhole gamma camera has been characterised using a new set of protocols adapted from standards previously developed for large field of view (LFOV) systems. Parameters investigated include intrinsic and extrinsic spatial resolution, spatial linearity, uniformity, sensitivity, count rate capability and energy resolution. Camera characteristics are compared to some clinical LFOV gamma cameras and also to other SFOV cameras in development.

Novel MRI tests of orocecal transit time and whole gut transit time: studies in normal subjects.

BACKGROUND: Colonic transit tests are used to manage patients with Functional Gastrointestinal Disorders. Some tests used expose patients to ionizing radiation. The aim of this study was to compare novel magnetic resonance imaging (MRI) tests for measuring orocecal transit time (OCTT) and whole gut transit time (WGT), which also provide data on colonic volumes. METHODS: 21 healthy volunteers participated. Study 1: OCTT was determined from the arrival of the head of a meal into the cecum using MRI and the Lactose Ureide breath test (LUBT), performed concurrently. Study 2: WGT was assessed using novel MRI marker capsules and radio-opaque markers (ROMs), taken on the same morning. Studies were repeated 1 week later. KEY RESULTS: OCTT measured using MRI and LUBT was 225 min (IQR 180-270) and 225 min (IQR 165-278), respectively, correlation r(s) = 0.28 (ns). WGT measured using MRI marker capsules and ROMs was 28 h (IQR 4-50) and 31 h ± 3 (SEM), respectively, correlation r(s) = 0.85 (p < 0.0001). Repeatability assessed using the intraclass correlation coefficient (ICC) was 0.45 (p = 0.017) and 0.35 (p = 0.058) for MRI and LUBT OCTT tests. Better repeatability was observed for the WGT tests, ICC being 0.61 for the MRI marker capsules (p = 0.001) and 0.69 for the ROM method (p < 0.001) respectively. CONCLUSIONS & INFERENCES: The MRI WGT method is simple, convenient, does not use X-ray and compares well with the widely used ROM method. Both OCTT measurements showed modest reproducibility and the MRI method showed modest inter-observer agreement.

A three dimensional drive system for use with fillable emission phantoms for SPECT and PET imaging.

Respiratory motion artefacts pose significant challenges for imaging of the lung and thorax. Dynamic phantoms have previously been applied to the study of respiratory motion, however, most moving platforms have been capable of movement in either one or two dimensions only. We describe a moving platform suitable for SPECT-CT and PET-CT imaging. The platform allows a fillable emission phantom to simulate rigid motion in three dimensions. Elliptical periodical motion of 1.5 cm in all three orthogonal planes was simulated using a series of cams moving a baseplate up and across a slope of 45°. The frequency of movement can be varied manually between 5 and 25 cycles per minute in a known calibrated and reproducible manner (This encompasses the range of physiological respiratory motion). Preliminary studies demonstrated that the phantom can be used to identify motion parameters and for the qualitative assessment of motion blurring in reconstructed images.

Reproducibility of neutron activated Sm-153 oral dose formulations intended for human administration.

Neutron activation of Sm-152 offers a method of radiolabeling for the in vivo study of oral dose formulations by gamma scintigraphy. Reproducibility measurements are needed to ensure the robustness of clinical studies. 204 enteric-coated guaifenesin core tablets (10mg of Sm(2)O(3)) were irradiated by thermal neutrons to achieve 1 MBq at 48 h. Administered activities were 0.86±0.03 MBq. Good reproducibility (CV=3.5%) was observed over 24 weeks ensuring that volunteer doses were within the dose reference level of 0.8 mSv.

Comparison of the epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African American women.

