Intramedullary spinal cord metastases: an institutional review of survival and outcomes

Journal of Neuro-Oncology - Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor...     

Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics

Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon α (IFN-α), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-α in Ad.TK/GCV+ Ad.Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-α release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-α delivered within the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-α, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad.TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-α led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-α-secreting pDCs, we administered an Ad vector encoding B18R, an IFN-α antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-α release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-α, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.     

The characteristics and outcomes of penetrating thoracic and abdominal trauma among children

Purpose

Trauma is the most important etiology of morbidity and mortality among children. Penetrating injuries to the thorax and abdomen are extremely rare in children. In the present study, we compared the characteristics of patients, management, and outcomes of penetrating thoracic and abdominal trauma in children.

Materials and methods

Data from children who were hospitalized for penetrating injuries of the thorax and abdomen from 2006 to 2012 were evaluated retrospectively. These injuries were evaluated with respect to patient details, clinical presentation, circumstances of trauma, management, and outcomes.

Results

Eighty-four patients were hospitalized for penetrating injuries to the thorax and abdomen. The mean age was 10.3 ± 3.79 years. Patient injuries comprised 26 gunshots injuries and 58 stabbing injuries. Thirty-one patients were wounded in the thorax, 43 were wounded in the abdomen, and 10 were wounded in both the thorax and abdomen. Thirty-one patients had undergone surgical interventions, while the other 53 were managed conservatively. The mean hospital stay was 4.41 ± 6.84 days.

Conclusions

The incidences of penetrating abdominal and thoracic trauma did not differ significantly. Penetrating injuries may be successfully managed by conservative therapy.     

Electrophysiological assessment of sexual dysfunction in spinal cord injured patients

STUDY DESIGN: Survey. OBJECTIVES: To determine associations between sexual dysfunctions and electrophysiological examinations of the genital system in spinal cord injured patients. SETTING: Ege University Hospital, Izmir, Turkey. METHODS: In total, 25 patients (17 men, eight women) who were out of the spinal shock period were examined. Neurological levels were determined according to the American Spinal Injury Association (ASIA) impairment scale. Data about erection, ejaculation and vaginal lubrication were obtained via inquiry forms. Bulbocavernosus reflex (BCR), pudendal somatosensorial evoked potentials (pSEP) and perineal sympathetic skin responses (pSSR) were recorded by an electromyographer unaware of the sexual state or neurological level of the patient. RESULTS: BCRs could be obtained from all patients with lesion levels above the sacral centre. A significant association was found between reflex erection and BCR positivity, while psychogenic erection was shown to have a significant association with the preservation of pSSR in men. Despite the lack of statistical significance due to the small sample size of the women examined, a similar association with lubrication was observed. Ejaculation and orgasm were not shown to be significantly associated with any electrophysiological examination. However, ejaculation was preserved in all men with a lesion level below T12 and with positive pSSR. There was no significant relationship between pSEP and sexual functions. The relationship between the existence of sacral sensation and pSEP positivity was statistically significant. CONCLUSION: This study has proved that BCR and pSSR have an important role in the estimation of the remaining sexual function in spinal cord injured patients. STATEMENT ON ETHICS: We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research.     

Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model

Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-?? or interleukin-2 to enhance effector T-cell functions, and 7) I??B?? or p65RHD (nuclear factor kappa-B [NF-??B] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-?? staining. Our data showed that overexpression of interferon-?? or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.     

Use of mometasone furoate aqueous nasal spray in the treatment of rhinitis medicamentosa: an experimental study.

