Lennart Viezens

Chemokine profile of disc degeneration with acute or chronic pain

OBJECT Disc-related disorders such as herniation and chronic degenerative disc disease (DDD) are often accompanied by acute or chronic pain. Different mediators have been identified in the development of radicular pain and DDD. Previous studies have not analyzed individual cytokine profiles discriminating between acute sciatic and chronic painful conditions, nor have they distinguished between different anatomical locations within the disc. The aim of this study was to elucidate the protein biochemical mechanisms in DDD. METHODS The authors determined expression levels of matrix metalloproteinase-3, transforming growth factor-β (TGF-β), tumor necrosis factor-α, interleukin-1α, and pro-substance P using enzyme-linked immunosorbent assay and Western blot analyses in patients suffering from DDD (n = 7), acute back pain due to herniated discs with radiculopathy (n = 7), and a control group (n = 7). Disc tissue samples from the anulus fibrosus (AF) and nucleus pulposus (NP) were analyzed. Statistical analysis was performed using nonparametric tests. RESULTS A distinct distribution of cytokines was found in different anatomical regions of intervertebral discs in patients with DDD and herniated NP. Increased TGF-β levels were predominantly found in DDD. Matrix metalloproteinase-3 was increased in acute herniated disc material. Increased levels of substance P were found in patients suffering from DDD but not in patients with disc herniation. The data showed significantly higher levels of proinflammatory cytokines in the AF and NP of patients with DDD, and the expression levels in the AF were even higher than in the NP, suggesting that the inflammatory response initiates from the AF. CONCLUSIONS These results highlight the complex mechanisms involved during disc degeneration and the need to distinguish between acute and chronic processes as well as different anatomical regions, namely the AF and NP. They also highlight potential problems in disc nucleus replacement therapies because the results suggest a biochemical link between AF and NP cytokine expression.

Dynamics of Microvascular Remodelling during Tumor Growth in Bone

Microcirculatory properties of tumors have been shown to play a pivotal role in tumor progression and inefficacy of therapies. Although the influence of the microenvironment on angiogenesis has been intensively investigated in soft tissue tumors, little is known about the microvascular properties in bone metastasis. To determine the impact of the bone microenvironment on tumor growth and microcirculation we performed intravital microscopy using the “femur window” after implantation of red‐fluorescent‐protein‐transduced breast cancer cells into the femura of severe‐combined‐immunodeficient mice. Tumor size, functional vascular density, vessel diameter, and vessel distribution were quantified over 14 days. Tumor growth and microcirculation could be quantified at a high spatial resolution. Tumor progression was associated with a rapid remodeling process of the microcirculation within the tumor and the surrounding tissue. Although the total functional vascular density remained unaltered, we found a significant loss in small vessels and a concomitant increase in vascular diameter. The presented study demonstrates for the first time dynamics of morphological microcirculatory alterations of tumor growth in bone. The observed changes in tumor vascularization exhibit strong similarities to soft tissue tumors; however, the dynamics of vascular alterations are more rapid in the bone microenvironment.

Microcirculation of secondary bone tumors in vivo: the impact of minor surgery at a distal site.

Microcirculatory properties of tumors play a pivotal role in tumor progression and inefficacy of therapies. It has been hypothesized that surgical interventions result in an accelerated tumor growth by increasing the level of pro‐angiogenic cytokines with subsequent amplification of tumor angiogenesis. To characterize the microvascular properties of secondary bone tumors in vivo and determine the impact of minor surgery on the microcirculation, we performed intravital microscopy over 25 days using a xenograft model of breast cancer tumor growth (MCF‐7) in bone. After engraftment of tumors the mice were treated with a mastectomy versus no surgery. Tumor growth was accompanied by angiogenic sprouting and decreased vascular diameters while blood flow rate and tumor perfusion remained constant. Mastectomy initially led to a significant reduction of functional vascular density, increased vascular diameter, and decreased blood flow velocities. However, neither tumor growth nor tissue perfusion was different between the groups. The presented study corroborates the assumption that tumor microcirculation in bone exhibits similar time‐dependent alterations compared to soft tissue tumors. A minor surgical intervention did not change tumor growth kinetics however microcirculatory properties were altered. Whether major surgery has an impact on tumor growth in bone should be clarified in further studies.

