Fighting for recovery on multiple fronts: The past, present, and future of clinical trials for spinal cord injury.

Through many decades of preclinical research, great progress has been achieved in understanding the complex nature of spinal cord injury (SCI). Preclinical research efforts have guided and shaped clinical trials, which are growing in number by the year. Currently, 1,149 clinical trials focused on improving outcomes after SCI are registered in the U.S. National Library of Medicine at ClinicalTrials.gov. We conducted a systematic analysis of these SCI clinical trials, using publicly accessible data downloaded from ClinicalTrials.gov. After extracting all available data for these trials, we categorized each trial according to the types of interventions being tested and the types of outcomes assessed. We then evaluated clinical trial characteristics, both globally and by year, in order to understand the areas of growth and change over time. With regard to clinical trial attributes, we found that most trials have low enrollment, only test single interventions, and have limited numbers of primary outcomes. Some gaps in reporting are apparent; for instance, over 75% of clinical trials with "Completed" status do not have results posted, and the Phase of some trials is incorrectly classified as "Not applicable" despite testing a drug or biological compound. When analyzing trials based on types of interventions assessed, we identified the largest representation in trials testing rehab/training/exercise, neuromodulation, and behavioral modifications. Most highly represented primary outcomes include motor function of the upper and lower extremities, safety, and pain. The most highly represented secondary outcomes include quality of life and pain. Over the past 15 years, we identified increased representation of neuromodulation and rehabilitation trials, and decreased representation of drug trials. Overall, the number of new clinical trials initiated each year continues to grow, signifying a hopeful future for the clinical treatment of SCI. Together, our work provides a comprehensive glimpse into the past, present, and future of SCI clinical trials, and suggests areas for improvement in clinical trial reporting.

Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone.

Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better understanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood and compared these to normal donors. In doing so, we identified changes in systemic immunity associated with both the tumor and dexamethasone treated tumor bearing patients. In particular, dexamethasone exacerbated tumor associated lymphopenia primarily in the T cell compartment. We have also identified unique tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes (CD14(+)HLA-DR(lo/neg)) had a phenotype distinct from classical myeloid suppressor cells. These cells inhibited T cell proliferation, were unable to fully differentiate into mature dendritic cells, were associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. We provide evidence that tumors express high levels of CCL2, can contain high numbers of CD14(+) cells, that tumor supernatants can transform CD14(+)HLA-DR(+) cells into CD14(+)HLA-DR(lo/neg) immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD14(+) cells.

Interphase cytogenetics for 1p19q and t(1;19)(q10;p10) may distinguish prognostically relevant subgroups in extraventricular neurocytoma.

Co-deletion of chromosome arms 1p and 19q, characteristic of oligodendroglial tumors, was recently found to be mediated by t(1;19)(q10;p10). To evaluate the prevalence of 1p19q co-deletion and t(1;19) in extraventricular neurocytomas (EVN), we studied tumors from 23 patients, including 13 females and 10 males (median age at diagnosis 34 years, range 2-76 years). Fluorescence in situ hybridization (FISH) studies were performed with probes targeting 1p36/1q25 and 19q13/19p13 to assess for 1p19q co-deletion, as well as chromosome 1 alpha-satellite and 19p12 to detect t(1;19)(q10;p10). FISH was successful in 21 (91%) cases and demonstrated 1p19q co-deletion in five cases (24%) or isolated 1p loss in two cases (10%). Evidence for t(1;19) was found in four (of five) cases with 1p19q co-deletion. Three tumors with 1p19q loss and t(1;19) demonstrated atypical histologic features, compared with one (of 17) tumors without 1p19q co-deletion (P = 0.01, Fisher exact test). In addition, tumors with t(1;19) showed increased mitotic activity compared with tumors without t(1;19) (P = 0.045; Wilcoxon rank sum test). The four patients with t(1;19) developed tumor recurrence (n = 3), or expired (n = 2) 3.5 to 5.5 years after first resection. These results suggest that 1p19q loss and t(1;19) occur in a subset of EVN, and may be associated with aggressive histology in these tumors.

Cerebellopontine angle craniopharyngioma: case report and literature review.

The authors report an unusual case of adamantinomatous craniopharyngioma occurring in isolation in the cerebellopontine angle of a 12-year-old female. The patient presented with a 1-year history of nausea, vomiting, and headache. MRI revealed a left cerebellopontine angle tumor without connection to the suprasellar space. Following near-total resection, histological review confirmed the lesion as an adamantinomatous craniopharyngioma. This is only the third published report of craniopharyngioma occurring in isolation in the cerebellopontine angle. The case report and a brief review of the literature are presented.

