OBJECTIVES Fractal analysis quantifies complex geometric structures by generating a fractal dimension, which can measure trabecular bone density. The use of non-standardized radiographic techniques potentially limits the reliability of fractal analysis. The objective of this study was to determine how variations in radiographic technique affect fractal dimension. METHODS Periapical radiographs of maxillary incisors taken on eight dry human skulls at varying angulation, tube potential and impulse settings were subjected to Fourier transform fractal analysis. RESULTS A significant (p < 0.05) difference in fractal dimension, ranging from 2.5 to 2.9, was found between the skulls, potentially reflecting variations in bone trabeculation. However, variations in angulation, tube potential or impulse did not have a statistically significant effect (p > 0.05) on fractal dimension, with the standard deviation of the fractal dimension ranging from +/- 0.005 to +/- 0.062 at various radiographic machine settings. CONCLUSIONS This study indicates that non-standardized periapical radiographs may provide a reliable method for determining fractal dimensions, which could be useful in analysing changes in alveolar bone density in various bone disorders.

The potential diagnostic usefulness of subtraction radiology in dentistry was evaluated by means of an experimental model of marginal periodontitis in cynomolgus monkeys. Beam-guiding, field-limiting, intraoral radiographic instruments were modified to allow construction of appliances which yielded repeatable superimposable radiographic images during the course of a 16-week study. Marginal periodontitis was induced in monkeys by means of circumferential silk sutures tied around mandibular second molar and second premolar cementoenamel junctions, and serial radiographs were taken at weekly intervals for 16 weeks. Control subtraction masks were made from pretreatment radiographs, and bone loss was evaluated by means of elapsed-time films to give the subtraction prints. The subtraction films clearly showed increasing bone loss with time and were produced easily with size O dental films. This technique appears to have considerable potential usefulness in the evaluation of bone-density changes in experimental models of dental diseases as well as in the clinical setting.

Measurements were made to determine if there was an optimal kVp that would maximize radiographic contrast for various materials while minimizing average patient dose. Radiographs were made of a 17-cm-thick plexiglass phantom (to simulate a typical abdomen) with added regions of plexiglass, hydroxyapatite, and iodine with peak kilovoltages from 40 to 150 kVp and 2 mm A1 added filtration. Radiographs were also made of a 4-cm-thick plexiglass phantom to simulate a typical breast, with added regions of plexiglass, hydroxyapatite, and fat at a peak kilovoltage from 35 to 100 kVp and with 1 mm added filtration. For the thicker phantom it was found that the contrast per average absorbed dose for the added plexiglass, hydroxyapatite, and iodine increased by about 3, 2, and 0.4, respectively, when going from 50 to 150 kVp. Contrast was measured relative to a reference region on the phantom. Similar data for the thinner phantom showed an increase of about 35% in contrast per average absorbed dose for plexiglass and fat but a decrease by about 30% for hydroxyapatite as the kVp changes from 35 to 100 kVp.

A suitable was phantom was designed for evaluating various film techniques used in subtraction radiography. Holes are drilled in a slab of wax and filled with various concentrations of iodinated wax, producing disk-shaped regions with diffuse borders. The technical details of construction and a representative application are described.

AIM: To assess the antibacterial efficacy of a human β-defensin-3 (HBD3) peptide against Enterococcus faecalis biofilms. METHODOLOGY: Standardized human dentine blocks were infected with E. faecalis ATCC 29212 for 3 weeks. Aqueous calcium hydroxide paste (n = 12, CH), a 2% chlorhexidine gel (n = 12, CHX), an HBD3 peptide gel (n = 12) and saline (n = 12) were tested as experimental groups. A mismatched peptide gel group (n = 12, MP) and sterilized but noninoculated block group (n = 12) were included as controls. After 1 week of medication, the dentinal samples at the depth of 200 and 400 μm were collected from medicated canal lumens. Bacterial growth was assessed by spectrophotometric analysis of optical density (OD) after 72 h of incubation. Statistical analysis was performed with repeated-measures anova and Tukey's post hoc test. RESULTS: The HBD3 group was associated with significantly lower OD values (P < 0.05) than the CH or CHX groups at both depths. The CH group did not differ significantly from MP or Saline group at either depth (P > 0.05). There was no significant difference (P > 0.05) in the OD values of the inner (200 μm) and outer (400 μm) dentinal samples for any group. CONCLUSIONS: The HBD3 peptide inhibited the growth of E. faecalis biofilms in infected dentine blocks.