BACKGROUND: Acne vulgaris is a common skin disease with a large quality of life impact, characterized by comedones, inflammatory lesions, secondary dyspigmentation and scarring. There are few large objective studies comparing acne epidemiology between racial and ethnic groups. OBJECTIVE: This study aimed to define the prevalence and subtypes of acne in women of different racial groups from four ethnicities. METHODS: The sample consisted of 2895 (384 African American, 520 Asian, 1295 Caucasian, 258 Hispanic and 438 Continental Indian) women ranging in age from 10 to 70 years. Photographs of subjects were graded for acne lesions, scars, dyspigmentation, and measurements taken of sebum excretion and pore size. RESULTS: Clinical acne was more prevalent in African American and Hispanic women (37%, 32% respectively) than in Continental Indian, Caucasian and Asian (23%, 24%, 30% respectively) women. All racial groups displayed equal prevalence of both subtypes of acne with the exception of Asians, for whom inflammatory acne was more prevalent than comedonal (20% vs. 10%) acne, and in Caucasians, for whom comedonal acne was more prevalent than inflammatory (14% vs. 10%) acne. Hyperpigmentation was more prevalent in African American and Hispanic (65%, 48% respectively) than in Asian, Continental Indian and Caucasian (18%, 10%, 25% respectively) women. Dyspigmentation and atrophic scarring were more common in African American and Hispanic women than in all other ethnicities. There was a negative correlation between pore size and skin lightness for all ethnicities. Sebum production was positively correlated with acne severity in African American, Asian and Hispanic women, and pore size was positively correlated with acne in African American, Asian and Continental Indian women, (for all above results, P<0.05). LIMITATIONS: Only female participants were recruited. Data collection was restricted to four cities, with some ethnicities from single cities. Acne was evaluated only on the left side of the face and the two-dimensional nature of photography may not capture all skin surface changes. CONCLUSION: Acne prevalence and sequelae were more common in those with darker skin types, suggesting that acne is a more heterogeneous condition than previously described and highlight the importance of skin-colour tailored treatment.

Design and use of mini-phantoms for high resolution planar gamma cameras.

There is now wide spread interest in the application of small field of view gamma cameras for clinical use in operating theatres, intensive care units and bedside imaging. The development of these imaging systems some of which have improved spatial resolution has necessitated a reappraisal of the suitability of conventional phantoms intended for use with gamma cameras. The testing of imagers having increased system resolution requires phantoms and test objects of smaller dimensions. We have investigated the use of high resolution mini-phantoms for the evaluation of planar imaging devices with spatial resolution of the order of 1 mm. We present images of a number of phantoms that show their suitability for evaluating high resolution planar gamma cameras. It is also apparent that there are a number of practical difficulties that have not been previously reported when using liquid filled phantoms with hole sizes between 1 and 4 mm. In particular problems of filling small diameter holes and liquid surface tension effects can limit the utility of these phantoms. Initial observations when imaging mini-phantoms with a high resolution CCD based gamma camera are presented.

Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging.

BACKGROUND: 5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility. AIM: To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry. METHODS: Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed. RESULTS: Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated. CONCLUSIONS: The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs.

Comparison of lateral thermal spread using monopolar and bipolar diathermy, the Harmonic Scalpel and the Ligasure.

BACKGROUND: Electrosurgery for dissection and haemostasis should be associated with minimal thermal spread to surrounding tissues. This study investigated lateral thermal spread following ex vivo application of four commonly utilized instruments. METHODS: Monopolar and bipolar diathermy (power settings 20, 30 and 40 W), the Harmonic Scalpel and Ligasure (power settings 1, 3 and 5) were studied after application to standardized porcine muscle cuts for 5, 10 or 15 s. Temperatures generated at the tips of the instruments, in the tissues adjacent to the tips and 1 cm away were recorded. RESULTS: Following a 5-s application at the highest power setting, the highest mean(s.d.) temperatures recorded at the tips of monopolar and bipolar diathermy, Harmonic Scalpel and Ligasure instruments were 78.9(4.1), 41.9(2.2), 47.6(2.5) and 44.2(2.6) degrees C respectively. Temperatures at the instrument tips after use for 15 s remained above 42 degrees C for 55, 25, 15 and 15 s respectively. Applying monopolar diathermy (10 s at 40 W) resulted in a temperature recording of 59.2(2.2) degrees C in tissues 1 cm away from the tip of the instrument. CONCLUSION: The degree of lateral thermal spread varied with instrument type, power setting and application time. Monopolar diathermy resulted in the highest temperatures and the greatest degree of thermal spread in tissues.

