Patrick J. Messerschmitt

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

Inhibitors of specific tyrosine kinases are attractive lead compounds for development of targeted chemotherapies for many tumors, including osteosarcoma. We asked whether inhibition of specific tyrosine kinases would decrease the motility, colony formation, and/or invasiveness by human osteosarcoma cell lines (TE85, MNNG, 143B, SAOS-2, LM-7). An EGF-R inhibitor reduced motility of all five cell lines by 50% to 80%. In contrast, an IGF-1R inhibitor preferentially reduced motility by 42% in LM-7 cells and a met inhibitor preferentially reduced motility by 80% in MNNG cells. The inhibitors of EGF-R, IGF-1R, and met reduced colony formation by more than 80% in all tested cell lines (TE85, MNNG, 143B). The EGF-R inhibitor reduced invasiveness by 62% in 143B cells. The JAK inhibitor increased motility of SAOS-2 and LM7 cells without affecting colony formation or invasiveness. Inhibitors of HER-2, NGF-R, and PDGF-Rs did not affect motility, invasiveness, or colony formation. These results support the hypothesis that specific tyrosine kinases regulate tumorigenesis and/or metastasis in osteosarcoma.

A multimodal approach for postoperative pain management after lumbar decompression surgery: a prospective, randomized study.

Study Design: A prospective and randomized study. Objectives: The objective of this study was to assess the efficacy of a novel multimodal analgesic regimen in reducing postoperative pain and intravenous morphine requirements after primary multilevel lumbar decompression surgery. Summary of Background Data: The use of opioid medications after surgery can lead to incomplete analgesia and may cause undesired side effects such as respiratory depression, somnolence, urinary retention, and nausea. Multimodal (opioid and nonopioid combination) analgesia may be an effective alternative to morphine administration leading to improved postoperative analgesia with diminished side effects. Methods: After Institutional Review Board approval, 22 patients who underwent a primary multilevel lumbar decompression procedure were randomly assigned to receive either only intravenous morphine or a multimodal (celecoxib, pregabalin, extended release oxycodone) analgesic regimen. Postoperatively, all patients were allowed to receive intravenous morphine on an as needed basis. Intravenous morphine requirements were then recorded immediately postoperative, at 6, 12, 24 hours, and the total requirement before discharge. Patient postoperative pain levels were determined using the visual analog pain scale and were documented at 0, 4, 8, 12, 16, 24, and 36 hours postoperative. Results: There were no significant differences in available patient demographics, intraoperative blood loss, or postoperative hemovac drain output between study groups. Total postoperative intravenous morphine requirements in addition to morphine requirements at all predetermined time points were less in patients randomized to receive the multimodal analgesic regimen. Visual analog pain scores were lower at all postoperative time points in patients randomized to receive the multimodal analgesic regimen. Time to solid food was significantly less in the multimodal group. There were no major identifiable postoperative complications in either treatment group. Conclusions: Opioid and nonopioid analgesic combinations appear to be safe and effective after lumbar laminectomy. Patients demonstrate lower intravenous morphine requirements, better pain scores, and earlier time to solid food intake.

Analysis of Retrieved Ultra–High-Molecular-Weight Polyethylene Tibial Components From Rotating-Platform Total Knee Arthroplasty

Mobile-bearing total knee Arthroplasties (TKAs) were designed to increase conformity, decrease contact stresses, and decrease polyethylene damage. Our objective was to evaluate the performance of retrieved mobile-bearing TKAs with respect to wear damage of the polyethylene in a series of components obtained at revision surgery. Tibial component polyethylene superior and inferior surface damage and radiographic radiolucency analysis was conducted on 40 retrieved mobile-bearing TKAs. Higher levels of superior articulating surface damage were found to be associated with higher levels of inferior surface damage in this retrieval study. Greater levels of damage were present on both surfaces in components with greater radiographic radiolucency scores and mechanically loose components. The mobile-bearing TKA remains vulnerable to polyethylene wear damage at the superior surface and introduces an independent inferior surface also vulnerable to wear damage.

Weight Loss in Overweight and Obese Patients Following Successful Lumbar Decompression

BACKGROUND Neurogenic claudication secondary to lumbar stenosis is often cited by overweight and obese patients as a factor limiting their ability to lose weight. Many patients believe that they will be able to increase their activity and subsequently lose weight following relief of symptoms. The objective of this study was to evaluate weight loss in overweight and obese patients who obtained substantial pain relief after lumbar decompression surgery for spinal stenosis. METHODS Changes in the body weight and body mass index of overweight and obese patients after lumbar decompression surgery were assessed at a mean of 34.4 months postoperatively. Sixty-three patients (thirty-seven men and twenty-six women with a mean age of 53.4 years) were included in the study. Preoperative and postoperative body weight and body mass indices were calculated, and Zurich Claudication Questionnaire (ZCQ) Symptom Severity and Physical Function scores were obtained. RESULTS The ZCQ Symptom Severity and Physical Function scores significantly improved, by a mean of 56.4% and 53.0%, respectively. At the time of follow-up, both the mean body weight and the mean body mass index significantly increased, by 2.48 kg and 0.83 kg/m(2), respectively. Overall, 35% of the patients gained >or=5% of their preoperative body weight, 6% of the patients lost >or=5% of their preoperative body weight, and 59% remained within 5% of their preoperative body weight. CONCLUSIONS The majority of overweight and obese patients maintain or increase their body weight and body mass index following successful lumbar decompression surgery. Substantial relief of symptoms and functional improvements do not appear to help overweight or obese patients to lose weight. This suggests that obesity is an independent disease and not simply a function of symptomatic spinal stenosis, and patients should be counseled regarding these expectations.

