Endplate Trauma During Implant Insertion Affects the Expulsion Risk of Anterior Lumbar Interbody Fusion Devices.

Background Anterior cage migration in anterior lumbar interbody fusion is a serious complication. To address this risk, cage designs are now available with integrated screw or blade fixation or specially designed surface geometries with large teeth or ridges. However, the implantation technique itself has not yet been addressed as a potential risk factor for cage migration. This study aimed to investigate whether a cage that is implantable without gouging the vertebral endplates has improved resistance to anterior migration. Methodology A novel three-piece modular cage was inserted between two vertebral body replacements (polyurethane (PU) foam grade 15 pcf) in two ways. In group 1 (modular), the cage was inserted in a wedge within a wedge fashion according to the manufacturer's instructions such that damage to the PU foam was minimized. In group 2 (mono-bloc), the modular cage was inserted pre-assembled as a one-piece, mono-bloc device. This insertion method required impaction and increased the potential of gouging the PU surfaces. Then, an axial preload was applied to the PU test blocks to simulate the preload on the spine in vivo and an anteriorly direct expulsion force was applied to the cages. Results The mean expulsion yield load in the test group with modular implantation was 392 ± 19 N compared to 287 ± 16 N in the test group where the mono-bloc implants were inserted and endplate gouging occurred. This difference was statistically significant (p < 0.05). Thus, the onset of cage migration occurred at significantly higher loads in the test group with modular insertion without endplate gouging compared to one-piece impaction with gouging taking place. In contrast, the stiffness and the ultimate load were similar in both test groups (p > 0.05). Conclusions This study showed that the cage insertion technique may have a significant effect on the cage migration risk. Prevention of endplate gouging during cage implantation has the potential to improve the primary stability of the cage.

The MOVE-C Cervical Artificial Disc - Design, Materials, Mechanical Safety.

PURPOSE: There are various cervical disc prostheses on the market today. They can be subdivided into implants with a ball-and-socket design and implants with a flexible core, which is captured between the implant endplates and sealed using various sheaths. Implants with an articulating surface are mostly metal-on-metal or metal-on-UHMWPE designs and, thus, do not allow for axial damping. The aim of this study is to provide mechanical safety and performance data of the MOVE-C cervical disc prosthesis which combines both an articulating surface and a flexible core. MATERIALS AND METHODS: MOVE-C consists of a cranial and caudal metal plate made of TiAl6V4. The cranial plate is TiNbN coated on its articulating surface. The caudal plate has a fixed polycarbonate-urethane (PCU) core. The TiNbN coating is meant to optimize the wear behavior of the titanium endplate, whereas the PCU core is meant to allow for a reversible axial deformation, a pre-defined neutral zone and a progressive load-deformation curve in all planes. RESULTS: Various standard testing procedures (for example, ISO 18192-1 and ASTM F2364) and non-standard mechanical tests were carried out to prove the implant's mechanical safety. Due to the new implant design, wear and creep testing was deemed most important. The wear rate for the PCU was in maximum 1.54 mg per million cycles. This value was within the range of the UHMWPE wear rates reported for other cervical disc prostheses (0.53 to 2.59 mg/million cycles). Also in the creep-relaxation test, a qualitatively physiological behavior was shown with a certain amount of remaining deformation but no failure. CONCLUSION: The mechanical safety of the MOVE-C cervical disc prosthesis was shown to be comparable to other cervical disc prostheses. Since PCU wear particles were elsewhere shown to be less bioactive than cross-linked UHMWPE particles, wear-related failure in vivo may be less frequent compared to other prostheses. This, however, will have to be shown in further studies.

In vitro analysis of kinematics and elastostatics of the human rib cage during thoracic spinal movement for the validation of numerical models.