BACKGROUND: We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. PATIENTS AND METHODS: Patients aged ⩾18years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10mg/kg days 1 and 15; paclitaxel 90mg/m(2) days 1, 8, and 15, every 4weeks; or Arm B: bevacizumab 15mg/kg day 1; capecitabine 1000mg/m(2) b.i.d., days 1-14, every 3weeks, until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2%(Arm A) and 78.0%(Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. CONCLUSION: These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials.

The 1st international Consensus Conference for Advanced Breast Cancer (ABC 1) took place on November 2011, in Lisbon. Consensus guidelines for the management of this disease were developed. This manuscript summarizes these international consensus guidelines.

Abstract Objective: EGF103009 (ClinicalTrials.gov identifier: NCT00105950) was a phase 2, open-label, multicenter study that showed lapatinib monotherapy to be clinically active in women with relapsed or refractory HER2+(ErbB2+) inflammatory breast cancer that progressed following prior therapy with anthracyclines, taxanes, and trastuzumab. The objective of the present study was to assess the impact of lapatinib on quality of life (QOL) and pain symptoms in these patients. Research design and methods: QOL and pain assessments were added during a study amendment and hence only 33 of 126 HER2+ patients were available for baseline assessment. QOL and pain were assessed using the EORTC QLQ-C30 and Brief Pain Inventory-Short Form (BPI-SF) questionnaires, respectively. Both questionnaires were completed at baseline and every 4 weeks thereafter. Change from baseline in QOL and pain scores were summarized by visit. In a post hoc analysis, scores were compared between patients with different clinical response status. Results: Over 60% of the 33 HER2+ patients with the baseline assessments completed the first three postbaseline assessments (week 4, n = 26; week 8, n = 21; week 12, n = 20). At week 8, improvement from baseline in mean EORTC QLQ-C30 scores was observed for global QOL (delta = 14.5; 95% CI: 4.0, 25.0), role functioning (delta = 15; 95% CI: 0.9, 29.1), social functioning (delta = 14.9; 95% CI:-0.5, 30.3), and physical functioning subscales (delta = 9.0; 95% CI: 1.2, 16.8). All symptom scales (except diarrhea) improved from baseline at most scheduled visits during the 20-week follow-up period. Mean scores for all four BPI-SF summary pain scores at week 8 suggested improvement in pain severity and pain interference. Clinical responders had improved scores on most aspects of QOL, compared with declining scores among nonresponders to treatment. Conclusions: The QOL improvement among the small number of patients with QOL data indicates that lapatinib monotherapy may improve level of functioning/QOL and provide relief from symptoms, including pain, in the short term. These QOL benefits add to the clinical improvement associated with lapatinib therapy in heavily pretreated patients with an aggressive form of breast cancer.

Background:In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.Methods:We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.Results:We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P=0.5) mutation carriers.Conclusion:This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.British Journal of Cancer advance online publication, 17 November 2009; doi:10.1038/sj.bjc.6605416 www.bjcancer.com.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression increases the aggressiveness of breast cancer cells resulting in poorer prognosis. Patients with HER2-positive disease are less responsive to endocrine therapies. Trastuzumab monotherapy results in objective responses in only approximately 15% of patients. Fulvestrant retains activity in cells overexpressing HER2 that are resistant to other endocrine treatments. This retrospective study evaluated response to fulvestrant treatment among HER2-positive patients with advanced breast cancer (ABC). PATIENTS AND METHODS: Clinical experience data from 10 treatment centres were pooled. Postmenopausal patients with predominantly hormone receptor-positive and HER2-positive disease were included. Clinical benefit (CB) was defined as the proportion of patients achieving a response to treatment (partial or complete) or stable disease lasting >/=6 months. RESULTS: Data for 102 patients were analysed. Fulvestrant resulted in an overall CB rate of 42%(43/101) in HER2-positive patients and 40%(25/63) in patients with visceral disease. Median duration of treatment was 14.5 months (range 6-44 months). Fulvestrant showed activity up to the fourth line of endocrine therapy and up to the seventh line of overall therapy. CONCLUSIONS: Results indicate that fulvestrant may be a suitable treatment option in extensively pre-treated patients with HER2-positive, hormone receptor-positive ABC. Further exploration of its use in this patient population is warranted.

