Unravelling differential Hes1 dynamics during axis elongation of mouse embryos through single-cell tracking.

The intricate dynamics of Hes expression across diverse cell types in the developing vertebrate embryonic tail have remained elusive. To address this, we have developed an endogenously tagged Hes1-Achilles mouse line, enabling precise quantification of dynamics at the single-cell resolution across various tissues. Our findings reveal striking disparities in Hes1 dynamics between presomitic mesoderm (PSM) and preneural tube (pre-NT) cells. While pre-NT cells display variable, low-amplitude oscillations, PSM cells exhibit synchronized, high-amplitude oscillations. Upon the induction of differentiation, the oscillation amplitude increases in pre-NT cells. Additionally, our study of Notch inhibition on Hes1 oscillations unveils distinct responses in PSM and pre-NT cells, corresponding to differential Notch ligand expression dynamics. These findings suggest the involvement of separate mechanisms driving Hes1 oscillations. Thus, Hes1 demonstrates dynamic behaviour across adjacent tissues of the embryonic tail, yet the varying oscillation parameters imply differences in the information that can be transmitted by these dynamics.

Ex vivo intervertebral disc cultures: degeneration-induction methods and their implications for clinical translation.

Because low back pain is frequently a result of intervertebral disc degeneration (IVDD), strategies to regenerate or repair the IVD are currently being investigated. Often, ex vivo disc cultures of non-human IVD organs or tissue explants are used that usually do not exhibit natural IVDD. Therefore, degenerative changes mimicking those reported in human IVDD need to be induced. To support researchers in selecting ex vivo disc cultures, a systematic search was performed for them and their potential use for studying human IVDD reviewed. Five degeneration induction categories (proinflammatory cytokines, injury/damage, degenerative loading, enzyme, and other) were identified in 129 studies across 7 species. Methods to induce degeneration are diverse and can induce mild to severe degenerative changes that progress over time, as described for human IVDD. The induced degenerative changes are model-specific and there is no "one-fits-all" IVDD induction method. Nevertheless, specific aspects of human IVDD can be well mimicked. Currently, spontaneously degenerated disc cultures from large animals capture human IVDD in most aspects. Combinatorial approaches of several induction methods using discs derived from large animals are promising to recapitulate pathological changes on several levels, such as cellular behaviour, extracellular matrix composition, and biomechanical function, and therefore better mimic human IVDD. Future disc culture setups might increase in complexity, and mimic human IVDD even better. As ex vivo disc cultures have the potential to reduce and even replace animal trials, especially during preclinical development, advancement of such models is highly relevant for more efficient and cost-effective clinical translation from bench-to-bedside.

How annulus defects can act as initiation sites for herniation.

PURPOSE: Both posture and loading rate are key factors in the herniation process and can determine the mechanism of disc failure. The aim of this study was to test the hypothesis that disruption visible with HR-MRI post-testing corresponds with microstructural features and further elucidate the mechanism by which this disruption weakens the disc. This will enable us to gain new insights into the herniation process. METHODS: Thirty ovine lumbar spinal segments were subjected to combinations of four loading conditions (0-12° flexion, 0-9° lateral bending, 0-4° axial rotation, 0-1500 N axial compression) for 1000 loading cycles at 2 Hz in a dynamic disc loading simulator. The discs were scanned in an ultra-high field MRI (11.7 T) then examined using brightfield microscopy to examine their microstructure. RESULTS: Four discs herniated and seven discs suffered nucleus displacement. These discs contained pre-existing defects in the central posterior annulus. Generally, following testing discs contained more posterior annulus disruption, Microstructural investigation revealed there was clear correspondence between HR-MRI and microstructural observations, and that the mid-outer annular-endplate junction had failed in all discs examined in this study. CONCLUSIONS: While all discs suffered outer annulus damage, only the discs containing pre-existing defects herniated. These pre-existing defects weakened the inner and mid annulus, allowing herniation to occur once the mid and outer annular wall was compromised. We propose this can occur during the degenerative cascade.

Does the neutral zone quantification method matter? Efficacy of evaluating neutral zone during destabilization and restabilization in human spine implant testing.

