Differential Response of Pelvic Bone Marrow Fluorodeoxyglucose Uptake in Patients Receiving Concurrent Chemoradiotherapy.

AIMS: Irradiation of pelvic bone marrow (PBM) at the level of the typical low dose bath of intensity-modulated radiotherapy delivery (10-20 Gy) is associated with an increased risk of haematological toxicity, particularly when combined with concurrent chemotherapy. Although sparing of the whole of the PBM at a 10-20 Gy dose level is unachievable, it is known that PBM is divided into haematopoietically active and inactive regions that are identifiable based on the threshold uptake of [18F]-fluorodeoxyglucose (FDG) seen on positron emission tomography-computed tomography (PET-CT). In published studies to date, the definition of active PBM widely used is that of a standardised uptake value (SUV) greater than the mean SUV of the whole PBM prior to the start of chemoradiation. These studies include those looking at developing an atlas-based approach to contouring active PBM. Using baseline and mid-treatment FDG PET scans acquired as part of a prospective clinical trial we sought to determine the suitability of the current definition of active bone marrow as representative of differential underlying cell physiology. MATERIALS AND METHODS: Active and inactive PBM were contoured on baseline PET-CT and using deformable registration mapped onto mid-treatment PET-CT. Volumes were cropped to exclude definitive bone, voxel SUV extracted and the change between scans calculated. Change was compared using Mann-Whitney U testing. RESULTS: Active and inactive PBM were shown to respond differentially to concurrent chemoradiotherapy. The median absolute response of active PBM for all patients was -0.25 g/ml, whereas the median inactive PBM response was -0.02 g/ml. Significantly, the inactive PBM median absolute response was shown to be near zero with a relatively unskewed distribution (0.12). CONCLUSIONS: These results would support the definition of active PBM as FDG uptake greater than the mean of the whole structure as being representative of underlying cell physiology. This work would support the development of atlas-based approaches published in the literature to contour active PBM based on the current definition as being suitable.

Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism.

BACKGROUND: PET imaging of 18F-fluorodeoxygucose (FDG) is used widely for tumour staging and assessment of treatment response, but the biology associated with FDG uptake is still not fully elucidated. We therefore carried out gene set enrichment analyses (GSEA) of RNA sequencing data to find KEGG pathways associated with FDG uptake in primary breast cancers. METHODS: Pre-treatment data were analysed from a window-of-opportunity study in which 30 patients underwent static and dynamic FDG-PET and tumour biopsy. Kinetic models were fitted to dynamic images, and GSEA was performed for enrichment scores reflecting Pearson and Spearman coefficients of correlations between gene expression and imaging. RESULTS: A total of 38 pathways were associated with kinetic model flux-constants or static measures of FDG uptake, all positively. The associated pathways included glycolysis/gluconeogenesis ('GLYC-GLUC') which mediates FDG uptake and was associated with model flux-constants but not with static uptake measures, and 28 pathways related to immune-response or inflammation. More pathways, 32, were associated with the flux-constant K of the simple Patlak model than with any other imaging index. Numbers of pathways categorised as being associated with individual micro-parameters of the kinetic models were substantially fewer than numbers associated with flux-constants, and lay around levels expected by chance. CONCLUSIONS: In pre-treatment images GLYC-GLUC was associated with FDG kinetic flux-constants including Patlak K, but not with static uptake measures. Immune-related pathways were associated with flux-constants and static uptake. Patlak K was associated with more pathways than were the flux-constants of more complex kinetic models. On the basis of these results Patlak analysis of dynamic FDG-PET scans is advantageous, compared to other kinetic analyses or static imaging, in studies seeking to infer tumour-to-tumour differences in biology from differences in imaging. Trial registration NCT01266486, December 24th 2010.

Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging.

BACKGROUND: 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS: 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION: NCT03036943.

Time to demand dosimetry for molecular radiotherapy?

Molecular radiotherapy (MRT) has been used clinically for around 75 years. Despite this long history of clinical use, there is no established dosimetry practice for calculating the absorbed dose delivered to tumour targets or to organs at risk. As a result, treatment protocols have often evolved based on experience with relatively small numbers of patients, each receiving a similar administered activity but, potentially, widely varying doses. This is in stark contrast to modern external-beam radiotherapy practice. This commentary describes some of the barriers to MRT dosimetry and gives some opinions on the way forward.

Iodine-131 monitoring in sewage plant outflow.