Comparison Between Minimally Invasive Surgery and Conventional Open Surgery for Patients With Spinal Metastasis: A Prospective Propensity Score-matched Study.

Study Design. Prospective propensity score-matched study. Objective. To compare the outcomes of minimal invasive surgery (MIS) and conventional open surgery for spinal metastasis patients. Summary of Background Data. There is lack of knowledge on whether MIS is comparable to conventional open surgery in treating spinal metastasis. Methods. Patients with spinal metastasis requiring surgery from January 2008 to December 2010 in two spine centers were recruited. The demographic, preoperative, operative, perioperative and postoperative data were collected and analyzed. Thirty MIS patients were matched with 30 open surgery patients using propensity score matching technique with a match tolerance of 0.02 based on the covariate age, tumor type, Tokuhashi score, and Tomita score. Results. Both groups had significant improvements in Eastern Cooperative Oncology Group (ECOG), Karnofsky scores, visual analogue scale (VAS) for pain and neurological status postoperatively. However, the difference comparing the MIS and open surgery group was not statistically significant. MIS group had significantly longer instrumented segments (5.5 ± 3.1) compared with open group (3.8 ± 1.7). Open group had significantly longer decompressed segment (1.8 ± 0.8) than MIS group (1.0 ± 1.0). Open group had significantly more blood loss (2062.1 ± 1148.0 mL) compared with MIS group (1156.0 ± 572.3 mL). More patients in the open group (76.7%) needed blood transfusions (with higher average units of blood transfused) compared with MIS group (40.0%). Fluoroscopy time was significantly longer in MIS group (116.1 ± 63.3 s) compared with open group (69.9 ± 42.6 s). Open group required longer hospitalization (21.1 ± 10.8 days) compared with MIS group (11.0 ± 5.0 days). Conclusion. This study demonstrated that MIS resulted in comparable outcome to open surgery for patients with spinal metastasis but has the advantage of less blood loss, blood transfusions, and shorter hospital stay. Level of Evidence: 3

An incomplete paraplegia following the dislocation of an artificial cervical total disc replacement

Replacement of the cervical intervertebral disc by artificial implants, known as cervical total disc replacement (CTDR), is becoming a generally applied method instead of using the gold standard of the anterior cervical discectomy and fusion. Hypothetically, the preserved mobility results in the protection of the neighboring segments. There is growing evidence that results in patients who underwent CTDR were not inferior when compared to results in patients who underwent anterior cervical discectomy and fusion. The authors report a case of a healthy 53-year-old man who suffered an incomplete paraplegia below C-6 following the dislocation of an artificial CTDR device into the spinal canal with consequent compression of the spinal cord.

Primary tumor dependent inhibition of tumor growth, angiogenesis, and perfusion of secondary breast cancer in bone

The systemic balance of angiogenic and anti‐angiogenic factors has been proposed to play a key‐role in primary tumor growth dependent growth suppression of secondary tumors. Despite the importance of the organ microenvironment to angiogenesis and microcirculation, the influence of a primary tumor on secondary bone tumors has not been investigated so far. Since breast cancer has a high propensity to spread to bone, we used an in vivo xenograft model to determine the impact of growing breast cancer cells (MCF‐7) in the mammary fat pad on the microvascular properties of subsequently inoculated secondary breast cancer tumors in bone. Mice were either treated with a resection of the primary tumor (n = 10) or no surgery (n = 9) and intravital microscopy was performed over 25 days in bone tumors. Tumor growth in bone was temporarily suppressed by the primary tumor on days 10 and 14. While microvascular permeability and vascular diameter decreased in both groups over time, the presence of the primary tumor was accompanied by a decreased tumor perfusion on days 8 and 10 through a reduction in vessels with diameters between 5 and 20 µm. The results imply a potential benefit of a therapeutic regime in which the resection of the primary tumor is combined with an anti‐angiogenic therapy in the perioperative or direct postoperative period. This might result in reduced progression of bone metastasis subsequent to excision of the primary tumor.

