A prototype low-cost secondary standard calorimeter for reference dosimetry with ultra-high pulse dose rates.

OBJECTIVES: Ultra-high pulse dose rate modalities present significant dosimetry challenges for ionisation chambers due to significant ion recombination. Conversely, calorimeters are ideally suited to measure high dose, short duration dose deliveries and this work describes a simple calorimeter as an alternative dosemeter for use in the clinic. METHODS: Calorimeters were constructed featuring a disc-shaped core and single sensing thermistor encased in a 3D-printed body shaped like a Roos ionisation chamber. The thermistor forms one arm of a DC Wheatstone bridge, connected to a standard DMM. The bridge-out-of-balance voltage was calibrated in terms of temperature. A graphite-core calorimeter was calibrated in terms of absorbed dose to water (J/kg) in Co-60 and conventional 6, 10 and 15 MV X-rays. Similarly, an aluminium-core calorimeter was calibrated in a conventional 20 MeV electron beam and tested in a research high dose per pulse 6 MeV electron beam. RESULTS: Calorimeters were successfully calibrated in terms of absorbed dose to water in conventional radiotherapy beams at approximately 5 Gy/min with an estimated uncertainty of ±2-2.5% (k = 2), and performed similarly in a 6 MeV electron beam delivering approximately 180 Gy/s. CONCLUSIONS: A simple, low-cost calorimeter traceably calibrated to existing primary standards of absorbed dose could be used as a secondary standard for dosimetry for ultra-high pulse dose rates in the clinic. ADVANCES IN KNOWLEDGE: Secondary standard calorimeters for routine measurements are not available commercially; this work presents the basis of a simple, low-cost solution for reference dosimetry for ultra-high pulse dose rate beams.

Multi-institutional dosimetric delivery assessment of intracranial stereotactic radiosurgery on different treatment platforms.

BACKGROUND AND PURPOSE: Assessment of dosimetric accuracy of radiosurgery on different treatment platforms. MATERIAL AND METHODS: Thirty-three single fraction treatment plans were assessed at thirty centres using an anthropomorphic head phantom with target and brainstem structures. The target being a single irregular shaped target, ~8 cc, 10 mm from the brainstem. The phantom was "immobilised", scanned, planned and treated following the local protocols. EBT-XD films and alanine pellets were used to measure absolute dose, inside both the target and the brainstem, and compared with TPS predicted dose distributions. RESULTS: PTV alanine measurements from gantry-based linacs showed a median percentage difference to the TPS of 0.65%. Cyberknife (CK) had the highest median difference of 2.3% in comparison to the other platforms. GammaKnife (GK) showed the smallest median of 0.3%. Similar trends were observed in the OAR with alanine measurements showing median percentage differences of1.1%, 2.0% and 0.4%, for gantry-based linacs, CK and GK respectively. All platforms showed comparable gamma passing rates between axial and sagittal films. CONCLUSIONS: This comparison has highlighted the dosimetric variation between measured and TPS calculated dose for each delivery platform. The results suggest that clinically acceptable agreement with the predicted dose distributions is achievable by all treatment delivery systems.

Adaptation and validation of a commercial head phantom for cranial radiosurgery dosimetry end-to-end audit.

OBJECTIVE: To adapt and validate an anthropomorphic head phantom for use in a cranial radiosurgery audit. METHODS: Two bespoke inserts were produced for the phantom: one for providing the target and organ at risk for delineation and the other for performing dose measurements. The inserts were tested to assess their positional accuracy. A basic treatment plan dose verification with an ionization chamber was performed to establish a baseline accuracy for the phantom and beam model. The phantom and inserts were then used to perform dose verification measurements of a radiosurgery plan. The dose was measured with alanine pellets, EBT extended dose film and a plastic scintillation detector (PSD). RESULTS: Both inserts showed reproducible positioning (±0.5 mm) and good positional agreement between them (±0.6 mm). The basic treatment plan measurements showed agreement to the treatment planning system (TPS) within 0.5%. Repeated film measurements showed consistent gamma passing rates with good agreement to the TPS. For 2%-2 mm global gamma, the mean passing rate was 96.7% and the variation in passing rates did not exceed 2.1%. The alanine pellets and PSD showed good agreement with the TPS (-0.1% and 0.3% dose difference in the target) and good agreement with each other (within 1%). CONCLUSION: The adaptations to the phantom showed acceptable accuracies. The presence of alanine and PSD do not affect film measurements significantly, enabling simultaneous measurements by all three detectors. Advances in knowledge: A novel method for thorough end-to-end test of radiosurgery, with capability to incorporate all steps of the clinical pathway in a time-efficient and reproducible manner, suitable for a national audit.