Three different hospital sites (Oxford, Sutton and Guildford) have performed sampling of their local sewage plant outflow to determine levels of radioactivity resulting from iodine-131 patients undergoing radionuclide therapies. It was found that a maximum of 20% of activity discharged from the hospitals was present in the sewage plant final effluent channel. This is significantly below the level predicted by mathematical models in current use. The results further show that abatement systems to reduce public exposure are unlikely to be warranted at hospital sites.

Management and outcome of appendicitis among octogenarians in an English hospital over a five year period.

INTRODUCTION: There is a different perspective on diagnosis and management of common surgical problems in elderly patients. This study aimed to analyse the management of acute appendicitis in octogenarians. METHODS: A retrospective study investigated all appendicectomies over five years. Patient records were studied for presenting features, pre-operative imaging, pre-operative ASA grade, site of incision, post-operative complications and length of inpatient stay. RESULTS: Presenting symptoms included lower abdominal pain (n = 31, 93.9%), anorexia (n = 19, 57.6%), nausea and vomiting (n = 15, 45.5%) and shifting pain (n = 10, 30.3%). Twenty patients had right iliac fossa pain (60.6%) and seven had pyrexia (21.2%). The commonest co-morbidity was cardiac (n = 19; 58%). The average time from admission to theatre was greater in octogenarian patients (1.24 ± 0.90 days) than other patients (0.64 ± 0.71 days), as was the average length of stay at 11 ± 2.6 days compared with 4.3 ± 3.1 days. The majority of octogenarian patients received a Lanz incision (48.3%), with others receiving laparotomy (24.1%), lower midline (13.8%), gridiron (13.8%), and right paramedian (3.4%). Complications were more common in the octogenarian patients (63.6%) than other patients (22.55%). The most common complications in the octogenarian population were post-operative ileus (n = 7; 21%), wound infection (n = 5; 15.2%) and pneumonia (n = 5; 15.2%). CONCLUSION: Appendicitis in the elderly can result in significant morbidity due to the atypical presentation causing an unnecessary delay in treatment. If indicated, age should not be a contraindication for an appendicectomy. The increased likelihood for these patients to have a post-operative complication should be at the forefront of their care.

Electroreception in the euryhaline stingray, Dasyatis sabina.

This study quantified the electrosensitivity of a euryhaline elasmobranch, the Atlantic stingray (Dasyatis sabina) across a range of salinities. Specimens from a permanent freshwater (FW) population in the St Johns River system, FL, USA, were compared with stingrays from the tidally dynamic Indian River Lagoon in east Florida, USA. Behavioral responses of stingrays to prey-simulating electric stimuli were quantified in FW (0 p.p.t., rho=2026 Omega cm), brackish (15 p.p.t., rho=41 Omega cm) and full strength seawater (35 p.p.t., rho=19 Omega cm). This study demonstrated that the electrosensitivity of D. sabina is significantly reduced in FW. In order to elicit a feeding response, stingrays tested in FW required an electric field 200-300x greater than stingrays tested in brackish and saltwater (median FW treatments=1.4 microV cm(-1), median brackish-saltwater treatments=6 nV cm(-1)), and the maximum orientation distance was reduced by 35.2%, from 44.0 cm in the brackish and saltwater treatments to 28.5 cm in FW. The St Johns River stingrays did not demonstrate an enhanced electrosensitivity in FW, nor did they exhibit reduced sensitivity when introduced to higher salinities. Stingrays from both populations responded similarly to the prey-simulating stimulus when tested at similar salinities, regardless of their native environment. The reduction in electrosensitivity and detection range in FW is attributed to both an environmental factor (electrical resistivity of the water) and the physiological function of the ampullary canals. The plasticity of this sensory system to function across such a wide environmental range demonstrates its adaptive significance.

Mercury vapour levels in dental practices and body mercury levels of dentists and controls.

