Rational thresholding of circulating tumor DNA concentration for improved surveillance of metastatic breast cancer.

BACKGROUND: The use of circulating tumor DNA (ctDNA) concentration for metastatic cancer surveillance is promising, but uncertainty remains about cut-offs with clinical validity. MATERIALS AND METHODS: This observational study recruited 136 subjects with advanced metastatic breast cancer (irrespective of ERBB2/hormone receptor status) for sequencing of their primary tumor in search for PIK3CA hotspot variants amenable for monitoring by droplet digital PCR (ddPCR). The study analyzed 341 on-treatment samples from 19 patients with PIK3CA variants H1047R or E545K enrolled for long-term (median 85 weeks, range 13-125 weeks), frequent (every 3-5 weeks, median of 14 time points per subject, range 2-29) blood sampling for ctDNA quantification by ddPCR, orthogonally validated by deep sequencing. The diagnostic accuracy of ctDNA versus cancer antigen 15-3 (CA15-3) concentrations to predict disease progression within 12 weeks was investigated using receiver operating characteristic (ROC) analysis. Likelihood ratios were used for rational selection of ctDNA result intervals. RESULTS: ctDNA [area under the ROC curve (AUC) 0.848, 95% confidence interval (CI) 0.791-0.895] showed superior diagnostic performance than CA15-3 (AUC 0.670, 95% CI 0.601-0.735, P < 0.001) to predict clinical progression within 12 weeks. ctDNA levels below 10 mutant allele copies/ml had high negative predictive value (88%), while levels above 100 copies/ml detected 64% of progressions 10 weeks earlier versus standard of care. Logistic regression analysis indicated complementary value of ctDNA and the presence of two consecutive CA15-3 rises, resulting in a model with 86% (95% CI 74% to 93%) positive predictive value and a clinically meaningful result in 89% of blood draws. CONCLUSIONS: Intensive ctDNA quantification improves metastatic breast cancer surveillance and enables individualized risk-based scheduling of clinical care.

The relationship between operative and radiographic acetabular component orientation: which factors influence resultant cup orientation?

There is great variability in acetabular component orientation following hip replacement. The aims of this study were to compare the component orientation at impaction with the orientation measured on post-operative radiographs and identify factors that influence the difference between the two. A total of 67 hip replacements (52 total hip replacements and 15 hip resurfacings) were prospectively studied. Intra-operatively, the orientation of the acetabular component after impaction relative to the operating table was measured using a validated stereo-photogrammetry protocol. Post-operatively, the radiographic orientation was measured; the mean inclination/anteversion was 43° (sd 6°)/ 19° (sd 7°). A simulated radiographic orientation was calculated based on how the orientation would have appeared had an on-table radiograph been taken intra-operatively. The mean difference between radiographic and intra-operative inclination/anteversion was 5° (sd 5°)/ -8° (sd 8°). The mean difference between simulated radiographic and intra-operative inclination/anteversion, which quantifies the effect of the different way acetabular orientation is measured, was 3°/-6° (sd 2°). The mean difference between radiographic and simulated radiographic orientation inclination/anteversion, which is a manifestation of the change in pelvic position between component impaction and radiograph, was 1°/-2° (sd 7°). This study demonstrated that in order to achieve a specific radiographic orientation target, surgeons should implant the acetabular component 5° less inclined and 8° more anteverted than their target. Great variability (2 sd about ± 15°) in the post-operative radiographic cup orientation was seen. The two equally contributing causes for this are variability in the orientation at which the cup is implanted, and the change in pelvic position between impaction and post-operative radiograph.

Pelvic position and movement during hip replacement.