Prospective analysis of incidence and risk factors of dysphagia in spine surgery patients: comparison of anterior cervical, posterior cervical, and lumbar procedures.

STUDY DESIGN: A 3-year prospective, cohort study. OBJECTIVES: To compare the incidence and risk factors of dysphagia after anterior cervical (AC), posterior cervical (PC), and posterior lumbar (PL) spine procedures. SUMMARY OF BACKGROUND DATA: Dysphagia is a known risk of AC surgery; however, comprehensive postoperative swallow evaluations have not been performed for a comparative cohort of AC, PC, and PL surgery patients. METHODS: Eighty-three patients were enrolled in the study, including 38 undergoing AC, 19 PC, and 26 PL procedures. Preoperative and postoperative swallowing evaluations were performed by questioning for subjective swallowing complaints and performing objective radiographic examination. Patients with severe dysphagia leading to an increased risk of aspiration were identified and treated until recovery or for 3 to 9 months. RESULTS: Comparison of preoperative and postoperative swallowing complaints revealed a significant increase for AC patients (P < 0.01) and a trend for PC (P = 0.06) and PL (P = 0.09) patients. Eighteen (47%) AC, 4 (21%) PC, but no PL patients demonstrated dysphagia on postoperative videofluoroscopic swallow evaluation. Age (>60 years, P < 0.01) was associated with increased risk of radiologic evidence of dysphagia. Surgical level, instrumentation, operative time, and presence of myelopathy or other comorbidities were not. Over 70% (12 of 17) of AC patients with dysphagia followed recovered within 2 months, while 23% (4 of 17) required some level of compensatory swallowing behavior up to 10 months following surgery. CONCLUSION: Dysphagia is a common occurrence after AC procedures but was also found after PC procedures. Intubation alone was not a risk factor for postoperative dysphagia in this cohort.

Prognostic value of magnetic resonance imaging-guided stereotactic biopsy in the evaluation of recurrent malignant astrocytoma compared with a lesion due to radiation effect.

OBJECT: The prognostic value of differentiating between recurrent malignant glioma and a lesion due to radiation effect by performing stereotactic biopsy has not been assessed. Thus, this study was undertaken to determine such value. METHODS: Between 1995 and 2001, 114 patients underwent magnetic resonance (MR) imaging-guided stereotactic biopsy to differentiate lesions caused by a recurrence of malignant astrocytoma and by radiation effect. All patients had previously undergone tumor resection (World Health Organization Grade III or IV) followed by radiotherapy. Disease diagnosis based on biopsy and patient characteristics were assessed as predictors of survival according to results of a multivariate Cox regression analysis. The diagnosis determined with the aid of biopsy was compared with that established during a subsequent resection in 26 patients. Survival following stereotactic biopsy was markedly increased in patients suffering from radiation effect compared with those harboring recurrent malignant glioma (p < 0.0001). In patients with radiation effect on biopsy, an increasing patient age (p < 0.05), having had two compared with one prior resection (p < 0.05), and a decreasing time from radiotherapy to biopsy (p < 0.001) were factors associated with decreased survival. Nevertheless, in patients with biopsy-defined radiation effect at second progression or with an age younger than 50 years the survival rate remained higher than that in patients with recurrent tumor on biopsy (p < 0.01). A biopsy-based diagnosis of radiation effect obtained less than 5 months after radiotherapy was not associated with an increased rate of patient survival compared with a diagnosis of recurrent malignant glioma on biopsy (p = 0.286). Eighty-six percent of lesions initially determined to be due to radiation effect on biopsy fewer than 5 months after radiotherapy were characterized as recurrent glioma by a mean of 11 months later. In contrast, only 25% of lesions initially diagnosed as attributable to radiation effect on biopsy more than 5 months after radiotherapy were classified as recurrent glioma a mean of 12 months later (p < 0.05). CONCLUSIONS: With the aid of stereotactic biopsy the authors demonstrated prognostic significance in differentiating recurrent malignant astrocytoma from a lesion due to radiation effect in patients presenting more than 5 months after having undergone radiotherapy. In patients who presented earlier than 5 months after radiotherapy, radiation effect on biopsy was not associated with an improved rate of survival compared with that in patients harboring recurrent malignant astrocytoma.