BACKGROUND: The Lapatinib Expanded Access Program (LEAP) was designed to provide access to lapatinib plus capecitabine for HER2-positive metastatic breast cancer patients who previously received an anthracycline, a taxane, and a trastuzumab and had no other treatment options. PATIENTS AND METHODS: LEAP opened globally and enrollment continued until lapatinib received regulatory approval in each participating country. Patients were assessed for progression-free survival (PFS) and overall survival (OS) and monitored for serious adverse events (SAEs). RESULTS: As of 30 September 2008, 4283 patients from 45 countries enrolled in LEAP. The median treatment duration was 24.7 weeks. The most common drug-related SAEs were diarrhea (9.7%), vomiting (4.3%), and nausea (2.4%) and were mainly grade 3 or higher. The incidences of special interest SAEs were decreased left ventricle ejection fraction (0.5%), interstitial lung disease/pneumonitis (0.2%), and serious hepatobiliary events (0.4%). This safety profile is consistent with the overall lapatinib program. The median PFS and OS were 21.1 [95% confidence interval (CI)= 20.1-22.3] and 39.6 (95% CI = 37.7-40.7) weeks, respectively (n = 4006). Subgroup analysis showed longer PFS and OS in patients who had not received prior capecitabine. CONCLUSIONS: These results demonstrate the safety and efficacy of lapatinib in a broader patient population compared with a clinical trial.

Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 non-carriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P=0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P=0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wild-type klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.

This report reviews the development and clinical application of myocardial perfusion imaging with myocardial contrast echocardiography (MCE). This includes the development of microbubble formulations that permit the detection of left ventricular contrast from venous injection and the imaging techniques that have been invented to detect the transit of these microbubbles through the microcirculation. The methods used to quantify myocardial perfusion during a continuous infusion of microbubbles are described. A review of the clinical studies that have examined the clinical utility of myocardial perfusion imaging with MCE during rest and stress echocardiography is then presented. The limitations of MCE are also discussed.

A cone-beam lowers the X-ray exposure level and the contrast material dose used compared to those for the conventional angiography-computed tomography (angio-CT) technique. Herein we present a patient with a metastatic skull base bone tumor in which the subtraction image of cone-beam CT with a flat panel detector was useful for evaluating the vascular supply during superselective intraarterial chemotherapy. Although the image quality of cone-beam CT is poorer than that of conventional angio-CT, the cone-beam CT system is sufficient for clinical use.

We describe a technique of injecting alcohol into venous malformations (VM) under slow digital subtraction angiography (DSA) which eliminates the need to pre-mix the alcohol with a contrast agent. The technique presented here is especially helpful when Metrizamide is not available or not permitted for use. It offers an elegant way to visualize, in real time, the alcohol injected into the VM, while preserving its high concentration and potency as a sclerosing agent.

Periodontal probing and measurements using intraoral radiographs are widely utilized clinical techniques to measure attachment and bone levels, respectively. Determination of progressive disease, healing, or regeneration in clinical studies may require maximal sensitivity and attention to measurement error in order to assure that changes detected by new methodology are accurate. Both types of methods are susceptible to errors due to resolution, repeatability, and accuracy of the technique. While both probing and radiographic methods are useful in clinical trials they vary widely with respect to these errors. For example, manual probing is repeatable to within 1 mm better than 90% of the time, and state-of-the-art radiographic methods, such as digital subtraction radiography, can detect as little as 1 mg of bony change.

