A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.

Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3

NSAID prescribing and adverse outcomes in common infections: a population-based cohort study.

OBJECTIVES: Infections in primary care are often treated with non-steroidal anti-inflammatory drugs (NSAIDs). This study evaluates whether NSAID prescribing is associated with adverse outcomes for respiratory (RTIs) or urinary track (UTI) infections. OBJECTIVES: To determine whether there is an association between NSAID prescribing and the rate of adverse outcomes for infections for individual consulting in primary care. DESIGN: Cohort study of electronic health records. SETTING: 87 general practices in the UK Clinical Practice Research Datalink GOLD. PARTICIPANTS: 142 925 patients consulting with RTI or UTI. PRIMARY AND SECONDARY OUTCOME MEASURES: Repeat consultations, hospitalisation or death within 30 days of the initial consultation for RTI or UTI. Poisson models estimated the associations between NSAID exposure and outcome. Rate ratios were adjusted for gender, age, ethnicity, deprivation, antibiotic use, seasonal influenza vaccination status, comorbidities and general practice. Since prescribing variations by practice are not explained by case mix-hence, less impacted by confounding by indication-both individual-level and practice-level analyses are included. RESULTS: There was an increase in hospital admission/death for acute NSAID prescriptions (RR 2.73, 95% CI 2.10 to 3.56) and repeated NSAID prescriptions (6.47, 4.46-9.39) in RTI patients, and for acute NSAID prescriptions for UTI (RR 3.03; 1.92 to 4.76). Practice-level analysis, controlling for practice population characteristics, found that for each percentage point increase in NSAID prescription, the percentages of hospital admission/death within 30 days increased by 0.32 percentage points (95% CI 0.16 to 0.47). CONCLUSIONS: In this non-randomised study, prescription of NSAIDs at consultations for RTI or UTIs in primary care is infrequent but may be associated with increased risk of hospital admission. This supports other observational and limited trial data that NSAID prescribing might be associated with worse outcomes following acute infection and should be prescribed with caution

What Can Proton Beam Therapy Achieve for Patients with Pectus Excavatum Requiring Left Breast, Axilla and Internal Mammary Nodal Radiotherapy?

AIMS: Exposure of the heart to radiation increases the risk of ischaemic heart disease, proportionate to the mean heart dose (MHD). Radiotherapy techniques including proton beam therapy (PBT) can reduce MHD. The aims of this study were to quantify the MHD reduction achievable by PBT compared with volumetric modulated arc therapy in breath hold (VMAT-BH) in patients with pectus excavatum (PEx), to identify an anatomical metric from a computed tomography scan that might indicate which patients will achieve the greatest MHD reductions from PBT. MATERIALS AND METHODS: Sixteen patients with PEx (Haller Index ≥2.7) were identified from radiotherapy planning computed tomography images. Left breast/chest wall, axilla (I-IV) and internal mammary node (IMN) volumes were delineated. VMAT and PBT plans were prepared, all satisfying target coverage constraints. Signed-rank comparisons of techniques were undertaken for the mean dose to the heart, ipsilateral lung and contralateral breast. Spearman's rho correlations were calculated for anatomical metrics against MHD reduction achieved by PBT. RESULTS: The mean MHD for VMAT-BH plans was 4.1 Gy compared with 0.7 Gy for PBT plans. PBT reduced MHD by an average of 3.4 Gy (range 2.8-4.4 Gy) compared with VMAT-BH (P < 0.001). PBT significantly reduced the mean dose to the ipsilateral lung (4.7 Gy, P < 0.001) and contralateral breast (2.7 Gy, P < 0.001). The distance (mm) at the most inferomedial extent of IMN volume (IMN to heart distance) negatively correlated with MHD reduction achieved by PBT (Spearman's rho -0.88 (95% confidence interval -0.96 to -0.67, P < 0.001)). CONCLUSION: For patients with PEx requiring left-sided breast and IMN radiotherapy, a clinically significant MHD reduction is achievable using PBT, compared with the optimal photon technique (VMAT-BH). This is a patient group in whom PBT could have the greatest benefit

Derivation of dose/volume constraints for the anorectum from clinician and patient-reported outcomes in the CHHiP trial of radiotherapy fractionation.