AIM: A study of 180 dentists in the West of Scotland was conducted to determine their exposure to mercury during the course of their work and the effects on their health and cognitive function. DESIGN: Data were obtained from questionnaires distributed to dentists and by visiting their surgeries to take measurements of environmental mercury. METHODS: Dentists were asked to complete a questionnaire including items on handling of amalgam, symptoms experienced, diet and possible influences on psychomotor function such as levels of stress and alcohol intake. They also completed the 12-item General Health Questionnaire. Dentists were asked to complete a dental chart of their own mouths and to give samples of urine, hair and nails for mercury analysis. The dentists were visited at their surgeries where environmental measurements were made in eight areas of the surgery and they undertook a computerised package of psychomotor tests. One hundred and eighty control subjects underwent a similar procedure, completing a questionnaire, having their amalgam surfaces counted, giving urine, hair and nail samples and undergoing the psychomotor test procedure. RESULTS: Dentists were found to have, on average, urinary mercury levels over 4 times that of control subjects although all but one dentist had urinary mercury below the Health and Safety Executive health guidance value of 20 mumol mmol(-1) creatinine. Urine was found to be a better biological marker for mercury exposure than hair or nails.Dentists were significantly more likely than control subjects to have suffered from disorders of the kidney but these symptoms were not significantly associated with their level of mercury exposure as measured in urine. One hundred and twenty two (67.8%) of the 180 surgeries visited had environmental mercury measurements in one or more areas above the Occupational Exposure Standard (OES) set by the Health and Safety Executive. In the majority of these surgeries the high levels of mercury were found at the skirting and around the base of the dental chair. In 45 surgeries (25%) the personal dosimetry measurement (ie in the breathing zone of dental staff) was above the OES. CONCLUSION: On the basis of these findings, it is recommended that greater emphasis should be made relating to safe handling of amalgam in the training and continuing professional development of dentists, that further studies are carried out on levels of mercury exposure of dental team members during the course of their working day, and that periodic health surveillance, including urinary mercury monitoring, of dental personnel should be conducted to identify possible effects of practising dentistry.

The effect of immunomodulatory treatment on multiple sclerosis fatigue.

OBJECTIVE: To assess the effects of glatiramer acetate and beta interferon on fatigue in multiple sclerosis. METHODS: Fatigue was measured at baseline and six months using the fatigue impact scale (FIS). Groups (glatiramer acetate and beta interferon) were evaluated for the proportion improved, using Fisher's exact test. Logistic regression analysis assessed the relation between treatment group and improvement and controlled for confounding variables. RESULTS: Six month paired FIS assessments were available for 218 patients (76% female). Ages ranged between 19 and 61 years, with 86% having relapsing-remitting disease. Glatiramer acetate was used by 61% and beta interferon by 39%. At baseline, total FIS and subscale scores were comparable in the two groups. More patients improved on glatiramer acetate than on beta interferon on total FIS (24.8% v 12.9%, p = 0.033; adjusted odds ratio = 2.36, 95% confidence interval 1.03 to 5.42), and on physical (28.6% v 14.1%, p = 0.013) and cognitive subscales (21.1% v 10.6%, p = 0.045). Logistic regression analysis confirmed the association between glatiramer acetate use and improved fatigue, after accounting for baseline group differences. CONCLUSIONS: The odds of reduced multiple sclerosis fatigue were around twice as great with glatiramer acetate treatment as with beta interferon. Confirmation of this result is required.

Extra-oral craniofacial endosseous implants and radiotherapy.

This paper discusses the use of extra-oral endosseous craniofacial implant (EOECI) therapy in irradiated bone. The survival rate of EOECIs in irradiated bone is reviewed and the controversy over the optimal time prior to place implants is described. The advantages and disadvantages of pre- and post-implant radiotherapy are addressed. The EOECI rehabilitation and osteoradionecrosis and the evidence of the potential role of hyperbaric oxygen are reviewed. Strategies for improving the clinical outcome of EOECIs are suggested.

Extra-oral endosseous craniofacial implants: current status and future developments.

The published experience of extra-oral endosseous craniofacial implants (EOECIs) is reviewed. The definition of osseointegration, concept of success, the relative merit of one- or two-stage implant placement, EOECI design and control of peri-abutment skin infection are discussed. A plea is made for more consistent and objective reading of clinical experience of this technique.

Health and neuropsychological functioning of dentists exposed to mercury.

OBJECTIVES: A cross sectional survey of dentists in the west of Scotland and unmatched controls was conducted to find the effect of chronic exposure to mercury on health and cognitive functioning. METHODS: 180 dentists were asked to complete a questionnaire that included items on handling of amalgam, symptoms experienced, possible influences on psychomotor function, and the 12 item general health questionnaire. Dentists were asked to complete a dental chart of their own mouths and to give samples of urine, hair, and nails for mercury analysis. Environmental measurements of mercury in dentists' surgeries were made and participants undertook a package of computerised psychomotor tests. 180 control subjects underwent a similar procedure, completing a questionnaire, having their amalgam surfaces counted, giving urine, hair, and nail samples and undergoing the psychomotor test package. RESULTS: Dentists had, on average, urinary mercury concentrations over four times that of control subjects, but all but one dentist had urinary mercury below the Health and Safety Executive health guidance value. Dentists were significantly more likely than control subjects to have had disorders of the kidney and memory disturbance. These symptoms were not significantly associated with urinary mercury concentration. Differences were found between the psychomotor performance of dentists and controls after adjusting for age and sex, but there was no significant association between changes in psychomotor response and mercury concentrations in urine, hair, or nails. CONCLUSIONS: Several differences in health and cognitive functioning between dentists and controls were found. These differences could not be directly attributed to their exposure to mercury. However, as similar health effects are known to be associated with mercury exposure, it would be appropriate to consider a system of health surveillance of dental staff with particular emphasis on symptoms associated with mercury toxicity where there is evidence of high levels of exposure to environmental mercury.

