MRI prostate contouring is not impaired by the use of a radiotherapy image acquisition set-up. An intra- and inter-observer paired comparative analysis with diagnostic set-up images.

PURPOSE: The use of MRI for radiotherapy planning purposes is growing but image acquisition using radiotherapy set-ups has impaired image quality. Whether differences in image acquisition set-up could modify organ contouring has not been evaluated. Therefore, we aimed to evaluate differences in contouring between paired of image sets that were acquired in the same scanning session using different parameters. MATERIAL AND METHODS: Ten patients underwent RT treatment planning with MRI co-registration. MRI was carried out using two different set-ups during the same session, MRI radiotherapy set-ups and MRI diagnostic set-ups. Prostates and rectums were retrospectively contoured in both image sets by 5 radiation oncologists and 4 radiologists. Intra-observer analysis was carried out comparing organ volumes, the Dice coefficient and hausdorff distance values between two contouring rounds. Inter-observer analysis was carried out by comparing individual contours to a generated STAPLE consensus contour, which is considered the gold standard reference. RESULTS: No significant differences were observed between MRI acquisition set-ups. Significant differences were observed for the dice and hausdorff parameters, comparing individual contours to the STAPLE consensus contour, when analysing diagnostic images between rounds, although raw values were similar. CONCLUSION: Prostate and rectum contours did not differ significantly when using diagnostic or radiotherapy MRI acquisition set-ups.

p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models.

BACKGROUND AND PURPOSE: Gemcitabine is an antitumour agent currently used in the treatment of several types of cancer with known properties as a radiosensitizer. p38MAPK signalling pathway has been shown to be a major determinant in the cellular response to gemcitabine in different experimental models. However, the molecular mechanism implicated in gemcitabine-associated radiosensitivity remains unknown. MATERIALS AND METHODS: The human sarcoma cell lines A673 and HT1080, and a mouse cell line derived from a 3-methylcholanthrene induced sarcoma were used as experimental models. Modulation of p38MAPKs was performed by pharmacological approaches (SB203580) and genetic interference using lentiviral vectors coding for specific shRNAs. Viability was assessed by MTT. Gene expression was evaluated by western blot and RT-qPCR. Induction of apoptosis was monitored by caspase 3/7 activity. Response to ionizing radiation was evaluated by clonogenic assays. RESULTS: Our data demonstrate that chemical inhibition of p38MAPK signalling pathway blocks gemcitabine radiosensitizing potential. Genetic interference of MAPK14 (p38α), the most abundantly expressed and best characterized p38MAPK, despite promoting resistance to gemcitabine, it does not affect its radiosensitizing potential. Interestingly, specific knockdown of MAPK11 (p38ß) induces a total loss of the radiosensitivity associated to gemcitabine, as well as a marked increase in the resistance to the drug. CONCLUSION: The present work identifies p38ß as a major determinant of the radiosensitizing potential of gemcitabine without implication of p38α, suggesting that p38ß status should be analysed in those cases in which gemcitabine is combined with ionizing radiation.

Acoustic probing of the particle concentration in turbulent granular suspensions in air.

Dilute gas-particle suspensions in which the particles are carried by the fluid are found in various industrial and geophysical contexts. One fundamental issue that limits our understanding of such systems is the difficulty to obtain information on the particle concentration inside these often optically opaque suspensions. To overcome this difficulty, we develop ultrasonic spectroscopy to monitor the local particle concentration [Formula: see text] of glass particles (with diameters [Formula: see text] 77 [Formula: see text]m or 155 [Formula: see text]m) suspended in air. First, we determine the minimal air velocity, [Formula: see text], necessary to suspend the particles from the maximum decrease in the transmitted wave amplitude and velocity of ultrasound propagating through the suspension. Next, setting the air velocity at [Formula: see text], we increase the mass of particles and monitor acoustically the local solid volume fraction, [Formula: see text], by measuring the ultrasound wave attenuation coefficient and phase velocity as a function of frequency on the basis of classical scattering and hydrodynamic models. For the frequency ranges and suspensions considered here, the viscous dissipation dominates over scattering and thermal conduction losses. We show that, for a characteristic air velocity [Formula: see text], the locally measured [Formula: see text] reaches a critical value, in agreement with a recent study on turbulent gas-particle mixtures. Moreover, we find that this critical [Formula: see text] increases with the size of the particles. Finally, analysis of the temporal fluctuations of the locally measured solid volume fraction, suggests that high density regions (clusters) are present even in suspensions with concentrations below the critical concentration. This differs from the current hypothesis according to which the critical concentration coincides with the onset of cluster formation.