Sunitinib treatment reduces tumor growth and limits changes in microvascular properties after minor surgical intervention in an in vivo model of secondary breast cancer growth in bone.

Surgical interventions can alter the balance between pro‐ and anti‐angiogenic growth factors and thereby modulate tumor growth. Since the microcirculatory properties of tumors underlie organ‐specific differences, the microhemodynamic characteristics of bone metastasis have not yet been fully described. Angiogenesis inhibitors are increasingly being used to treat advanced stages of cancer. We hypothesized that the anti‐angiogenic drug sunitinib abrogates alterations in microvascular properties following a minor surgical intervention in an in vivo model of secondary breast cancer growth in the bone.

In vivo functional and morphological characterization of bone and striated muscle microcirculation in NSG mice

Organ-specific microcirculation plays a central role in tumor growth, tumor cell homing, tissue engineering, and wound healing. Mouse models are widely used to study these processes; however, these mouse strains often possess unique microhemodynamic parameters, making it difficult to directly compare experiments. The full functional characterization of bone and striated muscle microcirculatory parameters in non-obese diabetic-severe combined immunodeficiency/y-chain; NOD-Prkds IL2rg (NSG) mice has not yet been reported. Here, we established either a dorsal skinfold chamber or femur window in NSG mice (n = 23), allowing direct analysis of microcirculatory parameters in vivo by intravital fluorescence microscopy at 7, 14, 21, and 28 days after chamber preparation. Organ-specific differences were observed. Bone had a significantly lower vessel density but a higher vessel diameter than striated muscle. Bone also showed higher effective vascular permeability than striated muscle. The centerline velocity values were similar in the femur window and dorsal skinfold chamber, with a higher volumetric blood flow in bone. Interestingly, bone and striated muscle showed similar tissue perfusion rates. Knowledge of physiological microhemodynamic values of bone and striated muscle in NSG mice makes it possible to analyze pathophysiological processes at these anatomic sites, such as tumor growth, tumor metastasis, and tumor microcirculation, as well as the response to therapeutic agents.

Posterior Only Vertebral Column Resection for the Treatment of Severe Spinal Deformities in Pediatric Patients: A Retrospective Case Series

OBJECTIVE The treatment of severe spinal deformities in pediatric patients is very challenging. Posterior only vertebral column resection (PVCR) allows for correcting of severe deformities of the vertebral column via a posterior only procedure. We analyzed radiologic outcome of PVCR performed on a series of pediatric patients with severe congenital and acquired spinal deformities. METHODS A case series of 11 pediatric patients with severe spinal deformity who were treated by PVCR between 2009 and 2013 were retrospectively analyzed. All patients had posterior instrumentation and reconstruction of the anterior column with titanium cages filled with autologous bone. Seven patients had pure kyphosis or kyphoscoliosis, whereas 4 patients were treated because of scoliotic deformities. The patient records were reviewed for demographic and general clinical data. Complications and adverse events, transfusion rates, and surgical time were recorded. Radiologic analysis included Cobb angles and percentage of correction, analysis of sagittal profile, time to fusion, and possible complications related to instrumentation. RESULTS Average preoperative scoliosis of 61° was corrected to 32°, resulting in a 50% correction at final follow-up. Coronal imbalance was improved to 36% at the most recent follow-up. Mean preoperative kyphotic deformity was 90° and was corrected to 43° at the last follow-up evaluation. Intraoperative complications included loss of the neuromonitoring signals in 2 cases and pleural laceration in 1 case. CONCLUSIONS PVCR for children is an effective and safe technique providing a successful correction of complex pediatric spinal deformities. Nevertheless, it remains a technically highly demanding procedure, implying the possibility of severe complications.