Neutral zone (NZ) is an important biomechanical parameter when evaluating spinal instability following destabilizing and restabilizing events, with particular relevance for implant efficacy testing. It remains unclear what NZ calculation methods are most sensitive at capturing NZ changes across treatment conditions and a direct comparison is needed. The purpose of this study was to determine the most sensitive method at quantifying instability in human spines. Six cadaveric lumbar motion segments were subjected to a repeated measures implant testing schema of four sequential conditions: (1) Intact, (2) injury by herniation, (3) device implantation, (4) long-term cyclic fatigue loading. NZ was expected to increase after destabilization (steps 2 & 4) and decrease after restabilization (step 3). NZ methods compared in this study were: trilinear (TL), double sigmoid (DS), zero load (ZL), stiffness threshold (ST), and extrapolated elastic zone (EEZ). TL, ZL, and EEZ identified statistically significant NZ differences after each condition in flexion/extension and lateral bending. The ZL method also captured differences in axial rotation. All methods identified expected NZ changes after destabilization and restabilization, except DS in axial rotation. The TL, ZL, and EEZ methods were the most sensitive methods with this human cadaveric dataset. Future investigations comparing methods with additional datasets will clarify outcome generalizability and determine what curve profiles are most suitable for DS and ST methods. Understanding the applicability of NZ methods can enhance rigor and reliability of spinal instability measurements when quantifying the efficacy of novel implants and permits insight into clinically relevant biomechanical changes.

Mesenchymal stem cell secretome decreases the inflammatory response in annulus fibrosus organ cultures.

Mesenchymal stem/stromal cell (MSC)-based therapies have been proposed for back pain and disc degeneration, despite limited knowledge on their mechanism of action. The impact of MSCs/their secretome on annulus fibrosus (AF) cells and tissue was analysed in bovine AF organ cultures (AF-OCs) exposed to upper-physiological cyclic tensile strain (CTS, 9 %, 1 Hz, 3 h/d) and interleukin (IL)-1ß in a custom-made device. A 4 d treatment of the CTS + IL-1ß-stimulated AF-OCs with MSC secretome downregulated the expression of inflammation markers [IL-6, IL-8, prostaglandin-endoperoxide synthase 2 (PTGS2)], complement system regulators [cluster of differentiation (CD)46, CD55, CD59] and matrix metalloproteinase 1 but also of tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) and collagen type I. At the protein level, it was confirmed that IL-6, MMP-3 and collagen content was decreased in AF-OCs treated with the MSC secretome compared to the CTS + IL-1ß stimulation alone. 9 d after treatment, a biomechanical peel-force test showed that the annular adhesive strength was significantly decreased by the MSC secretome treatment. Overall, MSC secretome had a stronger impact on AF tissue than MSCs in co-culture. The secretome contributed to a decrease in the inflammatory and catabolic status of AF cells activated by CTS + IL-1ß and played a role in the regulation of the complement system. However, it also contributed to a decrease in collagen at the gene/protein level and in AF mechanical strength compared to the CTS + IL-1ß stimulation alone. Therefore, the use of MSC secretome requires further investigation regarding its influence on disc matrix properties.

A Microfluidics Approach for the Functional Investigation of Signaling Oscillations Governing Somitogenesis.

Periodic segmentation of the presomitic mesoderm of a developing mouse embryo is controlled by a network of signaling pathways. Signaling oscillations and gradients are thought to control the timing and spacing of segment formation, respectively. While the involved signaling pathways have been studied extensively over the last decades, direct evidence for the function of signaling oscillations in controlling somitogenesis has been lacking. To enable the functional investigation of signaling dynamics, microfluidics is a previously established tool for the subtle modulation of these dynamics. With this microfluidics-based entrainment approach endogenous signaling oscillations are synchronized by pulses of pathway modulators. This enables modulation of, for instance, the oscillation period or the phase-relationship between two oscillating pathways. Furthermore, spatial gradients of pathway modulators can be established along the tissue to study how specific changes in the signaling gradients affect somitogenesis. The present protocol is meant to help establish microfluidic approaches for the first-time users of microfluidics. The basic principles and equipment needed to set up a microfluidic system are described, and a chip design is provided, with which a mold for chip generation can conveniently be prepared using a 3D printer. Finally, how to culture primary mouse tissue on a microfluidic chip and how to entrain signaling oscillations to external pulses of pathway modulators are discussed. This microfluidic system can also be adapted to harbor other in vivo and in vitro model systems such as gastruloids and organoids for functional investigation of signaling dynamics and morphogen gradients in other contexts.