Radiotherapy is safe in patients with implantable cardiac devices. Analysis of a systematic interrogation follow-up.

INTRODUCTION: The number of patients who have a cardiac implantable electronic device (CIEDs) that undergo a course of radiotherapy is increasing due to the ageing population. The majority of clinical studies only evaluate any CIED malfunction at the end of a course of irradiation or in a case of there being symptoms of possible malfunction. As a result, little data has been collected on CIED status acquired during an active course of irradiation. MATERIAL AND METHODS: We aimed to evaluate the correct functioning of a CIED during a course of radiotherapy. So, a retrospective analysis was made of all patients having CIEDS in a single institution during their course of radiotherapy. All CIEDs were systematically checked before and during the course of radiotherapy according to the risk of device failure and patient dependence. RESULTS: Data was analysed from 56 patients (43 men, 13 women) with a mean age of 78.2 years, of whom 87.5% of the patients carried a pacemaker (PM), the 39% of the patients were PM dependent, and the remaining patients carried an implantable cardioverter-defibrillator (ICD). An observable dose of irradiation was evident in only 10 cases. 69.1% of the CIEDs were checked daily and the remainder were checked weekly. During the radiotherapy course, 82% of the patients did not complain of any cardiological event. The CIED of five patients experienced an increase in the threshold and, in another case, a sudden reduction in the duration of the battery was reported. Another patient with a CIED experienced a cardiac insufficiency episode triggered by a ventricular tachycardia. CONCLUSION: In conclusions, although adverse clinical events from exposure of a CIED to irradiation are rare, they can appear in any group of risk. No dose-dependency was observed on the malfunction of the CIED.

P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy.

Targeting cell cycle has become one of the major challenges in cancer therapy, being Palbociclib, a CDK4/6 inhibitor, an excellent example. Recently, it has been reported that Palbociclib could be a novel radiosensitizer agent. In an attempt to clarify the molecular basis of this effect we have used cell lines from colorectal (HT29, HCT116) lung (A549, H1299) and breast cancer (MCF-7). Our results indicate that the presence of a p53 wild type is strictly required for Palbociclib to exert its radiosensitizing effect, independently of the inhibitory effect exerted on CDK4/6. In fact, abrogation of p53 in cells with functional p53 blocks the radiosensitizing effect of Palbociclib. Moreover, no radiosensitizing effect is observed in cells with non-functional p53, but restoration of p53 function promotes radiosensitivity associated to Palbociclib. Furthermore, the presence of Palbociclib blocks the transcriptional activity of p53 in an ATM-dependent-fashion after ionizing radiation exposure, as the blockage of p21/WAF1 expression demonstrates. These observations are a proof of concept for a more selective therapy, based on the combination of CDK4/6 inhibition and radiotherapy, which would only benefit to those patients with a functional p53 pathway.

Blockage of autophagic flux is associated with lymphocytosis and higher percentage of tumoral cells in chronic lymphocytic leukemia of B cells.

PURPOSE: Autophagy has lately emerged as an important biological process with implications in several hematological pathologies. Recently, a growing body of evidence supports a putative role of autophagy in chronic lymphocytic leukemia; however, no definitive clue has been established so far. To elucidate this issue, we have developed a pilot study to measure autophagic flux in peripheral blood mononuclear cells from chronic lymphocytic leukemia patients, and explored its correlation with classical clinical/analytical parameters. METHODS/PATIENTS: Thirty-three chronic lymphocytic leukemia patients participated in the study. Autophagic flux in peripheral blood mononuclear cells was determined by western blot measuring the levels of the proteins p62 and lipidated LC3. Moreover, p62 mRNA levels were analyzed by RT-qPCR. RESULTS: Lymphocytosis and the percentage of tumoral lymphocytes in chronic lymphocytic leukemia patients statistically correlate with a blocked autophagic flux. CONCLUSION: Alterations in autophagic flux could play an important role in the physiopathology of chronic lymphocytic leukemia.

Assessment of a press-fit proximal femoral modular reconstruction implant (PFMR®) at 14.5 years. A 48-case series with a disturbing rate of implant fracture.