BACKGROUND Diagnostic subtraction radiography (DSR) is a new digital radiographic image subtraction method designed to enhance detection of crestal or periapical bone density changes and to help evaluate caries progression in teeth. In this clinical study, the performance of the DSR method was evaluated for its ability to detect periodontal bone loss and was compared with that of conventional evaluation of radiographs and the standardized cephalostat-guided image acquisition and subtraction technique (LRA) which served as the "gold standard." METHODS In each of 25 subjects with alveolar crestal bone loss created by periodontal surgery, one set of DSR radiographs and one set of LRA radiographs were obtained before and after the surgery. Subtraction images were then generated by both the proprietary DSR and the LRA techniques. Four viewers evaluated the paired film sets and both subtraction image sets using a 5 point confidence scale to determine the presence or absence of crestal bone loss. Receiver operating characteristics (ROC) statistical procedures were applied to analyze the diagnostic accuracy and statistical differences between the three imaging modalities. RESULTS The DSR subtraction viewing generated an ROC area of 0.882. For 2 of the viewers this represented a statistically significant gain (P <0.05) over the conventional viewing of the radiographs which had an average ROC area of 0.730. In comparison, the LRA method achieved an area of 0.954. The differences between the LRA and the DSR subtraction methods were not statistically significant, but the statistical power for claiming equality was low ranging from 0.2 to 0.6. CONCLUSIONS The use of the DSR technique in clinical radiographic image acquisition and subsequent subtraction analysis clearly enhanced the accuracy of alveolar crestal bone loss detection when compared to conventional film viewing. Because this methodology is less resource demanding than LRA and the film exposure techniques and computer-based image analysis skills may be acquired with only a few hours of training, the DSR has potential in clinical practice.

Carbon dioxide digital subtraction angiography Carbon dioxide (CO2) digital subtraction angiography offers the possibility for diagnostic and interventional angiographic procedures in high risk patients for ionidated contrast material. As a gaseous contrast agent its physicochemical properties have special requirements concerning the radiologists knowledge, the X-ray equipment, the injector and the catheters. This article reviews the current literature concerning the history, physics and physiology, indications and contraindications, clinical use, adverse effects and possible complications of carbon dioxide digital subtraction angiography.

After a short review of the use of ultrasonography to study shoulder rotator tendons, the technique of the investigation is described, as well as the main landmarks, findings indicative of complete rotator cuff tear, and limitations of ultrasonography in this indication. A number of issues concerning the preoperative workup are discussed. Results in a prospective study of 100 patients are reported. Findings upon ultrasonography, arthrography, and surgical exploration in these patients are analyzed comparatively. Sensitivity and specificity of ultrasonography for the diagnosis of complete rotator cuff tear (RCT) were 95% and 100%, respectively. These data show that ultrasonography is a reliable investigation for confirming, detecting, and evaluating RCT, although extensive experience with the technique is required.

Techniques for imaging the vascular tree have undergone change and development. Nuclear imaging can lead to decisions concerning diagnoses of masses, while contrast angiography with digital subtraction gives a complete picture of the vessels. Magnetic resonance angiography is the most exciting advance. Completely noninvasive, it yields much the same information as conventional contrast angiography.

A modified assay for the determination of hydroxyproline in tissue is presented. The modifications greatly reduce the time required for analysis of excised tissue as first introduced by Stegemann and Stalder [1]. These modifications include a change in the technique for tissue hydrolysis and a change in the preparation of the hydroxyproline oxidizing agent. The analysis utilizes the standard addition technique, eliminating the need for correction of matrix effects between the specimen and standard. This paper attempts to give a complete detailed description of the assay such that the procedure may be repeated without requiring additional reference material.

A simple film subtraction technique has been devised that isolates calcium image contrast and mutes tissue image contrast. Two exposures are required. The first is made on XL film using a 65 kVp beam filtered with 2 mm aluminum. The second is made on OG (high contrast) film using a 130 kVp beam filtered with 2 mm copper and 2 mm aluminum. The effective energies of these two beams are approximately 45 keV and 83 keV, respectively. A subtraction image is made, using the low energy image for the mask. With this technique it is possible to detect concentrations of 125 mg/cm3 of diffuse calcification in a chest nodule 1 cm in diameter. If the presence of diffuse calcification is found to be an indicator of benignancy in solitary pulmonary nodules, this technique may have diagnostic value for the detection of such calcification. Computerized tomographic findings are discussed and related to this technique.