An evaluation of information on the Internet of a new device: the lumbar artificial disc replacement.

Study Design An analysis of websites, accessible to the public, was conducted pertaining to the lumbar artificial disc replacement. Objective The objective was to investigate the content of information available on the Internet pertaining to the lumbar artificial disc replacement. Summary of Background Data The Internet is widely used by patients as an educational tool for health care information. Additionally, the Internet is used as a medium for direct-to-consumer marketing. Recent approval of the lumbar artificial disc replacement has led to the emergence of numerous websites offering information about this procedure. It is thought that patients can be influenced by information found on the Internet; therefore, it is imperative that this information be accurate and as complete as possible. Methods Three commonly used search engines were used to locate 105 (35/search engine) websites providing information about the lumbar artificial disc replacement. Each website was evaluated with regard to authorship and content. Results Fifty-nine percent of the websites reviewed were authorized by a private physician group, 9% by an academic physician group, 6% by industry, 11% were news reports, and 15% were not otherwise categorized. Seventy-two percent offered a mechanism for direct contact and 30% provided clear patient selection criteria. Benefits were expressed in 87% of websites, whereas associated risks were described in 28% or less. European experiences were noted in 53%, whereas only 22% of websites detailed the current US experience. Conclusions The results of this study demonstrate that much of the content of Internet-derived information pertaining to the lumbar artificial disc replacement is potentially misleading. Until long-term data are available, patients should be cautioned when using the Internet as a source for health care information, particularly with regard to the lumbar artificial disc replacement.

Surface contaminants inhibit osseointegration in a novel murine model

Surface contaminants, such as bacterial debris and manufacturing residues, may remain on orthopedic implants after sterilization procedures and affect osseointegration. The goals of this study were to develop a murine model of osseointegration in order to determine whether removing surface contaminants enhances osseointegration. To develop the murine model, titanium alloy implants were implanted into a unicortical pilot hole in the mid-diaphysis of the femur and osseointegration was measured over a five week time course. Histology, backscatter scanning electron microscopy and X-ray energy dispersive spectroscopy showed areas of bone in intimate physical contact with the implant, confirming osseointegration. Histomorphometric quantification of bone-to-implant contact and peri-implant bone and biomechanical pullout quantification of ultimate force, stiffness and work to failure increased significantly over time, also demonstrating successful osseointegration. We also found that a rigorous cleaning procedure significantly enhances bone-to-implant contact and biomechanical pullout measures by two-fold compared with implants that were autoclaved, as recommended by the manufacturer. The most likely interpretation of these results is that surface contaminants inhibit osseointegration. The results of this study justify the need for the development of better detection and removal techniques for contaminants on orthopedic implants and other medical devices.

Anatomic variance of interfacet distance and its relationship to facet arthrosis and disk degeneration in the lumbar spine.

Inadequate separation of the L4-S1 facets predisposes individuals to spondylolytic defects. We proposed that decreased interfacet separation is a risk factor for increased lumbar degenerative disease. This study examined the correlation between interfacet distance and degenerative disease of the lumbar spine. Four hundred forty-four cadaveric lumbar spines were examined for evidence of lumbar facet arthrosis and disk degeneration. Arthrosis at each level was graded from 0 to 4 on a continuum from no arthritis to complete ankylosis. These results were then examined in relation to interfacet spread. Interfacet distances were measured at each level (L1-S1). The difference in interfacet spread (L4-S1) was then correlated to facet arthrosis and disk degeneration. In individuals younger than 50 years (n=251), increased interfacet spread (L4-S1) was associated with less facet arthrosis at the L5/Sl level (P<.05). Similarly, in individuals younger than 40 years (n=149), increased interfacet spread (L4-S1) was associated with less disk degeneration at the L5/S1 level (P<.03). Insufficient increase in interfacet distances (L4-S1) correlates with a greater risk of developing and maintaining spondylolytic defects. Similarly, this study suggests that increased interfacet spread (L4-S1) protects against early degenerative changes at the L5/Sl level. The more pyramidal the L4-S1 facet cascade, the lower the arthrosis. This effect appears early in the degenerative process before facet arthrosis and disk degeneration have become ubiquitous. In individuals younger than 50 years, increased interfacet distance correlates with less L5/Sl facet arthrosis.

Osteosarcoma Phenotype Is Inhibited by 3,4-Methylenedioxy-β-nitrostyrene

β-nitrostyrene compounds, such as 3,4-methylenedioxy-β-nitrostyrene (MNS), inhibit growth and induce apoptosis in tumor cells, but no reports have investigated their role in osteosarcoma. In this study, human osteosarcoma cell families with cell lines of varying tumorigenic and metastatic potential were utilized. Scrape motility assays, colony formation assays, and colony survival assays were performed with osteosarcoma cell lines, both in the presence and absence of MNS. Effects of MNS on human osteoblasts and airway epithelial cells were assessed in monolayer cultures. MNS decreased metastatic cell line motility by 72–76% and colony formation by 95–100%. MNS consistently disrupted preformed colonies in a time-dependent and dose-dependent manner. MNS had similar effects on human osteoblasts but little effect on airway epithelial cells. An inactive analog of MNS had no detectable effects, demonstrating specificity. MNS decreases motility and colony formation of osteosarcoma cells and disrupts preformed cell colonies, while producing little effect on pulmonary epithelial cells.