A low-cost phantom for simple routine testing of single photon emission computed tomography (SPECT) cameras.

A simple sphere test phantom has been developed for routine performance testing of SPECT systems in situations where expensive commercial phantoms may not be available. The phantom was based on a design with six universal syringe hubs set in the frame to support a circular array of six glass blown spheres of different sizes. The frame was then placed into a water-filled CT abdomen phantom and scanned with a triple head camera system (Philips IRIX, USA). Comparison was made with a commercially available phantom (Deluxe Jaszczak phantom). Whereas the commercial phantom demonstrates cold spot resolution, an important advantage of the sphere test phantom was that hot spot resolution could be easily measured using almost half (370MBq) of the activity recommended for use in the commercial phantom. Results showed that the contrast increased non-linearly with sphere volume and radionuclide concentration. The phantom was found to be suitable as an inexpensive option for daily performance tests.

A global role for zebrafish klf4 in embryonic erythropoiesis.

There are two waves of erythropoiesis, known as primitive and definitive waves in mammals and lower vertebrates including zebrafish. The founding member of the Kruppel-like factor (KLF) family of CACCC-box binding proteins, EKLF/Klf1, is essential for definitive erythropoiesis in mammals but only plays a minor role in primitive erythropoiesis. Morpholino knockdown experiments have shown a role for zebrafish klf4 in primitive erythropoiesis and hatching gland formation. In order to generate a global understanding of how klf4 might influence gene expression and differentiation, we have performed expression profiling of klf4 morphants, and then performed validation of many putative target genes by qRT-PCR and whole mount in situ hybridization. We found a critical role for klf4 in embryonic globin, heme synthesis and hatching gland gene expression. In contrast, there was an increase in expression of definitive hematopoietic specific genes such as larval globin genes, runx1 and c-myb from 24 hpf, suggesting a selective role for klf4 in primitive rather than definitive erythropoiesis. In addition, we show klf4 preferentially binds CACCC box elements in the primitive zebrafish beta-like globin gene promoters. These results have global implications for primitive erythroid gene regulation by KLF-CACCC box interactions.

Hypertension and impaired renal function accompany juvenile obesity: the effect of prenatal diet.

Obesity has been suggested to have a detrimental impact on kidney structure and function, leading to focal glomerulosclerosis and hypertension. It is also associated with hyperleptinemia and elevated renal sympathetic nerve activity. Prenatal undernutrition promotes postnatal obesity, hypertension, and an altered renal structure and function. In this study, we examined the effects of prenatal nutrient restriction and juvenile obesity in sheep. We found that juvenile obesity led to chronic hyperleptinemia and reduced renal function as assessed by nuclear scintigraphy. Additional factors include hypertension, glomerulosclerosis, and increased kidney apoptosis. Prenatal undernutrition, synchronous with early kidney development, coupled postnatally with juvenile obesity had no effect on systemic pathophysiological sequalae associated with obesity per se. Hypertension, hyperleptinemia, and poor renal function were all observed in this group. All indices of renal pathology such as increased expression of proinflammatory cytokines, angiotensin II, glucocorticoid receptors, and increased apoptosis and glomerulosclerosis were entirely absent in obese prenatally undernourished offspring. Our data indicate that juvenile obesity per se leads to systemic hypertension and renal structural and functional pathology. Prenatal undernutrition effectively abolishes any renal histopathology associated with juvenile obesity.

Radiolabelled aptamers for tumour imaging and therapy.