Radiotherapy dosimetry audit: three decades of improving standards and accuracy in UK clinical practice and trials.

Dosimetry audit plays an important role in the development and safety of radiotherapy. National and large scale audits are able to set, maintain and improve standards, as well as having the potential to identify issues which may cause harm to patients. They can support implementation of complex techniques and can facilitate awareness and understanding of any issues which may exist by benchmarking centres with similar equipment. This review examines the development of dosimetry audit in the UK over the past 30 years, including the involvement of the UK in international audits. A summary of audit results is given, with an overview of methodologies employed and lessons learnt. Recent and forthcoming more complex audits are considered, with a focus on future needs including the arrival of proton therapy in the UK and other advanced techniques such as four-dimensional radiotherapy delivery and verification, stereotactic radiotherapy and MR linear accelerators. The work of the main quality assurance and auditing bodies is discussed, including how they are working together to streamline audit and to ensure that all radiotherapy centres are involved. Undertaking regular external audit motivates centres to modernize and develop techniques and provides assurance, not only that radiotherapy is planned and delivered accurately but also that the patient dose delivered is as prescribed.

Inter-departmental dosimetry audits - development of methods and lessons learned.

External dosimetry audits give confidence in the safe and accurate delivery of radiotherapy. In the United Kingdom, such audits have been performed for almost 30 years. From the start, they included clinically relevant conditions, as well as reference machine output. Recently, national audits have tested new or complex techniques, but these methods are then used in regional audits by a peer-to-peer approach. This local approach builds up the radiotherapy community, facilitates communication, and brings synergy to medical physics.

A methodology for dosimetry audit of rotational radiotherapy using a commercial detector array.

PURPOSE: To develop a methodology for the use of a commercial detector array in dosimetry audits of rotational radiotherapy. MATERIALS AND METHODS: The methodology was developed as part of the development of a national audit of rotational radiotherapy. Ten cancer centres were asked to create a rotational radiotherapy treatment plan for a three-dimensional treatment-planning-system (3DTPS) test and audited. Phantom measurements using a commercial 2D ionisation chamber (IC) array were compared with measurements using 0.125 cm(3) IC, Gafchromic film and alanine pellets in the same plane. Relative and absolute gamma index (γ) comparisons were made for Gafchromic film and 2D-Array planes, respectively. RESULTS: Comparisons between individual detectors within the 2D-Array against the corresponding IC and alanine measurement showed a statistically significant concordance correlation coefficient (both ρc>0.998, p<0.001) with mean difference of -1.1 ± 1.1% and -0.8 ± 1.1%, respectively, in a high dose PTV. In the γ comparison between the 2D-Array and film it was that the 2D-Array was more likely to fail planes where there was a dose discrepancy due to the absolute analysis performed. CONCLUSIONS: It has been found that using a commercial detector array for a dosimetry audit of rotational radiotherapy is suitable in place of standard systems of dosimetry.

The use of PRIME-MD questionnaire in a rheumatology clinic.

OBJECTIVE: To determine whether the Primary Care Evaluation of Mental Disorders 1-page Brief Patient Health Questionnaire (PRIME-MD 1-page PHQ) can serve as: (1) a diagnostic test for fibromyalgia syndrome (FM), or (2) a questionnaire through which internists can be alerted to otherwise hidden mental disorders in patients attending internal medicine clinics. METHOD: Two hundred and thirteen consecutive patients attending a rheumatology clinic were given the PRIME-MD 1-page PHQ and seen by a rheumatologist who was blind to the PRIME-MD diagnosis. RESULTS: The PRIME-MD 1-page PHQ pointed to Major Depressive Disorder in 33.3% of FM patients, Other Depressive Disorder in 33.3% of FM patients, and Panic Disorder in 22.2% of FM patients (all of whom also had Major Depressive Disorder), as compared to 13.1, 13.1, and 3.0% respectively in patients with other rheumatic disorders. However, when used as a diagnostic test for FM, the PRIME-MD 1-page PHQ did not have adequate diagnostic value. When all the PRIME-MD 1-page PHQ diagnoses were compiled, however, a trend was observed. Compared to the rates of mental disorders in both the normal population and in primary care practices, the rates found in this rheumatology clinic were higher. CONCLUSIONS: The PRIME-MD 1-page PHQ is not an adequate diagnostic test for FM. Because FM is primarily a somatization disorder that draws its symptoms from other current diseases, it may in fact be impossible to diagnose FM based on specific symptoms alone. However, the PRIME-MD 1-page PHQ proved to be a useful diagnostic tool in a rheumatology clinic. It helped to alert the physician to the possibility of an elevated frequency of mental disorders that would otherwise have gone unnoticed and untreated.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.