Neither kinematic nor stiffness properties of the rib cage during thoracic spinal motion were investigated in previous studies, while being essential for the accurate validation of numerical models of the whole thorax. The aim of this in vitro study therefore was to quantify the kinematics and elastostatics of the human rib cage under defined boundary conditions. Eight fresh frozen human thoracic spine specimens (C7-L1, median age 55 years, ranging from 40 to 60 years) including entire rib cages were loaded quasi-statically in flexion/extension, lateral bending, and axial rotation using pure moments of 5Nm. Relative motions of ribs, thoracic vertebrae, and sternal structures as well as strains on the ribs were measured using optical motion tracking of 150 reflective markers per specimen, while specimens were loaded displacement-controlled with a constant rate of 1°/s for 3.5 cycles. The third full cycle was used to determine relative angles and strains at full loading of the spine for all motion directions. Largest relative angles were found in the main loading directions with only small motions at the mid-thoracic levels. Highest strains of the intercostal spaces were detected in the anterior section of the lowest fourth of the rib cage, showing compressions and elongations of more than 10% in all spinal motion planes. Elastostatic rib deformation was generally less than 1%. Rib-sternum relative motions exhibited complex motion patterns, overall showing relative angles below 2°. The results indicate that rib cage structures are not macroscopically deformed during spinal motion, but exhibit characteristic reproducible kinematics patterns.

The effect of follower load on the intersegmental coupled motion characteristics of the human thoracic spine: An in vitro study using entire rib cage specimens.

The mechanical coupling behaviour of the thoracic spine is still not fully understood. For the validation of numerical models of the thoracic spine, however, the coupled motions within the single spinal segments are of importance to achieve high model accuracy. In the present study, eight fresh frozen human thoracic spinal specimens (C7-L1, mean age 54 ±â€¯6 years) including the intact rib cage were loaded with pure bending moments of 5 Nm in flexion/extension (FE), lateral bending (LB), and axial rotation (AR) with and without a follower load of 400 N. During loading, the relative motions of each vertebra were monitored. Follower load decreased the overall ROM (T1-T12) significantly (p < 0.01) in all primary motion directions (extension: -46%, left LB: -72%, right LB: -72%, left AR: -26%, right AR: -26%) except flexion (-36%). Substantial coupled motion was found in lateral bending with ipsilateral axial rotation, which increased after a follower load was applied, leading to a dominant axial rotation during primary lateral bending, while all other coupled motions in the different motion directions were reduced under follower load. On the monosegmental level, the follower load especially reduced the ROM of the upper thoracic spine from T1-T2 to T4-T5 in all motion directions and the ROM of the lower thoracic spine from T9-T10 to T11-T12 in primary lateral bending. The facet joints, intervertebral disc morphologies, and the sagittal curvature presumably affect the thoracic spinal coupled motions depending on axial compressive preloading. Using these results, the validation of numerical models can be performed more accurately.

In vitro validation of a novel mechanical model for testing the anchorage capacity of pedicle screws using physiological load application.

Biomechanical in vitro tests analysing screw loosening often include high standard deviations caused by high variabilities in bone mineral density and pedicle geometry, whereas standardized mechanical models made of PU foam often do not integrate anatomical or physiological boundary conditions. The purpose of this study was to develop a most realistic mechanical model for the standardized and reproducible testing of pedicle screws regarding the resistance against screw loosening and the holding force as well as to validate this model by in vitro experiments. The novel mechanical testing model represents all anatomical structures of a human vertebra and is consisting of PU foam to simulate cancellous bone, as well as a novel pedicle model made of short carbon fibre filled epoxy. Six monoaxial cannulated pedicle screws (Ø6.5 × 45mm) were tested using the mechanical testing model as well as human vertebra specimens by applying complex physiological cyclic loading (shear, tension, and bending; 5Hz testing frequency; sinusoidal pulsating forces) in a dynamic materials testing machine with stepwise increasing load after each 50.000 cycles (100.0N shear force + 20.0N per step, 51.0N tension force + 10.2N per step, 4.2Nm bending moment + 0.8Nm per step) until screw loosening was detected. The pedicle screw head was fixed on a firmly clamped rod while the load was applied in the vertebral body. For the in vitro experiments, six human lumbar vertebrae (L1-3, BMD 75.4 ± 4.0mg/cc HA, pedicle width 9.8 ± 0.6mm) were tested after implanting pedicle screws under X-ray control. Relative motions of pedicle screw, specimen fixture, and rod fixture were detected using an optical motion tracking system. Translational motions of the mechanical testing model experiments in the point of load introduction (0.9-2.2mm at 240N shear force) were reproducible within the variation range of the in vitro experiments (0.6-3.5mm at 240N shear force). Screw loosening occurred continuously in each case between 140N and 280N, while abrupt failures of the specimen were observed only in vitro. In the mechanical testing model, no translational motion was detected in the screw entry point, while in vitro, translational motions of up to 2.5mm in inferior direction were found, leading to a slight shift of the centre of rotation towards the screw tip. Translational motions of the screw tip of about 5mm in superior direction were observed both in vitro and in the mechanical testing model, while they were continuous in the mechanical testing model and rapidly increasing after screw loosening initiation in vitro. The overall pedicle screw loosening characteristics were qualitatively and quantitatively similar between the mechanical testing model and the human vertebral specimens as long as there was no translation of the screw at the screw entrance point. Therefore, the novel mechanical testing model represents a promising method for the standardized testing of pedicle screws regarding screw loosening for cases where the screw rotates around a point close to the screw entry point.