BACKGROUND:The CHHiP trial randomised 3216 men with localised prostate cancer (1:1:1) to three radiotherapy fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively-collected clinician-reported outcomes (CRO) and patient-reported outcomes (PRO) and to assess the added predictive value of spatial dose metrics. METHODS:A case-control study design was used, seven CRO and five PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1-5 years post-radiotherapy, and did not have the symptom pre-radiotherapy. Controls did not experience the symptom at baseline, or between 1-5 years post-radiotherapy. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices and bootstrapped receiver-operating-characteristic (ROC) analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2Gy equivalent schedules using α/β=3Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve (AUC) with 95% confidence interval lower limits >0.5 were considered statistically significant. Any constraint derived in <95-99% of bootstraps was excluded. RESULTS:Statistically significant dose constraints were derived for CRO, but not PRO. Intermediate to high doses were important for rectal bleeding whereas intermediate doses were important for increased bowel frequency, faecal incontinence and rectal pain. Spatial dose metrics did not improve prediction of CRO or PRO. A new panel of dose constraints for hypofractionated schedules to 60Gy or 57Gy are V20Gy<85%, V30Gy<57%, V40Gy<38%, V50Gy<22% and V60Gy<0.01%. CONCLUSIONS:Dose constraints differed between symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms post-radiotherapy

Coding, Recording and Incidence of Different Forms of Coronary Heart Disease in Primary Care

To evaluate the coding, recording and incidence of coronary heart disease (CHD) in primary care electronic medical records.Data were drawn from the UK General Practice Research Database. Analyses evaluated the occurrence of 271 READ medical diagnostic codes, including categories for 'Angina', 'Myocardial Infarction', 'Coronary Artery Bypass Grafting' (CABG), 'percutaneous transluminal coronary angioplasty' (PCTA) and 'Other Coronary Heart Disease'. Time-to-event analyses were implemented to evaluate occurrences of different groups of codes after the index date.Among 300,020 participants aged greater than 30 years there were 75,197 unique occurrences of coronary heart disease codes in 24,244 participants, with 12,495 codes for incident events and 62,702 for prevalent events. Among incident event codes, 3,607 (28.87%) were for angina, 3,262 (26.11%) were for MI, 514 (4.11%) for PCTA, 161 (1.29%) for CABG and 4,951 (39.62%) were for 'Other CHD'. Among prevalent codes, 20,254 (32.30%) were for angina, 3,644 (5.81%) for MI, 34,542 (55.09%) for 'Other CHD' and 4,262 (6.80%) for CABG or PCTA. Among 3,685 participants initially diagnosed exclusively with 'Other CHD' codes, 17.1% were recorded with angina within 5 years, 5.6% with myocardial infarction, 6.3% with CABG and 8.6% with PCTA. From 2000 to 2010, the overall incidence of CHD declined, as did the incidence of angina, but the incidence of MI did not change. The frequency of CABG declined, while PCTA increased.In primary care electronic records, a substantial proportion of coronary heart disease events are recorded with codes that do not distinguish between different clinical presentations of CHD. The results draw attention to the need to improve coding practice in primary care. The results also draw attention to the importance of code selection in research studies and the need for sensitivity analyses using different sets of codes

Reliability and validity of a short form household food security scale in a Caribbean community

BACKGROUND: We evaluated the reliability and validity of the short form household food security scale in a different setting from the one in which it was developed. METHODS: The scale was interview administered to 531 subjects from 286 households in north central Trinidad in Trinidad and Tobago, West Indies. We evaluated the six items by fitting item response theory models to estimate item thresholds, estimating agreement among respondents in the same households and estimating the slope index of income-related inequality (SII) after adjusting for age, sex and ethnicity. RESULTS: Item-score correlations ranged from 0.52 to 0.79 and Cronbach's alpha was 0.87. Item responses gave within-household correlation coefficients ranging from 0.70 to 0.78. Estimated item thresholds (standard errors) from the Rasch model ranged from -2.027 (0.063) for the 'balanced meal' item to 2.251 (0.116) for the 'hungry' item. The 'balanced meal' item had the lowest threshold in each ethnic group even though there was evidence of differential functioning for this item by ethnicity. Relative thresholds of other items were generally consistent with US data. Estimation of the SII, comparing those at the bottom with those at the top of the income scale, gave relative odds for an affirmative response of 3.77 (95% confidence interval 1.40 to 10.2) for the lowest severity item, and 20.8 (2.67 to 162.5) for highest severity item. Food insecurity was associated with reduced consumption of green vegetables after additionally adjusting for income and education (0.52, 0.28 to 0.96). CONCLUSIONS: The household food security scale gives reliable and valid responses in this setting. Differing relative item thresholds compared with US data do not require alteration to the cut-points for classification of 'food insecurity without hunger' or 'food insecurity with hunger'. The data provide further evidence that re-evaluation of the 'balanced meal' item is required

All-Cause Mortality After Diabetes-Related Amputation in Barbados: A prospective case-control study

OBJECTIVE—To determine the mortality rate after diabetes-related lower-extremity amputation (LEA) in an African-descent Caribbean population