Outcome of extra-oral craniofacial endosseous implants.

We report our experience of endosseous implants designed to retain various types of facial prostheses that were inserted by the West of Scotland Oral and Maxillofacial Surgery Service between January 1988 and September 1998. Forty-seven patients were given a total of 150 implants, most of which were auricular (n= 85) or orbital (n= 53). The functioning success rates were 100% and 75%, respectively. Soft tissue infection was the commonest complication, and could occur at any time after exposure of the implant, suggesting that life-long follow-up is required.

The microflora associated with extra-oral endosseous craniofacial implants: a cross-sectional study.

Infection of soft tissues surrounding extra-oral craniofacial endosseous implants is a common clinical problem. The aim of this study was to analyse the microflora associated with such implants, in both health and disease. Eighteen patients with a total of 49 implants were studied. Each patient was seen on two occasions for both a clinical examination and for collection of microbiological samples, using swabs and paper points, from the peri-abutment soft tissues. Specimens were cultured on blood agar and on agars selective for staphylococci and yeasts. Isolates were identified and selective antibiotic susceptibility testing undertaken. No single organism emerged as a predominant cause of peri-abutment skin infection but Staphylococcus aureus, Gram-negative bacilli and yeasts were all present as potential pathogens in this context. Culture and sensitivity results should therefore guide the treatment of these infections.

Amyloid-like inclusions in Huntington's disease.

Huntington's disease is a progressive, autosomal dominantly inherited, neurodegenerative disease that is characterized by involuntary movements (chorea), cognitive decline and psychiatric manifestations. This is one of a number of late-onset neurodegenerative disorders caused by expanded glutamine repeats, with a likely similar biochemical basis. Immunohistochemical studies on Huntington's disease tissue, using antibodies raised to the N-terminal region of huntingtin (adjacent to the repeat) and ubiquitin, have recently identified neuronal inclusions within densely stained neuronal nuclei, peri-nuclear and within dystrophic neuritic processes. However, the functional significance of inclusions is unknown. It has been suggested that the disease-causing mechanism in Huntington's disease (and the other polyglutamine disorders) is the ability of polyglutamine to undergo a conformational change that can lead to the formation of very stable anti-parallel beta-sheets; more specifically, amyloid structures. We examined, using Congo Red staining and both polarizing and confocal microscopy, post mortem human brain tissue from five Huntington's disease cases, two Alzheimer's disease cases and two normal controls. Brains from five transgenic mice (R6/2)(12) expressing exon 1 of the human huntingtin gene with expanded polyglutamine, and five littermate controls, were also examined by the same techniques. We have shown that some inclusions in Huntington's disease brain tissue possess an amyloid-like structure, suggesting parallels with other amyloid-associated diseases such as Alzheimer's and prion diseases.

CD39L2, a gene encoding a human nucleoside diphosphatase, predominantly expressed in the heart.

E-NTPDases are extracellular enzymes that hydrolyze nucleotides. The human E-NTPDase gene family currently consists of five reported members (CD39, CD39L1, CD39L2, CD39L3, and CD39L4). Both membrane-bound and secreted family members have been predicted by encoded transmembrane and leader peptide motifs. In this report, we demonstrate that the human CD39L2 gene is expressed predominantly in the heart. In situ hybridization results from heart indicate that the CD39L2 message is expressed in muscle and capillary endothelial cells. We also show that the CD39L2 gene encodes an extracellular E-NTPDase. Flow cytometric experiments show that transiently expressed CD39L2 is present on the surface of COS-7 cells. Transfected cells also produce recombinant glycosylated protein in the medium, and this process can be blocked by brefeldin A, an inhibitor of the mammalian secretory pathway. The enzymology of CD39L2 shows characteristic features of a typical E-NTPDase, but with a much higher degree of specificity for NDPs over NTPs as enzymatic substrates. The kinetics of the ADPase activity exhibit positive cooperativity. The predominance of CD39L2 expression in the heart supports a functional role in regulating platelet activation and recruitment in this organ.