The rib cage stabilizes the human thoracic spine: An in vitro study using stepwise reduction of rib cage structures.

The stabilizing effect of the rib cage on the human thoracic spine is still not sufficiently analyzed. For a better understanding of this effect as well as the calibration and validation of numerical models of the thoracic spine, experimental biomechanics data is required. This study aimed to determine (1) the stabilizing effect of the single rib cage structures on the human thoracic spine as well as the effect of the rib cage on (2) the flexibility of the single motion segments and (3) coupled motion behavior of the thoracic spine. Six human thoracic spine specimens including the entire rib cage were loaded quasi-statically with pure moments of ± 2 Nm in flexion/extension (FE), lateral bending (LB), and axial rotation (AR) using a custom-built spine tester. Motion analysis was performed using an optical motion tracking system during load application to determine range of motion (ROM) and neutral zone (NZ). Specimens were tested (1) in intact condition, (2) after removal of the intercostal muscles, (3) after median sternotomy, after removal of (4) the anterior rib cage up to the rib stumps, (5) the right sixth to eighth rib head, and (6) all rib heads. Significant (p < 0.05) increases of the ROM were found after dissecting the intercostal muscles (LB: + 22.4%, AR: + 22.6%), the anterior part of the rib cage (FE: + 21.1%, LB: + 10.9%, AR: + 72.5%), and all rib heads (AR: + 5.8%) relative to its previous condition. Compared to the intact condition, ROM and NZ increased significantly after removing the anterior part of the rib cage (FE: + 52.2%, + 45.6%; LB: + 42.0%, + 54.0%; AR: + 94.4%, + 187.8%). Median sternotomy (FE: + 11.9%, AR: + 21.9%) and partial costovertebral release (AR: + 11.7%) significantly increased the ROM relative to its previous condition. Removing the entire rib cage increased both monosegmental and coupled motion ROM, but did not alter the qualitative motion behavior. The rib cage has a strong effect on thoracic spine rigidity, especially in axial rotation by a factor of more than two, and should therefore be considered in clinical scenarios, in vitro, and in silico.

Biomechanical in vitro comparison of radiofrequency kyphoplasty and balloon kyphoplasty.

PURPOSE: Balloon kyphoplasty (BK) has emerged as a popular method for treating osteoporosis vertebral compression fractures (OVCFs). In response to several shortcomings of BK, alternative methods have been introduced, among which is radiofrequency kyphoplasty (RFK). Biomechanical comparisons of BK and RFK are very sparse. The purpose of this study was to perform a biomechanical study in which BK and RFK are compared. METHODS: Each of the two study groups comprised six specimens prepared from two functional spinal units (FSUs) cut from fresh-frozen cadaveric spines (3 of T9-T11 and 3 of T12-L2). VCFs (A1.2 type) were created in the middle VB of each of the FSUs, with a height loss of 30% of the VB. After that, the specimens were subjected to cyclic compression-compression loading. The following parameters were determined: range of motion (ROM), height of the middle VB, augmentation time, cement interdigitation and cement distribution. Also, the cement layer, the trabecular bone in the augmented VB and the bone-cement interface were examined for cracks. All of these parameters were determined at various stages, namely in the intact middle VB and after its fracture, cement augmentation and subject to the cyclic loading protocol. RESULTS: Fractures caused a significant increase in median ROM and a significant reduction in the height of fractured VB. Cement augmentation significantly stabilized the fractures and led to partial height restoration. ROM and vertebral height, however, were not restored to the intact levels. Cyclic loading led to a further significant increase in ROM and a significant height reduction. There were no significant differences between BK and RFK in terms of any of these parameters. CONCLUSIONS: BK and RFK achieved similar results for fracture stabilization and restoration of the height of the fractured VB. RFK involved shorter cement augmentation time and less damage to the trabecular bone.