OBJECTIVE: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. METHODS: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). RESULTS: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). CONCLUSION: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.

Effort testing in patients with fibromyalgia and disability incentives.

OBJECTIVE: To examine whether symptom exaggeration is a factor in complaints of cognitive dysfunction using 2 new validated instruments in patients with fibromyalgia (FM). METHODS: Ninety-six patients with FM and 16 patients with rheumatoid arthritis (RA) were administered 2 effort or symptom validity tests designed to detect exaggerated memory complaints as part of a battery of psychological tests and self-report questionnaires. RESULTS: A large percentage of patients with FM who were on or seeking disability benefits failed the effort tests. Only 2 patients with FM who were working and/or not claiming disability benefits and no patient with RA scored below the cutoffs for exaggeration of memory difficulties. CONCLUSION: This study illustrates the importance of assessing for exaggeration of cognitive symptoms and biased responding in patients with FM presenting for disability related evaluations.

Management of rheumatoid arthritis: the historical context.

We review the historical highlights of the management of rheumatoid arthritis (RA). Studies of nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, and biological agents over 5 decades were evaluated and summarized. There is emphasis on drug therapy as it has developed and evolved from empirical relief of symptoms with salicylates to targeted intervention in the immunoinflammatory process with tumor necrosis factor inhibitors. A therapeutic paradigm has been proposed to rationalize the use of the available therapies. If one accepts the thesis that both the acute and chronic consequences of RA are due to persistent misdirected and inadequately controlled inflammation that causes tissue destruction and loss of function, then prolonged complete control of the abnormal inflammatory process is the fundamental first step in the management of all patients with RA. Unfortunately, even with the newest therapeutic options to treat RA, most patients achieve only partial suppression of inflammation and many lose therapeutic benefit after an initial good response. The management of persistent or recurrent rheumatoid inflammation and disability continues to be a challenge. It remains to be determined whether the future addition of more potent specific interventions in the immunoinflammatory process will be able to solve this problem without disarming host defenses against infections and tumors.

Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy.

OBJECTIVE: To examine the potential therapeutic properties of an aminobisphosphonate, pamidronate, using clinical and laboratory outcome variables together with dynamic magnetic resonance imaging (MRI) and gadolinium augmentation in patients with spondyloarthropathy (SpA) refractory to nonsteroidal antiinflammatory drugs (NSAID). METHODS: We studied 9 patients (7 male, 2 female) of mean age 27.9 years (range 19-38) and mean disease duration of 5.5 years (range 0.5-20). Five had ankylosing spondylitis (AS), 3 had undifferentiated SpA, and one had reactive arthritis. Seven were HLA-B27 positive. Two had inflammatory bowel disease. Pamidronate (60 mg) was given intravenously on Days 1, 2, 14, 28, and 56, over 4 h in 500 ml of 5% dextrose. Clinical outcome assessments included the BASDAI (disease activity), BASFI (function), BASGI (global well being) composite visual analog instruments, and swollen and tender joint count. Laboratory variables included the erthrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Dynamic MRI with gadolinium augmentation of synovium and bone was performed at baseline and at Day 84 in the first 6 patients enrolled in the study. RESULTS: All patients completed the study and there was a significant improvement in all clinical and laboratory variables assessed. Mean swollen and tender joint count decreased by 93.8% (p = 0.017) and 98.2% (p = 0.012), respectively, and complete clinical resolution of synovitis was noted in 5 patients. BASDAI decreased by 44.2% (p = 0.028), BASFI by 47.3% (p = 0.015), and BASGI by 42.2% (p = 0.011). ESR and CRP declined by 49.4% (p = 0.012) and 66.9% (p = 0.008), respectively. Acute lymphopenia accompanied by elevated CRP levels was noted in 8 patients in the 48 h after first pamidronate infusion. Maximal rate and magnitude of enhanced MRI signal after gadolinium augmentation decreased after pamidronate therapy, especially in the bone marrow. CONCLUSION: Preliminary data from uncontrolled studies support the efficacy of pamidronate therapy for NSAID refractory SpA and warrant further evaluation in controlled trials.

Treatment of refractory symphysitis pubis with intravenous pamidronate.