The effect of multiplanar loading on the intradiscal pressure of the whole human spine: systematic review and meta-analysis.

For spinal load and muscle force estimation as well as for numerical model and experimental setup validation, data on human intradiscal pressure are essential. Therefore, the aim of the present meta-analysis was to summarise all in vitro measurements of human intradiscal pressure performed under defined boundary conditions, i.e. without external loading (intrinsic pressure), under axial loading (compression, traction, shear) and under single-planar bending loading (flexion, extension, lateral bending, axial rotation). Data were evaluated based on segmental level and normalised to force and moment. Regression analysis was performed to investigate coefficients of determination and statistical significance of relationships between intradiscal pressure and segmental level for the single loading conditions. 35 studies fulfilled the inclusion criteria, from which a total of 451 data points were collected for the meta-analysis. High coefficients of determination were found in axial compression (r2 = 0.875) and flexion (r2 = 0.781), while being low for intrinsic pressure (r2 = 0.266) and lateral bending (r2 = 0.385), all showing significant regression fitting (p < 0.01). Intradiscal pressure decreases from the upper cervical spine to the sacrum in all loading conditions, considering the same amount of loading for all segmental levels, while the intrinsic pressure exhibits a minimum of the regression curve in the mid-thoracic spine. Apart from its potential for numerical and experimental model validation, this dataset may help to understand the load distribution along the human spine.

Disc wall structural abnormalities can act as initiation sites for herniation.

Both posture and loading rate are key factors in the herniation process and can determine the failure mechanism of the disc. The influence of disc structure on the herniation process has yet to be directly observed, thus the aim of this study was to test the hypothesis that discs containing greater levels of pre-existing disruption would be more vulnerable to herniation when subjected to severe levels of posture and loading. 30 ovine lumbar motion segments were subjected to combinations of 4 loading conditions (0 - 12° flexion,0 - 9° lateral bending, 0 - 4° axial rotation, 0-1500 N axial compression) for 1000 loading cycles at 2 Hz in a dynamic disc loading simulator. The discs were scanned in an ultra-high field MRI (magnetic resonance imaging, 11.7 T) prior to and following testing. 4 discs herniated and 7 discs suffered nucleus displacement. These discs contained pre-existing defects in the central dorsal annulus. Generally, following testing, discs contained more dorsal annulus disruption, including 7 discs which developed similar characteristic defects although these did not herniate. Overall, more severe complex postures produced more disruption. While more severe postures such as twisting and bending increased disc damage, these results are probably the first directly showing that naturally occurring defects in the disc can act as initiation sites for herniation. The clinical significance of these findings is that, in principle at least, MRI based techniques could be capable of identifying vulnerable discs, with the obvious caveat that further correlation with clinical techniques is required.

Analysis of microscopic bone properties in an osteoporotic sheep model: a combined biomechanics, FE and ToF-SIMS study.

The present study deals with the characterization of bone quality in a sheep model of postmenopausal osteoporosis. Sheep were sham operated ( n = 7), ovariectomized ( n = 6), ovariectomized and treated with deficient diet ( n = 8) or ovariectomized, treated with deficient diet and glucocorticoid injections ( n = 7). The focus of the study is on the microscopic properties at tissue level. Microscopic mechanical properties of osteoporotic bone were evaluated by a combination of biomechanical testing and mathematical modelling. Sample stiffness and strength were determined by compression tests and finite-element analysis of stress states was conducted. From this, an averaged microscopic Young's modulus at tissue level was determined. Trabecular structure as well as mineral and collagen distribution in samples of sheep vertebrae were analysed by micro-computed tomography and time-of-flight secondary ion mass spectrometry. In the osteoporotic sheep model, a disturbed fibril structure in the triple treated group was observed, but bone loss only occurred in form of reduced trabecular number and thickness and cortical decline, while quality of the residual bone was preserved. The preserved bone tissue properties in the osteoporotic sheep model allowed for an estimation of bone strength which behaves similar to the human case.

Moderately degenerated lumbar motion segments: Are they truly unstable?