EUROSPINE 2016 FULL PAPER AWARD: Wire cerclage can restore the stability of the thoracic spine after median sternotomy: an in vitro study with entire rib cage specimens.

PURPOSE: The influence of the anterior rib cage on the stability of the human thoracic spine is not completely known. One of the most common surgical interventions on the anterior rib cage is the longitudinal median sternotomy and its fixation by wire cerclage. Therefore, the purpose of this in vitro study was to examine, if wire cerclage can restore the stability of the human thoracic spine after longitudinal median sternotomy. METHODS: Six fresh frozen human thoracic spine specimens (C7-L1, 56 years in average, range 50-65), including the intact rib cage without intercostal muscles, were tested in a spinal loading simulator and monitored with an optical motion tracking system. While applying 2 Nm pure moment in flexion/extension (FE), lateral bending (LB), and axial rotation (AR), the range of motion (ROM) and neutral zone (NZ) of the functional spinal units of the thoracic spine (T1-T12) were studied (1) in intact condition, (2) after longitudinal median sternotomy, and (3) after sternal closure using wire cerclage. RESULTS: The longitudinal median sternotomy caused a significant increase of the thoracic spine ROM relative to the intact condition (FE: 12° ± 5°, LB: 18° ± 5°, AR: 25° ± 10°) in FE (+12 %) and AR (+22 %). As a result, the sagittal cut faces of the sternum slipped apart visibly. Wire cerclage fixation resulted in a significant decrease of the ROM in AR (-12 %) relative to condition after sternotomy. ROM increased relative to the intact condition, in AR even significantly (+8 %). The NZ showed a proportional behavior compared to the ROM in all loading planes, but it was distinctly higher in FE (72 %) and in LB (82 %) compared to the ROM than in AR (12 %). CONCLUSIONS: In this in vitro study, the longitudinal median sternotomy resulted in a destabilization of the thoracic spine and relative motion of the sternal cut faces, which could be rectified by fixation with wire cerclage. However, the stability of the intact condition could not be reached. Nevertheless, a fixation of the sternum should be considered clinically to avoid instability of the spine and sternal pseudarthrosis.

Does impaction of titanium-coated interbody fusion cages into the disc space cause wear debris or delamination?

BACKGROUND CONTEXT: A large number of interbody fusion cages are made of polyetheretherketone (PEEK). To improve bone on-growth, some are coated with a thin layer of titanium. This coating may fail when subjected to shear loading. PURPOSE: The purpose of this testing was to investigate whether impaction of titanium-coated PEEK cages into the disc space can result in wear or delamination of the coating, and whether titanium cages with subtractive surface etching (no coating) are less susceptible to such failure. STUDY DESIGN/SETTING: A biomechanical study was carried out to simulate the impaction process in clinical practice and to evaluate if wear or delamination may result from impaction. MATERIALS AND METHODS: Two groups of posterior lumbar interbody fusion cages with a similar geometry were tested: n=6 titanium-coated PEEK and n=6 surface-etched titanium cages. The cages were impacted into the space in between two vertebral body substitutes (polyurethane foam blocks). The two vertebral body substitutes were fixed in a device, through which a standardized axial preload of 390 N was applied. The anterior tip of the cage was positioned at the posterior border of the space between the two vertebral body substitutes. The cages were then inserted using a drop weight with a mass representative of a surgical hammer. The drop weight impacted the insertion instrument at a maximum speed of about 2.6 m/s, which is in the range of the impaction speed in vivo. This was repeated until the cages were fully inserted. The wear particles were captured and analyzed according to the pertinent standards. RESULTS: The surface-etched titanium cages did not show any signs of wear debris or surface damage. In contrast, the titanium-coated PEEK cages resulted in detached wear particles of different sizes (1-191 µm). Over 50% of these particles had a size <10 µm. In median, on 26% of the implants' teeth, the coating was abraded. Full delamination was not observed. CONCLUSIONS: In contrast to the surface-etched implants, the titanium-coated PEEK implants lost some coating material. This was visible to the naked eye. More than half of all particles were of a size range that allows phagocytosis. This study shows that titanium-coated implants are susceptible to impaction-related wear debris.

A new approach to prevent contralateral hip fracture: Evaluation of the effectiveness of a fracture preventing implant.