Advances in biotechnology have led to new techniques for the design, selection and production of ligands suitable for molecular targeting. One promising approach is the production of specific receptor binding molecules based on defined nucleic acid sequences that are capable of recognising a wide array of target molecules. These oligonuclide ligands are known as aptamers. The technology that allows production of aptamer molecules is known as systematic evolution of ligands by exponential enrichment (SELEX). Using these techniques, aptamers can now be produced rapidly, inexpensively, and with high homogeneity. Furthermore, they are stable over long term storage at ambient room temperatures. A monomeric aptamer is small in size, with a molecular weight as low as 5 to 10 kDa. However, the aptamer molecule may be used as building block for custom designed targeting agents, offering several advantages. These molecules penetrate tumour readily, reach peak levels quickly and clear from the body rapidly, thus having properties of low toxicity and immunoreactivity. Previous work with radiolabelled aptamers is limited and is currently restricted to preclinical studies, but the body of evidence is steadily growing and aptamers are emerging as valuable clinical products for diagnostic imaging and therapy. We have shown that aptamers directed against the mucin 1 (MUC1) antigen, a tumour marker previously extensively used in tumour imaging and therapy, demonstrated high specificity and uniform penetration in tumour xenografts. The future strategy will be to manipulate the molecular weight of the molecules to achieve an optimum balance between the low immunogenicity and excellent tumour penetration for diagnostic imaging and targeted therapy. In this way, a balance can be achieved between the rapid renal clearance and adequate tumour uptake required for diagnostic imaging and targeted therapy.

Postnatal changes in the expression of genes located in the callipyge region in sheep skeletal muscle.

The expression of five genes surrounding the callipyge (CLPG) mutation was analysed in skeletal muscles from lambs at one prenatal and two postnatal ages that coincide with the onset and establishment of muscle hypertrophy. Genotype-specific changes in transcript abundance were detected for paternal allele-specific DLK1 and PEG11 (the official symbol of the latter is RTL1) and the maternal allele-specific MEG3, PEG11AS and MEG8 when the mutation was inherited in cis. There were differences in the temporal and muscle-specific effects on expression between the maternal allele-specific genes and paternal allele-specific genes. Maternal inheritance of the CLPG allele had a significant effect on the expression of MEG3 and MEG8 at prenatal and postnatal ages, whereas paternal inheritance of DLK1 and PEG11 only affected postnatal expression. Genotype-specific changes in PEG11AS expression were detected only in prenatal muscle. Maternal inheritance of the mutation caused similar changes in MEG3 and MEG8 expression in the semimembranosus, which undergoes hypertrophy, and the supraspinatus, which does not hypertrophy. Paternal inheritance of the mutation caused changes in PEG11 expression in both muscles, although the magnitude of expression in semimembranosus was more than 100-fold greater than in supraspinatus. DLK1 expression was upregulated in callipyge animals at both postnatal ages in the semimembranosus, but there was no effect of genotype on DLK1 expression in the supraspinatus at any age. Increased DLK1 expression was likely the primary cause of muscle hypertrophy, but a contribution of PEG11 to the phenotype cannot be ruled out based on gene expression.

Preparation of Tc-99m-macroaggregated albumin from recombinant human albumin for lung perfusion imaging.

Human serum albumin (HSA) extracted from pooled blood taken from human donors is used in the production of (99m)Tc-labelled macroaggregated albumin (MAA) for lung perfusion imaging. However, concerns for the safety of blood-derived products due to potential contamination by infective agents (e.g. new variant CJD), make alternative production methods necessary. Recombinant DNA technology is a promising method of albumin production avoiding problems associated with human-derived HSA. This paper presents results comparing MAA prepared from recombinant human albumin (rHA, Recombumin) (rMAA) with in-house produced HSA MAA (hMAA) and commercially available MAA (cMAA). (99m)Tc-MAA was prepared using previously published production methods by heating a mixture of albumin and stannous chloride in acetate buffer (pH 5.4) at 70 degrees C for 20 min. Parameters investigated include aggregate size, radiolabelling efficiency, radiochemical and aggregate stability at 4 degrees C and in vitro (in whole human blood) at 37 degrees C and biodistribution studies. Results showed that rMAA could be produced with similar morphology, labelling efficiency and stability to hMAA and cMAA. Our findings confirm that rHA shows significant potential as a direct replacement for HSA in commercially available MAA.