Osteitis pubis is a noninfectious painful inflammatory disorder of the symphysis pubis. Etiologic factors include urologic procedures, abdomino-perineal and gynecological surgery, and spondyloarthropathies, although many cases are idiopathic. Most respond to conservative measures consisting primarily of rest and analgesic/antiinflammatory agents. We describe 3 cases, 2 with idiopathic osteitis pubis and one that was associated with a spondyloarthropathy, that failed to respond to conservative measures but experienced clinical remission with 3 to 6 monthly courses of intravenous pamidronate. Remission was also evident in 2 patients on isotope bone scan. Followup has revealed no recurrence. Intravenous pamidronate may constitute a safe and effective treatment option for patients with refractory osteitis pubis.

Is high titre ANA specific for connective tissue disease?

OBJECTIVE: A positive antinuclear antibody (ANA), while sensitive, is not specific for systemic lupus erythematosus or connective tissue diseases (CTD). The purpose of the present study was to review those sera with a high titre (> or = dilutions above screening) ANA and determine from a review of the charts if these higher titres offered a satisfactory specificity for CTD. METHODS: All FANA testing in this region is carried out in one of two related laboratories. We reviewed the medical records of patients who had a positive ANA at a titre 4 dilutions above screening at this city-wide laboratory over a 6-month period to determine whether this titre ("high titre") may offer relative diagnostic certainty. Antibodies to extractable nuclear antigens (ENA) and native DNA were also obtained. RESULTS: 422 ANA results were positive at high titre. The medical record was available for review in 320 patients, of whom 238 (75%) were seen by a specialist physician, almost always including a rheumatologist. Our review determined that 35% had a diagnosis of connective tissue disease, 21% had a diagnosis of a possible/probable inflammatory disease, 16% had an alternative specific diagnosis provided, and in 29% no final disease specific diagnosis was recorded but CTD was not suggested to us or the specialist by the data available. One or more anti-ENA antibodies and/or anti-DNA were positive in 69 (22%) and 8% of the sera tested respectively. CONCLUSION: While long term follow-up is still required, a significant proportion of patients with high titre ANA have no CTD at the time of testing. Setting a higher cutoff for reporting of ANA may not increase specificity sufficiently to make it a useful alternative or addition to reporting a positive or negative value at screening titre alone.

LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative Caucasian and Mexican Mestizo patients with ankylosing spondylitis.

OBJECTIVE: To determine the effects of HLA Class II genes, particularly LMP2 and previously implicated Class I genes, on susceptibility and disease expression in HLA-B27 negative ankylosing spondylitis (AS). METHODS: Patients included 41 HLA-B27 negative Caucasians from a total AS population of 546 and 17 HLA-B27 negative Mexican Mestizo. Controls included 4352 random HLA-B27 negative Caucasians. LMP2 genotype assignments were made on all patients and 282 random Caucasian controls by polymerase chain reaction-restriction fragment length polymorphism with the Cfo I restriction enzyme while HLA typing was performed on patients and controls using microcytotoxicity assays for Class I, and sequence specific probe-PCR for HLA-B60, B39, B38, and DR. RESULTS: The LMP2BB genotype was significantly decreased in Caucasian AS patients without extraspinal (ES) disease (25%) compared to AS patients with ES (64.7%) (p = 0.01) and random Caucasian controls (53.9%) (p = 0.007), even when those with colitis and psoriasis were excluded from analysis (ES+ 55.6% versus ES- 22.2%). This finding remained significant after stratification by HLA-DR. Similar trends were noted in the Mexican population. A potential role for HLA-DR8 and DR2 in susceptibility to disease was observed in Caucasian patients, although this observation requires confirmation. We could not confirm reported associations with HLA-B60 or B39. Peripheral arthritis was significantly more commonly observed in those who had had acute anterior uveitis (AAU) (75%) than in those who had not developed AAU (27.3%) (p = 0.04). CONCLUSION: HLA Class II encoded genes may have effects on disease susceptibility and/or phenotype in HLA-B27 negative individuals similar to those noted in HLA-B27 positive AS. Eccentric and axial phenotypes of disease may be immunogenetically determined.

Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis.

AIMS: Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. METHODS: Eight RA patients were age- and sex-matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin-6 (IL-6) and nitrite (NO2-) were measured in predose samples. RESULTS: IL-6 and NO2- concentrations were significantly increased in parallel with disease severity. Oral clearance of both S- and R-verapamil was significantly decreased by RA. While the unbound fraction of S- and R-verapamil decreased by 5 and 7-fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S-verapamil. AUC of norverapamil enantiomers was increased 2-3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. CONCLUSIONS: RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-inflammatory cytokines and/or NO.