BACKGROUND: Among the millions of people suffering from a hip fracture each year, 20% may sustain a contralateral hip fracture within 5 years with an associated mortality risk increase reaching 64% in the 5 following years. In this context, we performed a biomechanical study to assess the performance of a hip fracture preventing implant. METHODS: The implant consists of two interlocking peek rods unified with surgical cement. Numerical and biomechanical tests were performed to simulate single stance load or lateral fall. Seven pairs of femurs were selected from elderly subjects suffering from osteoporosis or osteopenia, and tested ex-vivo after implantation of the device on one side. FINDINGS: The best position for the implant was identified by numerical simulations. The loadings until failure showed that the insertion of the implant increased significantly (P<0.05) both fracture load (+18%) and energy to fracture (+32%) of the implanted femurs in comparison with the intraindividual controls. The instrumented femur resisted the implementation of the non-instrumented femur fracture load for 30 cycles and kept its performance at the end of the cyclic loading. INTERPRETATION: Implantation of the fracture preventing device improved both fracture load and energy to fracture when compared with intraindividual controls. This is consistent with previous biomechanical side-impact testing on pairs of femur using the same methodology. Implant insertion seems to be relevant to support multiple falls and thus, to prevent a second hip fracture in elderly patients.

Development of a scoliotic spine model for biomechanical in vitro studies.

BACKGROUND: In vitro experiments are important to compare surgical treatments. Especially new implants need preclinical evaluation. However, in vitro experiments with scoliotic specimens are impossible because they are not available. The purpose of this study was to develop an in vitro scoliosis model with cadaveric calf spine specimens, which may serve as a surrogate for human scoliotic spines. METHODS: Six cadaveric calf spine specimens (T8-L6) were modified in three different steps to create a thoracolumbar scoliosis, convex to the right. First, all intervertebral discs received a nucleotomy. In the second step the cavity was filled with silicone. The silicone hardened in a bend position to obtain an asymmetrical nucleus. Finally, a wedge profile of the vertebral bodies was achieved by unilateral horizontal cuts (T9-L5), followed by spreading and fixation. Flexibility tests in a spine tester were performed in all motion planes with the original spine and after the different steps during the creation of the model. FINDINGS: A Cobb angle >40° in the frontal plane could be achieved. Additionally, the vertebrae showed an axial rotation to the convex side. The range of motion increased due to the nucleotomy, decreased slightly after replacement with silicone, and decreased below the values of the intact spine after producing the wedge shape of the vertebrae. In each loading direction there was no significant asymmetry in the motion behavior. INTERPRETATION: This study suggests a method to modify a straight spine specimen into a scoliotic one, which can be used for biomechanical in vitro experiments.

Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma.

BACKGROUND: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[(18)F] fluorothymidine (FLT). METHODS: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. RESULTS: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue. CONCLUSION: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.

Preliminary investigations on intradiscal pressures during daily activities: an in vivo study using the merino sheep.

PURPOSE: Currently, no studies exist, which attest the suitability of the ovine intervertebral disc as a biomechanical in vivo model for preclinical tests of new therapeutic strategies of the human disc. By measuring the intradiscal pressure in vivo, the current study attempts to characterize an essential biomechanical parameter to provide a more comprehensive physiological understanding of the ovine intervertebral disc. METHODS: Intradiscal pressure (IDP) was measured for 24 hours within the discs L2-L3 and L4-L5 via a piezo-resistive pressure sensor in one merino sheep. The data were divided into an activity and a recovery phase and the corresponding average pressures for both phases were determined. Additionally, IDPs for different static and dynamic activities were analyzed and juxtaposed to human data published previously. After sacrificing the sheep, the forces corresponding to the measured IDPs were examined ex vivo in an axial compression test. RESULTS: The temporal patterns of IDP where pressure decreased during activity and increased during rest were comparable between humans and sheep. However, large differences were observed for different dynamic activities such as standing up or walking. Here, IDPs averaged 3.73 MPa and 1.60 MPa respectively, approximately two to four times higher in the ovine disc compared to human. These IDPs correspond to lower ex vivo derived axial compressive forces for the ovine disc in comparison to the human disc. For activity and rest, average ovine forces were 130 N and 58 N, compared to human forces of 400-600 N and 100 N, respectively. CONCLUSIONS: In vivo IDPs were found to be higher in the ovine than in the human disc. In contrast, axial forces derived ex vivo were markedly lower in comparison to humans. Both should be considered in future preclinical tests of intradiscal therapies using the sheep. The techniques used in the current study may serve as a protocol for measuring IDP in a variety of large animal models.