The orientation of the acetabular component is influenced not only by the orientation at which the surgeon implants the component, but also the orientation of the pelvis at the time of implantation. Hence, the orientation of the pelvis at set-up and its movement during the operation, are important. During 67 hip replacements, using a validated photogrammetric technique, we measured how three surgeons orientated the patient's pelvis, how much the pelvis moved during surgery, and what effect these had on the final orientation of the acetabular component. Pelvic orientation at set-up, varied widely (mean (± 2, standard deviation (sd))): tilt 8° (2sd ± 32), obliquity -4° (2sd ± 12), rotation -8° (2sd ± 14). Significant differences in pelvic positioning were detected between surgeons (p < 0.001). The mean angular movement of the pelvis between set-up and component implantation was 9° (sd 6). Factors influencing pelvic movement included surgeon, approach (posterior > lateral), procedure (hip resurfacing > total hip replacement) and type of support (p < 0.001). Although, on average, surgeons achieved their desired acetabular component orientation, there was considerable variability (2sd ± 16) in component orientation. We conclude that inconsistency in positioning the patient at set-up and movement of the pelvis during the operation account for much of the variation in acetabular component orientation. Improved methods of positioning and holding the pelvis are required.

Metal ion levels from well-functioning Birmingham Hip Resurfacings decline significantly at ten years.

A retrospective study was conducted to investigate the changes in metal ion levels in a consecutive series of Birmingham Hip Resurfacings (BHRs) at a minimum ten-year follow-up. We reviewed 250 BHRs implanted in 232 patients between 1998 and 2001. Implant survival, clinical outcome (Harris hip score), radiographs and serum chromium (Cr) and cobalt (Co) ion levels were assessed. Of 232 patients, 18 were dead (five bilateral BHRs), 15 lost to follow-up and ten had been revised. The remaining 202 BHRs in 190 patients (136 men and 54 women; mean age at surgery 50.5 years (17 to 76)) were evaluated at a minimum follow-up of ten years (mean 10.8 years (10 to 13.6)). The overall implant survival at 13.2 years was 92.4% (95% confidence interval 90.8 to 94.0). The mean Harris hip score was 97.7 (median 100; 65 to 100). Median and mean ion levels were low for unilateral resurfacings (Cr: median 1.3 µg/l, mean 1.95 µg/l (< 0.5 to 16.2); Co: median 1.0 µg/l, mean 1.62 µg/l (< 0.5 to 17.3)) and bilateral resurfacings (Cr: median 3.2 µg/l, mean 3.46 µg/l (< 0.5 to 10.0); Co: median 2.3 µg/l, mean 2.66 µg/l (< 0.5 to 9.5)). In 80 unilateral BHRs with sequential ion measurements, Cr and Co levels were found to decrease significantly (p < 0.001) from the initial assessment at a median of six years (4 to 8) to the last assessment at a median of 11 years (9 to 13), with a mean reduction of 1.24 µg/l for Cr and 0.88 µg/l for Co. Three female patients had a > 2.5 µg/l increase of Co ions, associated with head sizes ≤ 50 mm, clinical symptoms and osteolysis. Overall, there was no significant difference in change of ion levels between genders (Cr, p = 0.845; Co, p = 0.310) or component sizes (Cr, p = 0.505; Co, p = 0.370). Higher acetabular component inclination angles correlated with greater change in ion levels (Cr, p = 0.013; Co, p = 0.002). Patients with increased ion levels had lower Harris hip scores (p = 0.038). In conclusion, in well-functioning BHRs the metal ion levels decreased significantly at ten years. An increase > 2.5 µg/l was associated with poor function.

MRI in hypertrophic mono- and polyneuropathies.

Different conditions that may lead to enlarged nerves or nerve roots include hereditary motor and sensory neuropathy (HMSN), neurofibromatosis (NF) type 1, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and intraneural perineurioma. Differential diagnosis of hypertrophic mono- and polyradiculopathies remains challenging but is important because of different treatments and prognosis. Magnetic resonance imaging (MRI) can identify the hypertrophic nerve segments and guide a fascicular biopsy. A fascicular biopsy will often be necessary for precise diagnosis.

Pott's puffy tumour in a 5-year old boy: the role of ultrasound and contrast-enhanced CT imaging; surgical case report.