The two main load bearing tissues of the intervertebral disc are the nucleus pulposus and the annulus fibrosus. Both tissues are composed of the same basic components, but differ in their organization and relative amounts. With degeneration, the clear distinction between the two tissues disappears. The changes in biochemical content lead to changes in mechanical behaviour of the intervertebral disc. The aim of the current study was to investigate if well-documented moderate degeneration at the biochemical and fibre structure level leads to instability of the lumbar spine. By taking into account biochemical and ultrastructural changes to the extracellular matrix of degenerating discs, a set of constitutive material parameters were determined that described the individual tissue behaviour. These tissue biomechanical models were then used to simulate dynamic behaviour of the degenerated spinal motion segment, which showed instability in axial rotation, while a stabilizing effect in the other two principle bending directions. When a shear load was applied to the degenerated spinal motion segment, no sign of instability was found. This study found that reported changes to the nucleus pulposus and annulus fibrosus matrix during moderate degeneration lead to a more stable spinal motion segment and that such biomechanical considerations should be incorporated into the general pathophysiological understanding of disc degeneration and how its progress could affect low back pain and its treatments thereof.

Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine-platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m(2)) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. RESULTS: Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, P = 0.0508), deterioration by ≥1 PS level (HR = 0.802, P = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. CONCLUSION: In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. CLINICALTRIALSGOV: NCT01170663.

Cyclic tensile stress of human annulus fibrosus cells induces MAPK activation: involvement in proinflammatory gene expression.

OBJECTIVE: To study the role of mitogen-activated protein kinases (MAPKs) in human annulus fibrosus (AF) cells subjected to cyclic tensile stress (CTS). DESIGN: An in vitro system for CTS studies was established using AF cultures on fibronectin-coated silicone dishes. MAPK phosphorylation was studied by western analysis, while gene expression was followed by qRT-PCR. DNA synthesis was assessed by both tritiated thymidine incorporation and flow cytometry, and collagen synthesis using tritiated proline incorporation and the protease-free collagenase method. RESULTS: All three MAPKs studied, i.e., ERK, SAPK/JNK, and p38 were found to be phosphorylated immediately after CTS application within physiological range. A second wave of phosphorylation appeared at later time points. MAPK activation was elevated at higher CTS magnitudes, but independent of the frequency. CTS did not stimulate DNA synthesis neither extracellular matrix turnover, but it stimulated the proinflammatory genes, COX-2, IL-6, and IL-8. This stimulation was more intense at the highest magnitude (8%) tested and at the median frequency (1 Hz) and time interval (12 h). Blocking of ERK, SAPK/JNK, and p38 MAPK inhibited the CTS-induced stimulation of COX-2 and IL-8, while IL-6 expression was mediated only by SAPK/JNK and p38 MAPK. CONCLUSIONS: We have described for the first time the activation of MAPKs in human AF cells in response to CTS and showed that it drives an inflammatory reaction. These observations shed light on the mechanisms of intervertebral disc (IVD) cell responses to mechanical stress, contributing to the understanding of disc pathophysiology and possibly to the design of novel therapeutic interventions.

[History of the German Spine Society]. / Geschichte der Deutschen Wirbelsäulengesellschaft.

The objective of this article is to summarize the history of the German Spine Society (DWG). This society resulted in the year 2006 after several attempts from the fusion of two established German societies, which were dealing with topics around the spine, der "German Society for Spine Research" founded in the year 1958 and the "German Society for Spine Surgery" founded in the year 1987. This fusion was the beginning of a success story, as from this time on the annual membership increased so much that the DWG became the largest spine society in Europe and one of all spine societies worldwide.

[Biomechanical aspects of vertebral augmentation]. / Biomechanische Aspekte der Augmentation im Bereich der Wirbelsäule.