Can prevention of a reherniation be investigated? Establishment of a herniation model and experiments with an anular closure device.

STUDY DESIGN: Biomechanical in vitro study. OBJECTIVE: To establish a reliable in vitro herniation model with human cadaver spines that enables evaluation of anular closure devices. SUMMARY OF BACKGROUND DATA: Biomechanically, it is desirable to close anulus defects after disc herniation to preserve as much nucleus as possible. Multiple anular closure options exist to prevent reherniation. A reliable test procedure is needed to evaluate the efficacy and reliability of these implants. METHODS: Two groups of human lumbar segments (n = 6 per group) were tested under cyclic loading until herniation occurred or 100,000 load cycles were applied. One group contained moderate/severe degenerated discs. A second group had mild degenerated discs. Intradiscal pressure was measured in the intact state to confirm disc quality.If herniation occurred, the extruded material was reinserted into the disc and the anulus defect was treated with the Barricaid anular closure device (Intrinsic Therapeutics, Inc., Woburn, MA). Disc height and 3-dimensional flexibility of the specimens in the intact, defect, and implanted states were measured under pure moments in each principal motion plane. Afterwards, provocation of reherniation was attempted with additional 100,000 load cycles. RESULTS: Likelihood of herniation was strongly linked to disc degeneration and supported by the magnitude of intradiscal pressure. In moderate/severe degenerated discs, only 1 herniation was created. In mild degenerated discs, herniations were reliably created in all specimens. Using this worst-case model, herniation caused a significant reduction of disc height, which was nearly restored with the implant. In no case was reherniation or implant migration visible after 100,000 load cycles after Barricaid implantation. CONCLUSION: We established a human herniation model that reliably produced nucleus extrusion during cyclic loading by selecting specimens with low disc degeneration. The Barricaid seems to prevent nucleus from reherniating. The reliability of this method suggests the opportunity to investigate other anulus closure devices and nucleus replacement techniques critically.

[18F]FLT is superior to [18F]FDG for predicting early response to antiproliferative treatment in high-grade lymphoma in a dose-dependent manner.

PURPOSE: Positron emission tomography (PET) with the thymidine analogue [(18)F]fluorothymidine ([(18)F]FLT) has been shown to detect early response to chemotherapy in high-grade lymphoma. In this preclinical in vitro and in vivo study we compared [(18)F]FLT to the glucose analogue [(18)F]fluorodeoxyglucose ([(18)F]FDG) regarding dose-dependent visualization and prediction of early therapy response. METHODS: Immunodeficient mice bearing human diffuse large B-cell lymphoma (SUDHL-4) xenotransplants were treated intraperitoneally with increasing doses of the cytotoxic agent doxorubicin. Metabolic and antiproliferative effects were assessed 2 days after therapy by [(18)F]FLT and [(18)F]FDG PET. Explanted lymphomas were analysed histologically and by immunostaining against Ki67 and caspase 3. In vitro, lymphoma cells were incubated with increasing concentrations of doxorubicin and analysed using the tetrazolium assay, fluorescence-activated cell sorting, and [(18)F]FLT and [(18)F]FDG uptake 48 h later. RESULTS: In vivo, tumour growth was inhibited by doses of doxorubicin ranging from 25 µg to 200 µg. The mean tumour-to-background ratio (TBR) of [(18)F]FLT on day +2 was significantly reduced in all dose groups compared to control and baseline values and preceded changes in tumour volume. Importantly, there was a significant inverse correlation between reduction in TBR and dose of chemotherapy (r = -0.54, p = 0.021). The mean TBR of [(18)F]FDG, however, increased after therapy and differed considerably between groups (r = -0.13, p = 0.668). Explanted tumours showed a dose-dependent decrease in the proliferation marker Ki67, but no change in the apoptotic marker caspase 3. In vitro, doxorubicin led to a dose-dependent reduction in cell viability and a decrease in S phase. Lymphoma cells showed a dose-dependent reduction in [(18)F]FLT uptake, in contrast to a variable and decelerated reduction in [(18)F]FDG uptake. Thus, the increase in [(18)F]FDG uptake in vivo presumably reflected nonspecific glucose metabolism of inflammatory cells, as confirmed by histology of explanted lymphomas. CONCLUSION: Early responses to dose-dependent antiproliferative treatment in high-grade lymphoma are more accurately visualized with [(18)F]FLT PET than with [(18)F]FDG PET.