We report a case of Pott's puffy tumour, a subperiosteal abscess of the frontal bone associated with an underlying frontal osteomyelitis, in a 5-year-old boy. Ultrasonography played a crucial role in the diagnosis of our patient, suggesting the presence of a Pott's puffy tumour with epidural abscess by showing a subperiosteal abscess associated with erosion of the frontal bone. Subsequently, the diagnosis of Pott's puffy tumour with epidural abscess was confirmed by contrast-enhanced CT scanning. Prompt neurosurgical intervention with drainage of abscesses and debridement of bone sequestrate, together with prolonged antibiotic therapy, significantly contributes to a favorable outcome.

Sphenoid mucocoele as a complication of fibrous dysplasia of the facial bones.

We report on a 28-year-old man with severe headache. Imaging studies included CT and MR. A large sphenoid mucocoele was demonstrated as well as findings compatible with fibrous dysplasia of the facial bones. Both disorders had been previously unknown. Imaging findings suggested that the sphenoid mucocoele was related to an obstruction caused by the expansile bone of fibrous dysplasia. These findings were confirmed surgically. Fibrous dysplasia with subsequent outflow obstruction is an extremely rare cause of sphenoid mucocoele development.

Uterus didelphys with obstructed hemivagina and renal agenesis: MRI findings.

Müllerian duct abnormalities (MDA) are developmental disorders leading to dysmorphism of the female genital tract. Currently the Buttram and Gibbons classification of these entities is widely used. We present a case of a young girl with uterus didelphys and ipsilateral renal agenesis.

Adverse reaction to metal debris following hip resurfacing: the influence of component type, orientation and volumetric wear.

We sought to establish the incidence of joint failure secondary to adverse reaction to metal debris (ARMD) following metal-on-metal hip resurfacing in a large, three surgeon, multicentre study involving 4226 hips with a follow-up of 10 to 142 months. Three implants were studied: the Articular Surface Replacement; the Birmingham Hip Resurfacing; and the Conserve Plus. Retrieved implants underwent analysis using a co-ordinate measuring machine to determine volumetric wear. There were 58 failures associated with ARMD. The median chromium and cobalt concentrations in the failed group were significantly higher than in the control group (p < 0.001). Survival analysis showed a failure rate in the patients with Articular Surface Replacement of 12.8% [corrected] at five years, compared with < 1% at five years for the Conserve Plus and 1.5% at ten years for the Birmingham Hip Resurfacing. Two ARMD patients had relatively low wear of the retrieved components. Increased wear from the metal-on-metal bearing surface was associated with an increased rate of failure secondary to ARMD. However, the extent of tissue destruction at revision surgery did not appear to be dose-related to the volumetric wear.

Spontaneous soccer-induced pneumomediastinum in a 39-year-old man.

We report on a healthy 39-year-old man who developed spontaneous pneumomediastinum during a soccer game without a traumatic impact. Chest radiography and CT demonstrated the extensive pneumomediastinum and subcutaneous emphysema. Treatment of this rare condition is conservative and prognosis is excellent.

Cortisone associated diverticular perforation.

Patients on glucocorticosteroid therapy are at increased risk of gastrointestinal perforation. The associated morbidity and mortality of perforations in this group is increased, compared with normal groups. This difference is due to the delay between onset of clinical symptoms and treatment. In the presence of steroids, gastrointestinal perforation is more difficult to diagnose clinically because signs and symptoms of perforation are masked by the anti-inflammatory effect of the steroids.

Leiomyomatosis peritonealis disseminata in a 50-year-old woman: imaging findings.

Leiomyomatosis peritonealis disseminata (LPD)--or diffuse abdominal leiomyomatosis--is a very rare benign abdominal entity. Only a little more than 100 cases have been reported in the English literature since its first description in 1965. Middle aged female are typically affected and the clinical presentation is rather aspecific. The differential diagnosis between benign LPD and diffuse peritoneal carcinomatosis or abdominal disseminated malignancy represents the crucial diagnostic challenge that can only definitively be made through biopsy and histologic analysis. Multimodal imaging features (ultrasound, CT, MR and PET) of a case of LPD diagnosed in a 50-year-old female are presented with review the literature.

Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods.

Quality assurance is becoming increasingly important. Good laboratory practice (GLP) and good manufacturing practice (GMP) are now established standards. The biomedical field aims at an increasing reliance on the use of in vitro methods. Cell and tissue culture methods are generally fast, cheap, reproducible and reduce the use of experimental animals. Good cell culture practice (GCCP) is an attempt to develop a common standard for in vitro methods. The implementation of the use of chemically defined media is part of the GCCP. This will decrease the dependence on animal serum, a supplement with an undefined and variable composition. Defined media supplements are commercially available for some cell types. However, information on the formulation by the companies is often limited and such supplements can therefore not be regarded as completely defined. The development of defined media is difficult and often takes place in isolation. A workshop was organised in 2009 in Copenhagen to discuss strategies to improve the development and use of serum-free defined media. In this report, the results from the meeting are discussed and the formulation of a basic serum-free medium is suggested. Furthermore, recommendations are provided to improve information exchange on newly developed serum-free media.

Metal-on-metal hip resurfacing: a consensus from the Advanced Hip Resurfacing Course, Ghent, June 2009.

We report the consensus of surgical opinions of an international faculty of expert metal-on-metal hip resurfacing surgeons, with a combined experience of over 18,000 cases, covering required experience, indications, surgical technique, rehabilitation and the management of problematic cases.

Overground vs. treadmill walk-to-run transition.

Determination of the walk-to-run transition (WRT) speed is a crucial aspect of gait transition research, which has been conducted on treadmill as well as overground. Overground WRT-speeds were reported to be higher than on treadmill. Part of this difference could be related to the lower acceleration magnitudes on treadmill. In this study, spontaneous WRT overground was compared to WRT at a comparable acceleration on treadmill. In addition, calculation procedures correcting for movement in the lab reference frame on treadmill were implemented. As such, this study was, in contrast to previous treadmill studies, able to detect a speed jump. This speed jump was until now a typical feature of overground WRT and contributed to the higher transition speed. By incorporating horizontal movements of the COM, a speed jump was also detected on treadmill. Yet, treadmill WRT-speed (2.61 ms(-1)) remained lower than overground (2.85 ms(-1)). Nevertheless, this difference was much smaller than assumed in the literature. The remaining difference could be explained by a larger speed jump (treadmill: 0.40 ms(-1); overground: 0.51 ms(-1)), and a higher speed at the start of the transition step overground (treadmill: 2.21 ms(-1); overground: 2.34 ms(-1)). In conclusion, even when controlling for effects of acceleration and movement in the lab reference frame a treadmill influence on WRT was visible.

Occurrence of pulmonary artery aneurysms and pulmonary artery thrombosis in a young man.

Behçet's disease (BD) is a multisystemic inflammatory disorder of unknown aetiology. Arterial involvement is uncommon but associated with important morbidity and mortality. We describe the clinical course of BD with severe pulmonary artery involvement in a 19-year-old man. He presented with massive haemoptysis related to pulmonary artery aneurysms. Initial treatment consisted in urgent right inferior lobectomy, corticosteroids and monthly intravenous cyclophosphamide. Subsequently, he developed pulmonary artery thrombosis at non-aneurysmatic sites. Corticosteroid therapy was intensified, monthly intravenous cyclophosphamide was continued and an anticoagulant was added to the treatment with a favourable clinical and radiological response. Our case illustrates that timely initiation of highly potent immunosuppressive therapy is critical to obtain a favourable outcome. At present, a consensus regarding optimal management of vascular BD is lacking. ALthough anticoagulation is not generally recommended, our report encourages a patient-based decision after carefully tailoring potential risks and benefits.