BACKGROUND: With increasing age, bone mass decreases and the structure of the cancellous bone in the vertebral body changes. Especially in osteoporotic patients, but also with metastases in the vertebral body, this leads to decreased strength and, thus, to an increased risk of vertebral fractures. It is expected that this problem will increase significantly because of demographic developments. To treat or to prevent such vertebral fractures, different augmentation techniques have been developed. They can mainly be divided into vertebroplasty or kyphoplasty procedures. PURPOSE: The goal of this paper is to summarize biomechanical aspects of these augmentations procedures and to present some alternative methods. MATERIALS AND METHODS: With vertebroplasty, the loss of bone mass is balanced by injecting bone cement which improves the failure strength of the affected vertebral body. With kyphoplasty, cavities are created and these are filled with bone cement. RESULTS: Disadvantages of vertebroplasty are uncontrollable cement extrusion and increased fracture risk in the adjacent vertebral bodies. With balloon kyphoplasty, the adjacent cancellous bone is compacted during dilation and, thus, does not allow good integration with the remaining trabeculae. In addition, this method is associated with an increased risk of fracture in the adjacent vertebrae. To counter these disadvantages, a number of new types of cement and alternative augmentation methods are being developed, with which the vertebral body may be filled or distracted. CONCLUSION: The efficacy of these new methods should be tested in appropriate experimental biomechanical studies before they are used in patients.

Comparison of eight published static finite element models of the intact lumbar spine: predictive power of models improves when combined together.

Finite element (FE) model studies have made important contributions to our understanding of functional biomechanics of the lumbar spine. However, if a model is used to answer clinical and biomechanical questions over a certain population, their inherently large inter-subject variability has to be considered. Current FE model studies, however, generally account only for a single distinct spinal geometry with one set of material properties. This raises questions concerning their predictive power, their range of results and on their agreement with in vitro and in vivo values. Eight well-established FE models of the lumbar spine (L1-5) of different research centers around the globe were subjected to pure and combined loading modes and compared to in vitro and in vivo measurements for intervertebral rotations, disc pressures and facet joint forces. Under pure moment loading, the predicted L1-5 rotations of almost all models fell within the reported in vitro ranges, and their median values differed on average by only 2° for flexion-extension, 1° for lateral bending and 5° for axial rotation. Predicted median facet joint forces and disc pressures were also in good agreement with published median in vitro values. However, the ranges of predictions were larger and exceeded those reported in vitro, especially for the facet joint forces. For all combined loading modes, except for flexion, predicted median segmental intervertebral rotations and disc pressures were in good agreement with measured in vivo values. In light of high inter-subject variability, the generalization of results of a single model to a population remains a concern. This study demonstrated that the pooled median of individual model results, similar to a probabilistic approach, can be used as an improved predictive tool in order to estimate the response of the lumbar spine.

[Current S3 guidelines on surgical treatment of gastric carcinoma]. / Aktuelle S3-Leitlinie zur Chirurgie des Magenkarzinoms.

The current S3 guidelines on the diagnosis and treatment of gastric carcinoma including those of the esophagogastric junction describe optimal clinical practice based on a high level of evidence and expert consensus from different medical disciplines. Endoscopy and performance of multiple biopsies is the standard approach to detect malignant tumors in the upper gastrointestinal tract. Further diagnostic procedures are necessary to evaluate the tumor stage. With the exception of mucosal carcinomas, surgical therapy is the cornerstone of curative treatment in all potentially resectable stages. In locally advanced carcinomas perioperative chemotherapy should be carried out and in high-seated tumors preoperative radiochemotherapy might be an alternative option. Palliative surgical resection should be avoided in disseminated asymptomatic stages. In a palliative situation complications of the tumor should primarily be treated by interventional or conservative procedures.

Xenon anesthesia for liver transplant surgery: a report of four cases.

It is well established that patients presenting for orthotopic liver transplantation pose challenging surgical and anesthesiological problems. Intraoperatively, severe hemodynamic instability due to profuse bleeding and acute cardiomyopathy during reperfusion are major concerns. In addition, ischemia-reperfusion injury can compromise postoperative graft function. Xenon, with its potential to maintain hemodynamic stability, preserve cardiac function, and protect the liver graft of the recipient, seems to be a promising anesthetic agent for liver transplant surgery. To date, xenon has not been used as an anesthetic in liver transplantations. We therefore have reported our initial experience with four patients who underwent orthotopic deceased donor liver transplantation under xenon anesthesia. Although all patients had advanced liver disease and experienced significant intraoperative bleeding, their intraoperative courses, including reperfusion, under xenon anesthesia were remarkably stable. The patients required only moderate, temporary catecholamine support, which was withdrawn at the end of the surgery. Xenon anesthesia for liver transplant procedures proved to be feasible. Immediate postoperative organ function was satisfactory in all patients.