FLT-PET is superior to FDG-PET for very early response prediction in NPM-ALK-positive lymphoma treated with targeted therapy.

The prognosis of relapsed or refractory aggressive lymphoma is poor. The huge variety of currently evolving targeted treatment approaches would benefit from tools for early prediction of response or resistance. We used various ALK-positive anaplastic large cell lymphoma (ALCL) cell lines to evaluate two inhibitors, the HSP90 inhibitor NVP-AUY922, and the mTOR inhibitor everolimus, both of which have shown to interfere with ALK-dependent oncogenic signal transduction. Their therapeutic effect was determined in vitro by MTT assay, [(18)F]fluorodeoxyglucose (FDG)- and [(18)F]fluorothymidine (FLT)-uptake, and by biochemical analysis of ALK-induced signaling. Micro-FDG- and FLT-positron emission tomography (PET) imaging studies in immunodeficient mice bearing ALCL xenotransplants were carried out with the cell lines SUDHL-1 and Karpas299 to assess early treatment response to NVP-AUY922 or everolimus in vivo. SUDHL-1 cells showed sensitivity to both inhibitors in vitro. Importantly, we detected a significant reduction of FLT-uptake in SUDHL-1 bearing animals using both inhibitors compared with baseline as early as 5 days after initiation of targeted therapy. Immunostaining showed a decrease in Ki-67 and an increase in cleaved caspase-3 staining. In contrast, FDG-uptake did not significantly decrease at early time points. Karpas299 xenotransplants, which are resistant to NVP-AUY922 and sensitive to everolimus treatment, showed an increase of mean FLT-uptake on day 2 after administration of NVP-AUY299, but a significant reduction in FLT-uptake upon everolimus treatment. In conclusion, we show that FLT-PET but not FDG-PET is able to predict response to treatment with specific inhibitors very early in the course of treatment and thus enables early prediction of treatment efficacy.

Posterior motion preserving implants evaluated by means of intervertebral disc bulging and annular fiber strains.

BACKGROUND: The aims of motion preserving implants are to ensure sufficient stability to the spine, to release facet joints by also allowing a physiological loading to the intervertebral disc. The aim of this study was to assess disc load contribution by means of annular fiber strains and disc bulging of intact and stiffened segments. This was compared to the segments treated with various motion preserving implants. METHODS: A laser scanning device was used to obtain three-dimensional disc bulging and annular fiber strains of six lumbar intervertebral discs (L2-3). Specimens were loaded with 500N or 7.5Nm moments in a spine tester. Each specimen was treated with four different implants; DSS™, internal fixator, Coflex™, and TOPS™. FINDINGS: In axial compression, all implants performed in a similar way. In flexion, the Coflex decreased range of motion by 13%, whereas bulging and fiber strains were similar to intact. The DSS stabilized segments by 54% compared to intact. TOPS showed a slight decrease in fiber strains (5%) with a range of motion similar to intact. The rigid fixator allowed strains up to 2%. In lateral bending, TOPS yielded range of motion values similar to intact, but maximum fiber strains doubled from 6.5% (intact) to 13.8%. Coflex showed range of motion, bulging and strain values similar to intact. The DSS and the rigid fixator reduced these values. The implants produced only minor changes in axial rotation. INTERPRETATION: This study introduces an in vitro method, which was employed to evaluate spinal implants other than standard biomechanical methods. We could demonstrate that dynamic stabilization methods are able to keep fiber strains and disc bulging in a physiological range.

A pilot study to evaluate 3'-deoxy-3'-18F-fluorothymidine pet for initial and early response imaging in mantle cell lymphoma.