INTRODUCTION: The PFMR® proximal femoral modular reconstruction implant (Protek, Sulzer Orthopedics, Switzerland) is a straight modular stem in sanded titanium with press-fit anchorage, intended to achieve spontaneous bone reconstruction following Wagner's principle. The aim of the present study was to analyze long-term clinical and radiological outcome. MATERIAL AND METHOD: A single-center retrospective study included 48 PFMR stems implanted in 47 patients between 1998 and 2002. Results in this series were previously reported at 7 years' follow-up. Clinical assessment used PMA and Harris scores. Radiologic assessment focused on stem stability and osseointegration, and bone stock following Le Béguec. RESULTS: Twenty-three patients were seen at a mean 14.5 years' follow-up (13 deceased, 11 lost to follow-up), including 1 with bilateral implants, i.e., 24 stems. PMA and Harris scores, stem stability and osseointegration and bone stock were stable with respect to the 7-year findings. Radiology found 7 stem fractures in the Morse taper, i.e., in 29% of implants. Two of these cases required femoral implant replacement; 5 were asymptomatic. DISCUSSION AND CONCLUSION: Long-term outcome for PFMR stems was clinically and radiologically satisfactory for the 16 patients free of mechanical complications. The Morse taper fracture rate was high, and higher than reported elsewhere. The usual risk factors for implant fracture were not found in the present series. The modular design of the press-fit revision implant is its weak point; monoblock implants should be used in patients with good life-expectancy. LEVEL OF EVIDENCE: IV (retrospective study).

Developments in imaging methods used in hip arthroplasty: A diagnostic algorithm.

BACKGROUND: Several imaging modalities can be used to diagnose complications of hip prosthesis placement. Despite progress in these imaging techniques, there are, as yet, no guidelines as to their respective indications. METHODS: We formed a panel of experts in fields related to prosthesis imaging (radiology, nuclear medicine, orthopedic surgery) and conducted a review of the literature to determine the value of each modality for diagnosing complications following hip replacement. RESULTS: Few recent studies have investigated the benefits related to the use of the latest technical developments, and studies comparing different methods are extremely rare. CONCLUSIONS: We have developed a diagnostic tree based on the characteristics of each imaging technique and recommend its use. Computed topography was found to be the most versatile and cost-effective imaging solution and therefore a key tool for diagnosing the complications of hip replacement surgery.

Influence of fixation with two vs. three screws on union of arthroscopic tibio-talar arthrodesis: Comparative radiographic study of 111 cases.

BACKGROUND: Ankle arthrodesis is a treatment of choice for advanced tibio-talar disease unresponsive to conservative treatment. Using arthroscopy to perform this procedure minimises soft-tissue trauma while providing similar outcomes to those of open surgery. Union rates have ranged across studies from 85% to 100%. The objective of this study was to assess the potential influence on union of the number of screws used for arthrodesis fixation. HYPOTHESIS: The working hypothesis was that using three screws for arthrodesis produced a higher union rate than did using only two screws. MATERIAL AND METHODS: This single-centre retrospective comparative study included 111 cases of arthroscopic ankle arthrodesis (in 108 patients) carried out between February 1994 and October 2012. The number of screws was two in 75 cases and three in 36 cases. Union was assessed on radiographs taken 2, 6, and 12months postoperatively. RESULTS: Mean age at surgery was 55.8years. After 12months, union was achieved in 87.4% cases overall. The non-union rate was 16% with two screws and 5.6% with three screws. Three-screw fixation was associated with a significantly higher rate of union of the medial gutter after 6months and of the lateral gutter after 12months. DISCUSSION: Our findings support the use of three screws for fixation of arthroscopic tibio-talar arthrodesis. Adding a third screw seems associated with a lower risk of non-union and a shorter time to union. These effects can be ascribed to greater stability of the construct. LEVEL OF EVIDENCE: Level IV, retrospective study.

Two-stage total hip arthroplasty for complex pelvic abnormalities: Example of hip arthrodesis conversion with concomitant treatment of pelvic and acetabular non-union.