OBJECTIVE: We aimed to investigate, histopathologic changes in the nasal mucosa of guinea pig's after prolonged administration of oxymetazoline and the development of rhinitis medicamentosa, and the efficacy of mometasone furoate aqueous nasal spray and saline in reversing the ultrastructural changes attributable to rhinitis medicamentosa. METHODS: In the study, 24 male guinea pigs (500 to 600 gr) were used. Oxymetazolin (0.05%) was sprayed into the nasal cavities of the guinea pigs 3 times daily for 8 weeks. At the end of this period, 6 guinea pigs were killed and examined to make sure that the animals had developed rhinitis medicamentosa. The remaining guinea pigs were randomly divided into 3 groups. In the first group, one spray-puff of 0.05% mometasone furoate aqueous nasal spray (50 microg) was applied twice daily for 14 days. In the second group, saline solution (0.9% NaCl) was applied twice daily for 14 days. No treatment was performed in the third group. At the end of the treatment period, nasal mucosal changes were evaluated by light microscopy and electron microscopy. RESULTS: After oxymetazolin application for 8 weeks, the main histologic changes were edema, congestion, proliferation of subepithelial glands, and squamous cell metaplasia. After topical mometasone furoate aqueous spray application for 2 weeks, the edema fluid was found to diminish markedly. In the saline and no treatment groups, edema and congestion continued. In these groups of guinea pigs, fibrosis has been seen in the nasal mucosa. CONCLUSION: We found that mometasone furoate nasal spray was effective against experimentally induced rhinitis medicamentosa in guinea pigs. Mometasone furoate nasal spray may have value in the treatment of patients with rhinitis medicamentosa.     

Protective role of osteopontin in endodontic infection

Endodontic infections are polymicrobial infections resulting in bone destruction and tooth loss. The host response to these infections is complex, including both innate and adaptive mechanisms. Osteopontin (OPN), a secreted, integrin‐binding protein, functions in the regulation of immune responses and enhancement of leucocyte migration. We have assessed the role of OPN in the host response to endodontic infection using a well‐characterized mouse model. Periapical bone loss associated with endodontic infection was significantly more severe in OPN‐deficient mice compared with wild‐type 3 weeks after infection, and was associated with increased areas of inflammation. Expression of cytokines associated with bone loss, interleukin‐1α (IL‐1α) and RANKL, was increased 3 days after infection. There was little effect of OPN deficiency on the adaptive immune response to these infections, as there was no effect of genotype on the ratio of bacteria‐specific immunoglobulin G1 and G2a in the serum of infected mice. Furthermore, there was no difference in the expression of cytokines associated with T helper type 1/type2 balance: IL‐12, IL‐10 and interferon‐γ. In infected tissues, neutrophil infiltration into the lesion area was slightly increased in OPN‐deficient animals 3 days after infection: this was confirmed by a significant increase in expression of neutrophil elastase in OPN‐deficient samples at this time‐point. We conclude that OPN has a protective effect on polymicrobial infection, at least partially because of alterations in phagocyte recruitment and/or persistence at the sites of infection, and that this molecule has a potential therapeutic role in polymicrobial infections.     

The effects of losartan and immobilization stress on heart rate variability and plasma corticosterone levels in rats

In this study, the effects of losartan, an angiotensin II receptor antagonist, on heart rate variability and the changes of plasma corticosterone levels caused by immobilization stress were investigated. Losartan (3 mg/kg, p.o.) significantly prevented increases in plasma corticosterone levels in both losartan+acute stress and losartan+chronic stress groups. But, losartan did not prevent the diminution of the power of heart rate variability caused by stress. Our results supported the idea that the renin-angiotensin system is also involved in the stress- induced cardiovascular response, besides the autonomic nervous system. But, the effects of losartan on heart rate variability remained controversial.     

Losartan may prevent the elevation of plasma glucose levels induced by chronic stress

The effect of angiotensin II antagonist, losartan, on chronic stress-induced elevation of blood glucose levels was investigated in rats. Chronic immobilization stress caused an increase in blood glucose levels in rats. Administration of losartan (3 mg/kg, po) before stress exposure significantly prevented this increment. We suggest that losartan showed this effect by decreasing the excessive sympathetic response to stress. In conclusion, there is a relationship between stress, sympathetic nervous system, and renin-angiotensin system.