UNLABELLED: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma. Proliferation activity is considered an important prognostic marker. Immunohistochemical analysis from core biopsy or lymph node may not represent the proliferation rate. We investigated the in vivo proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) to characterize MCL. METHODS: Eight untreated MCL patients were recruited prospectively. (18)F-FLT PET/CT was performed 45 min after injection of (18)F-FLT. (18)F-FDG PET/CT served as reference. Mean (18)F-FLT standardized uptake values were assessed per lesion and compared with respective (18)F-FDG uptake. Correlation of mean (18)F-FLT and (18)F-FDG uptake in the hottest lesion to Ki67 immunostaining was performed. Five patients underwent repetitive early (18)F-FLT PET. RESULTS: All lymphoma lesions identified by (18)F-FDG PET/CT showed increased (18)F-FLT uptake. Semiquantitative analysis revealed a high mean (18)F-FLT standardized uptake value of 9.9 (range, 5.5-15.9). Mean (18)F-FLT uptake and Ki67 expressions showed a strong positive correlation. CONCLUSION: PET using (18)F-FLT as a biomarker for proliferative activity showed a high sensitivity for MCL. (18)F-FLT uptake shows a correlation with proliferation. Our results warrant further analysis of (18)F-FLT PET in MCL.

Predictive value of initial 18F-FLT uptake in patients with aggressive non-Hodgkin lymphoma receiving R-CHOP treatment.

UNLABELLED: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy is the standard therapy in aggressive B-cell lymphoma. (18)F-FDG PET has high prognostic implications at treatment completion but is limited as an early predictor. Here, we present the results of a prospective study correlating the initial uptake of the in vivo proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) with the clinical outcome of patients with aggressive non-Hodgkin lymphoma treated with R-CHOP. METHODS: Sixty-six eligible patients were evaluated prospectively with (18)F-FLT PET before R-CHOP. PET was performed 45 min after injection of 300-370 MBq of (18)F-FLT. Mean and maximum standardized uptake values (SUVs) were calculated on a lesion-by-lesion basis. Response was assessed at the end of therapy. International Prognostic Index (IPI) scores and clinical parameters (Ann Arbor stage, lactate dehydrogenase, performance status, extranodal disease) were determined in all patients. Response was assessed according to revised response criteria after the end of therapy. After treatment, patients were followed in intervals from 4 wk to 6 mo (mean follow-up, 23.1 mo [range, 1-63 mo]), and progression-free and overall survival were determined. RESULTS: All lymphoma lesions identified by a reference method ((18)F-FDG PET/CT or multislice CT of the trunk) showed increased focal tracer uptake (mean (18)F-FLT SUV, 7.3 ± 2.5). Response assessment revealed progressive disease in 4, partial response in 3, and complete response (CR) in the remaining 55 patients. The IPI score was predictive for achieving CR (P = 0.034). Importantly, initial mean SUV was also significantly higher in patients who showed progressive disease and partial response than in patients who achieved CR (P = 0.049). In addition, we found a significant correlation between IPI score and initial (18)F-FLT uptake. CONCLUSION: Taken together, high (18)F-FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell non-Hodgkin lymphoma and correlates with the IPI score. Thus, (18)F-FLT PET may represent a useful tool for implementing risk-adapted treatment in these patients.

Imaging proliferation to monitor early response of lymphoma to cytotoxic treatment.

PURPOSE: Positron emission tomography with the thymidine analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been reported to closely reflect lymphoma proliferation in vivo. In this preclinical study, we have investigated if FLT can also be utilized for imaging therapy-induced alterations of the nucleoside metabolism and if FLT is a surrogate marker for early response to cytotoxic treatment. MATERIALS AND METHODS: Immunodeficient mice bearing high-grade lymphoma xenotransplants were treated with the cytotoxic agent doxorubicin (day 0). In the time course of day +1 to +9, antiproliferative effects were assessed non-invasively with FLT-PET and correlated to changes of the proliferation fraction and induction of apoptosis, as assessed by immunohistochemistry. RESULTS: Tumor growth in untreated animals was significantly higher than in treated animals. In FLT-PET scans, these observations correlated with a significant decrease of tumor-to-background ratio in the therapy group already at day 1. Likewise, median tumor-to-muscle ratio of FLT uptake already declined at day 1. The proliferation fraction assessed by Ki-67 immunohistochemistry decreased after chemotherapy, while activated caspase 3 increased, suggesting both cell cycle arrest and induction of apoptosis as underlying mechanisms of the observed PET-signal alterations. CONCLUSION: In a lymphoma xenotransplant model, we show that positron emission tomography using the proliferation marker FLT is suitable to detect early response to cytotoxic treatment. A significant decrease of FLT uptake but not tumor growth was detectable already 24 h after therapy and correlated with reduced proliferation and induction of apoptosis. Thus, FLT-PET has a potential for imaging early response to treatment in malignant lymphoma.