[Gastric cancer: current status of multimodality treatment]. / Magenkarzinom: Aktueller Stand der multimodalen Therapie.

BACKGROUND: The overall prognosis of gastric cancer with an overall 5-year survival of 25% is still poor despite improvements of the surgical and perioperative procedures. To improve the surgical treatment results other therapeutic options as chemo- and/or radiotherapy have been investigated for more than 20 years. METHODS: After a literature review, the results of actual trials of multimodality treatment were analysed and described. RESULTS: Adjuvant treatment was less effective compared with neoadjuvant or perioperative chemotherapy performed in advanced tumour categories T3/4. Actual trials could show that the rate of curative (R0) resection can be augmented resulting in an increase of the overall 5-year survival rate of more than 10 %. CONCLUSION: To confirm this trend, further studies with high pathological and surgical quality control are necessary as well as a more exact definition of prediction and evaluation of the response following chemotherapy.

Do early stages of lumbar intervertebral disc degeneration really cause instability? Evaluation of an in vitro database.

Early stages of intervertebral disc degeneration are postulated to cause instability. In the literature, however, some authors report the opposite. These contradictory positions are probably supported by the mostly small number of segments which are investigated. The aim of this project therefore was to investigate the influence of intervertebral disc degeneration on lumbar spine rotational stability using a large data set. The flexibility data from all spine specimens tested in our institute so far were collected in a large in vitro database. From this database, all lumbar spine specimens were selected, which had been tested for flexibility under pure moment loads of ±7.5 N m and for which radiographs were accessible. 203 segments met these criteria. Their radiographic degree of disc degeneration was determined on a scale from 0 (no degeneration) to 3 (severe degeneration) and their influence on the respective range of motion and neutral zone was examined. The different lumbar levels differ in flexibility, which increases the variability of the data if pooled together. To minimise this effect a statistical model was fitted. The model-based mean estimates showed a decrease of the range of motion from grade 0 to 3 in flexion/extension (by 3.1°, p < 0.05) and lateral bending (by 3.4°, p < 0.05). In contrast, in axial rotation the range of motion tended to increase; however, not only from grade 0 to 1 but also towards grade 3 (by 0.2°) (p > 0.05). The neutral zone was affected in a similar way but to a smaller degree (p > 0.05). In conclusion, the results indicated that early stages of intervertebral disc degeneration do not necessarily cause rotational instability. In contrast, stability increased in flexion/extension and lateral bending. Only in axial rotation stability tended to decrease.

Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study.

BACKGROUND: Clinical data showed promising antitumour activity with feasible tolerability for matuzumab plus epirubicin, cisplatin and capecitabine (ECX) chemotherapy in untreated advanced oesophago-gastric (OG) cancer. The aim was to evaluate the efficacy of matuzumab plus ECX versus ECX alone. PATIENTS AND METHODS: In this multicentre, randomised open-label phase II study, 72 patients with metastatic OG cancer were randomly assigned to either 800 mg matuzumab weekly plus epirubicin 50 mg/m², cisplatin 60 mg/m² on day 1 and capecitabine 1250 mg/m² daily in a 21-day cycle (ECX) or the same ECX regimen alone. The primary end point was objective response. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life, safety and tolerability. RESULTS: Following random assignment, 35 patients (median age 59 years) received ECX/matuzumab and 36 patients (median age 64 years) ECX. The addition of matuzumab to ECX did not improve objective response: 31% for ECX/matuzumab [95% confidence interval (CI) 17-49] compared with 58% for the ECX arm (95% CI 41-74) P = 0.994 (one sided). There was no significant difference in median PFS: 4.8 months (95% CI 2.9-8.1) for ECX/matuzumab versus 7.1 months (95% CI 4.4-8.5) for ECX, or in median OS: 9.4 months (95% CI 7.5-16.2), compared with 12.2 months (95% CI 9.8-13.8 months). Grade 3/4 treatment-related toxicity was observed in 27 and 25 patients in the ECX/matuzumab and ECX groups, respectively. CONCLUSION: Matuzumab 800 mg weekly combined with ECX chemotherapy does not increase response or survival for patients with advanced OG cancer. Therefore, ECX/matuzumab should not be examined further in phase III trials.