Hip prosthesis implantation requires a stable pelvic foundation, which may be lacking in patients with complex pelvic abnormalities (e.g., arthrodesis conversion, tumour excision, or revision with large bony defects). Many reconstructive options exist for these situations, but their outcomes vary with the initial amount of bone loss and with the technique used. We describe a two-stage arthroplasty technique (acetabular cup first, then femoral stem) and report its use in a case of arthrodesis conversion with concomitant treatment of pelvic and acetabular non-union. Clinical and radiological outcomes after 5 years are reported. This procedure can be adapted to the most complex cases of pelvic reconstruction.

Slow-moving and far-travelled dense pyroclastic flows during the Peach Spring super-eruption.

Explosive volcanic super-eruptions of several hundred cubic kilometres or more generate long run-out pyroclastic density currents the dynamics of which are poorly understood and controversial. Deposits of one such event in the southwestern USA, the 18.8 Ma Peach Spring Tuff, were formed by pyroclastic flows that travelled >170 km from the eruptive centre and entrained blocks up to ∼ 70-90 cm diameter from the substrates along the flow paths. Here we combine these data with new experimental results to show that the flow's base had high-particle concentration and relatively modest speeds of ∼ 5-20 m s(-1), fed by an eruption discharging magma at rates up to ∼ 10(7)-10(8) m(3) s(-1) for a minimum of 2.5-10 h. We conclude that sustained high-eruption discharge and long-lived high-pore pressure in dense granular dispersion can be more important than large initial velocity and turbulent transport with dilute suspension in promoting long pyroclastic flow distance.

Infection recurrence factors in one- and two-stage total knee prosthesis exchanges.

PURPOSE: Revision of infected total knee replacements (TKR) is usually delayed for a period in which the joint space is filled with an antibiotic-loaded acrylic spacer. In contrast, one-stage re-implantation supposes immediate re-implantation. Formal comparisons between the two methods are scarce. A retrospective multi-centre study was conducted to investigate the effects of surgery type (one-stage vs. two-stage) on cure rates. It was hypothesised that this parameter would not influence the results. METHOD: All infected TKR, treated consecutively between 2005 and 2010 by senior surgeons working in six referral hospitals, were included retrospectively. Two hundred and eighty-five patients, undergoing one-stage or two-stage TKR, with more than 2-year follow-up (clinical and radiological) were eligible for data collection and analysis. Of them, 108 underwent one-stage and 177 received two-stage TKR. Failure was defined as infection recurrence or persistence of the same or unknown pathogens. Factors linked with infection recurrence were analysed by uni- and multi-variate logistic regression with random intercept. RESULTS: Factors associated with infection recurrence were fistulae (odds ratio (OR) 3.4 [1.2-10.2], p = 0.03), infection by gram-negative bacteria (OR 3.3 [1.0-10.6], p = 0.05), and two-stage surgery with static spacers (OR 4.4 [1.1-17.9], p = 0.04). Gender and type of surgery interacted (p = 0.05). In men (133 patients), type of surgery showed no significant linkage with infection recurrence. In women (152 patients), two-stage surgery with static spacers was associated independently with infection recurrence (OR 5.9 [1.5-23.6], p = 0.01). Among patients without infection recurrence, International Knee Society scores were similar between those undergoing one-stage or two-stage exchanges. CONCLUSION: Two-stage procedures offered less benefit to female patients. It suggests that one-stage procedures are preferable, because they offer greater comfort without increasing the risk of recurrence. Routine one-stage procedures may be a reasonable option in the treatment of infected TKR. LEVEL OF EVIDENCE: III.

Bone density and functional results after femoral revision with a cementless press-fit stem.

