Cost and quality of life outcome analysis of postoperative infections after subaxial dorsal cervical fusions.

OBJECT: Infections following spine surgery negatively affect patient quality of life (QOL) and impose a significant financial burden on the health care system. Postoperative wound infections occur at higher rates following dorsal cervical procedures than ventral procedures. Quantifying the health outcomes and costs associated with infections following dorsal cervical procedures may help to guide treatment strategies to minimize the deleterious consequences of these infections. Therefore, the goals of this study were to determine the cost and QOL outcomes affecting patients who developed deep wound infections following subaxial dorsal cervical spine fusions. METHODS: The authors identified 22 (4.0%) of 551 patients undergoing dorsal cervical fusions who developed deep wound infections requiring surgical debridement. These patients were individually matched with control patients who did not develop infections. Health outcomes were assessed using the EQ-5D, Pain Disability Questionnaire (PDQ), Patient Health Questionnaire (PHQ-9), and visual analog scale (VAS). QOL outcome measures were collected preoperatively and after 6 and 12 months. Health resource utilization was recorded from patient electronic medical records over an average follow-up of 18 months. Direct costs were estimated using Medicare national payment amounts, and indirect costs were based on patients' missed workdays and income. RESULTS: No significant differences in preoperative QOL scores were found between the 2 cohorts. At 6 months postsurgery, the noninfection cohort had significant pre- to postoperative improvement in EQ-5D (p = 0.02), whereas the infection cohort did not (p = 0.2). The noninfection cohort also had a significantly higher 6-month postoperative EQ-5D scores than the infection cohort (p = 0.04). At 1 year postsurgery, there was no significant difference in EQ-5D scores between the groups. Health care-associated costs for the infection cohort were significantly higher ($16,970 vs $7658; p < 0.0001). Indirect costs for the infection cohort and the noninfection cohort were $6495 and $2756, respectively (p = 0.03). Adjusted for inflation, the total costs for the infection cohort were $21,778 compared with $9159 for the noninfection cohort, reflecting an average cost of $12,619 associated with developing a postoperative deep wound infection (p < 0.0001). CONCLUSIONS: Dorsal cervical infections temporarily decrease patient QOL postoperatively, but with no long-term impact; they do, however, dramatically increase the cost of care. Knowledge of the financial burden of wound infections following dorsal cervical fusion may stimulate the development and use of improved prophylactic and therapeutic techniques to manage this serious complication.

Platform and cannula design improvements for spinal cord therapeutics delivery.

BACKGROUND: Only recently have data been published attempting to validate a technology and technique suitable for targeted delivery of biological payloads to the human spinal cord. OBJECTIVE: To characterize the development and evolution of a spine-stabilized microinjection platform as a vehicle for biologics delivery to the cervical and thoracolumbar spine on the basis of preclinical experience in both non-Good Laboratory Practice (GLP) experimental series and GLP studies. METHODS: Our laboratory completed > 100 cervical and lumbar porcine microinjection procedures between July 2004 and June 2010. This included both non-GLP- and GLP-adherent survival series to validate the safety and accuracy achievable with intraspinal microinjection. During this time, 3 different microinjection platforms, injection stages, and cannula designs were tested. RESULTS: Repetitive technological improvements reduced incision length, decreased procedural complexity, and simplified ventral horn targeting and accuracy. These changes reduced procedural invasiveness and the likelihood of neurological morbidity while improving targeting accuracy. In part as a result of these technological improvements and procedural modifications, we have safely progressed from single unilateral microinjections to multiple bilateral injections without long-term neurological sequelae. CONCLUSION: Technological and procedural refinements have significantly enhanced the capabilities of intraspinal microinjection-based biologics delivery. Reductions in procedural invasiveness and the capability to deliver sequential biological payloads effectively have broadened the flexibility of intraspinal microinjection to a widened array of intrinsic spinal cord pathologies. These advances have laid the groundwork for clinical translation of spinal cord microinjections.

Open biopsy in patients with acute progressive neurologic decline and absence of mass lesion.

OBJECTIVE: Patients with acute to subacute neurologic decline undergo a battery of imaging and laboratory tests to determine a diagnosis and treatment plan. Often, after an extensive evaluation, a brain biopsy is recommended as yet another tool to assist in determining the diagnosis. The goal of this retrospective cohort analysis is to measure the sensitivity of open brain biopsy in this patient population, compare these results with the preoperative presumed diagnosis, and evaluate if the biopsy result significantly alters treatment. METHODS: The authors reviewed the medical records of 135 consecutive patients who underwent open brain biopsies for acute to subacute progressive neurologic decline between January 1999 and September 2008 at a single institution. All patients with mass lesions, with HIV/AIDS, and who were younger than 20 years of age were excluded from the study. Fifty-one patients met these criteria and all preoperative tests, imaging, and treatment plans were examined and compared with postbiopsy interventions to determine the impact of the biopsy on patient outcome. RESULTS: The sensitivity of open brain biopsy at our institution was 35%. The most common preoperative presumed diagnosis was vasculitis and the most common postoperative finding was Creutzfeldt-Jakob disease, followed by amyloid angiopathy. Postbiopsy hemorrhage was a complication in 4% of patients. Treatment plans changed as a direct result of the biopsy in 8% of patients, and in only 4% did the biopsy findings make a difference in disease course. CONCLUSION: In patients with progressive neurologic decline without a radiographic mass lesion or immunodeficiency, open brain biopsy often fails to provide a diagnosis and even more rarely does it significantly alter treatment.