INTRODUCTION: The influence of radiographic bone density changes in the area surrounding a total hip arthroplasty (THA) revision with a cementless press-fit stem is unknown, notably in terms of functional results. We have therefore conducted a study aiming to (1) propose a radiographic method to assess bone density, (2) measure the functional effects of reduced bone density, and (3) determine the factors contributing to these modifications. HYPOTHESIS: A reduction in radiographic bone density has a negative influence on the functional result after revision using a cementless press-fit stem. MATERIAL AND METHODS: We retrospectively assessed 150 THA revisions at a mean follow-up of 6.3 ± 3.2 years (range, 2-15 years). The clinical assessment was based on the Harris Hip Score. Bone density modifications were measured radiographically and the method was evaluated. The change in bone density was classified into two groups: (1) bone density not reduced or < 2 Gruen zones (118 cases [79%]); (2) bone density reduced ≥ 2 zones (32 cases [21%]). The variables showing a potential influence were the Cortical Index (CI), the type of primary stability with the press-fit system, and the femoral implant length. RESULTS: Inter- and intraobserver reliability of radiographic bone density measurement was evaluated as moderate or good (Kappa, 0.58; 0.60 and 0.67, respectively). For the Harris Hip Score at follow-up, there was a borderline statistical relation between stages 1 and 2: for the 118 stage 1 patients, this score was 83.62 ± 11.54 (range, 27-99) versus 78.34 ± 15.98 (range, 62-91) for stage 2 patients (P = 0.09). A CI ≤ 0.44 showed mediocre bone quality contributing to decreased bone density (P < 0.02). On the other hand, there was no statistically significant relation with the type of primary fixation (P = 0.34) or the length of the implant (P = 0.23). CONCLUSIONS: A cementless revision femoral stem can induce a reduction in bone density with possible functional effects. The negative role played by bone scarcity on the functional score is confirmed, and even though the difference is not statistically significant, we suggest using a short stem when this is possible.

EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.

The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin-A3 through a novel hypoxia-inducible factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (lnc) RNAs from EFNA3 locus and these lncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation.

Is rotator cuff repair appropriate in patients older than 60 years of age? prospective, randomised trial in 103 patients with a mean four-year follow-up.

BACKGROUND: The objective of this randomised trial was to compare surgical rotator cuff repair to simple decompression by acromioplasty and biceps tenotomy in patients older than 60 years of age with a mean follow-up of 4 years. HYPOTHESIS: Tendon repair produces better functional outcomes than simple decompression and prevents progression towards cuff tear arthropathy in the longer term. PATIENTS AND METHOD: Of 130 initially included patients older than 60 years of age and having rotator cuff tears deemed amenable to surgical repair, 103 (79%) were evaluated after a mean of 4 years. These patients had been randomly allocated to acromioplasty and tenotomy (AT group, n=49) or to acromioplasty, tenotomy, and tendon suture (CR group, n=54). The tear was distal in 41 patients, intermediate in 40, and retracted in 22. At last follow-up, the evaluation included the clinical Constant's Score, radiographs and, in the CR group, ultrasonography. RESULTS: The complication rate was 4%. The mean Constant Score was 44 preoperatively; values after 4 years were 76 overall (P=0.01), 78 in the CR group, and 73 in the AT group (P=0.01). The tendon-healing rate as assessed using ultrasonography was 63%. The Constant Score was significantly better when tendon healing was achieved (82/73, P<0.001). In the AT group, the acromio-humeral distance was significantly shorter (6.9 mm/7.8mm, P=0.03) and eccentric humeral head position was more common (44%/26%, P=0.01). DISCUSSION: Arthroscopic rotator cuff repair provides better functional outcomes than does simple decompression in patients older than 60 years and prevents cuff tear arthropathy with eccentric humeral head position in the medium term. Tendon healing is the main determinant of outcomes after rotator cuff repair. LEVEL OF EVIDENCE: II, randomised trial.

Dynamics of dense granular flows of small-and-large-grain mixtures in an ambient fluid.

Dense grain flows in nature consist of a mixture of solid constituents that are immersed in an ambient fluid. In order to obtain a good representation of these flows, the interaction mechanisms between the different constituents of the mixture should be considered. In this article, we study the dynamics of a dense granular flow composed of a binary mixture of small and large grains immersed in an ambient fluid. In this context, we extend the two-phase approach proposed by Meruane et al. [J. Fluid Mech. 648, 381 (2010)] to the case of flowing dense binary mixtures of solid particles, by including in the momentum equations a constitutive relation that describes the interaction mechanisms between the solid constituents in a dense regime. These coupled equations are solved numerically and validated by comparing the numerical results with experimental measurements of the front speed of gravitational granular flows resulting from the collapse, in ambient air or water, of two-dimensional granular columns that consisted of mixtures of small and large spherical particles of equal mass density. Our results suggest that the model equations include the essential features that describe the dynamics of grains flows of binary mixtures in an ambient fluid. In particular, it is shown that segregation of small and large grains can increase the front speed because of the volumetric expansion of the flow. This increase in flow speed is damped by the interaction forces with the ambient fluid, and this behavior is more pronounced in water than in air.