Intestinal epithelial cells modulate PMN activation and apoptosis following bacterial and hypoxic challenges.

BACKGROUND: The post-ischemic gut may serve to prime and activate neutrophils which may lead to the subsequent development of the systemic inflammatory response syndrome (SIRS) and multiple organ failure. However, the initiating event which may trigger this immunoinflammatory cascade from the gut is unknown. Recent studies have indicated that intestinal epithelial cells (IEC) play an integral role in generating and transmitting signals between luminal bacteria and the host cells in the underlying gut tissues. The purpose of this study was to investigate the ability of IEC to modulate PMN responses to bacteria and/or hypoxia/reoxygenation (H/R) challenges in vitro. METHODS: Caco2 cell monolayers were established in a two-chamber cell culture system. Neutrophils from normal human volunteers were placed in the basal chamber and the cell co-culture exposed to either apical bacteria (E. coli) and/or H/R challenge. PMN apoptosis, and percentage of CD11b expression, superoxide anion production, and elastase release were subsequently quantitated. RESULTS: Coculture of PMNs with Caco2 cells led to a significant reduction in neutrophil apoptosis in both normoxic and H/R conditions. CD11b expression was increased in PMNs exposed to bacteria but the greatest expression was noted with PMN cocultured with Caco2 cells and H/R. Superoxide anion production was increased in all groups following either H/R or bacterial challenge and H/R. Elastase release was highest in neutrophils following H/R and exposure to E. coli. CONCLUSION: IEC modulate PMN response to bacteria and H/R insults. This results in the production of activated neutrophils with an exaggerated lifespan which may promote remote organ failure. Attempts to modulate this response may be useful in preventing multiple organ failure following severe traumatic shock.

Bradykinin receptor subtype 1 expression and function in prostate cancer.

Kinins exert multiple pathophysiological functions, including vascular permeability and mitogenesis, by activating their cognate receptors, bradykinin subtype 1 receptor (B1R) and bradykinin subtype 2 receptor (B2R), which belong to the superfamily of G protein-coupled receptors. Tissue-specific expression pattern or contribution of the individual kinin receptors to pathological prostate cell growth is not known. We report here the differential expression of B1R and B2R in human benign and malignant prostate specimens. Whereas B2R is ubiquitously expressed, the B1R is detected only in prostatic intraepithelial neoplasia and malignant lesions and not in benign prostate tissues. Using androgen-insensitive prostate cancer PC3 cells, we show that specific stimulation of endogenous B1R promotes cell growth, migration, and invasion. These findings identify B1R as an early marker for pathological growth of the prostate and suggest its potential utility as a drug target effective for the treatment of prostate cancer.

Lysophosphatidic acid-regulated mitogenic ERK signaling in androgen-insensitive prostate cancer PC-3 cells.

Advanced and recurrent prostate tumors contain elevated levels of activated extracellular signal-regulated kinases 1 and 2 (ERK) in comparison to early-stage or benign specimens, and inhibition of ERK activation attenuates growth factor-dependent proliferation of prostate cells, suggesting a potential regulatory role for ERK in prostate tumorigenesis. Factors responsible for ERK activation in prostate cells are not well defined. Here, we show positive cooperative interaction between the G protein-coupled lysophosphatidic acid (LPA) and tyrosine kinase epidermal growth factor (EGF) receptors in androgen-insensitive prostate cancer PC-3 cells. Pre-treatment of the PC-3 cells with LPA decreases the dose of EGF required to elicit maximal activation of EGFR. Furthermore, treatment with LPA alone induces the rapid (maximal signal within 2 min) tyrosine phosphorylation of EGFR, and subsequent (maximal signal after 5 min) activation of ERK, suggesting that EGFR activation precedes ERK phosphorylation and may constitute a required component for signal relay from the LPA receptor to ERK. Accordingly, we show that inhibition of EGFR kinase activity attenuates the LPA-regulated ERK activation. In addition, we find that the LPA-regulated tyrosine phosphorylation of EGFR and activation of ERK are attenuated by batimastat, a generic inhibitor of matrix metalloproteinases (MMP). However, unlike the situation in fibroblasts, we find that the LPA-induced transactivation of EGFR in PC-3 cells is not mediated by shedding of heparin-binding EGF. Together, our data show that LPA and EGF cooperate to induce mitogenic signaling in prostate cancer cells in an MMP-regulated activation of the ERK pathway.