Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy

Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-FcγR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific FcγR alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P = 0.03). There was a trend toward patients with the FcγR2A 131-H/H genotype showing a higher response rate than other FcγR2A genotypes (P = 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response.     

Mesenchymal Stem Cells Arrest Intervertebral Disc Degeneration Through Chondrocytic Differentiation and Stimulation of Endogenous Cells

Degenerative disc disease (DDD) is a common disease which affects millions of people. Autograft of the bone marrow derived mesenchymal stem cells (BMSCs) have been shown to have the ability to arrest degeneration in rabbit and canine intervertebral discs. In this study, we have used the mouse model to investigate the mechanism of degeneration arrest. BMSC from Egfp transgenic mice were injected into the degenerated murine intervertebral discs induced by annular puncture. We found that BMSC could arrest the progressive degeneration of the discs with significant regeneration of the nucleus pulposus (NP). In the regeneration, expression of proteoglycan genes were upregulated and extracellular matrix (ECM) progressively accumulated in the NP after BMSC injection. Combined in situ hybridization and immunohistochemistry revealed that BMSC underwent chondrocytic differentiation in the regeneration process. Interestingly, BMSC-induced an increase of endogenous notochordal cells in NP and expression of chondrocytic markers. In this study, we have firstly shown that the BMSC could arrest the degeneration of the murine notochordal NP and contribute to the augmentation of the ECM in the NP by both autonomous differentiation and stimulatory action on endogenous cells.     

Switching between ranibizumab and aflibercept for the treatment of neovascular age-related macular degeneration

The introduction of antivascular endothelial growth factor agents such as ranibizumab and aflibercept has revolutionized the management of neovascular age-related macular degeneration. A number of randomized clinical trials have shown that ranibizumab and aflibercept produce similar efficacy and safety outcomes. Most of the switching studies published to date show that efficacy benefits are uncontrolled, retrospective trials with limitations in terms of their selection, monitoring, numbers, and assessment criteria. Based on the published literature to date, we propose arguments for and against switching antivascular endothelial growth factor agents, provide our own perspective on this topic, and suggest a focus for future research.     

Opioids Switching with Transdermal Systems in Chronic Cancer Pain

Background

Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy

Objective

To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment.

Methods

A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks

Results

Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 ± 20.5 (mean ± SD) to 3.75 ± 8.06, and 33.8 ± 18.9 to 3.75 ± 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment.

Conclusion

Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.     

In vitro angiogenesis by human umbilical vein endothelial cells (HUVEC) induced by three-dimensional co-culture with glioblastoma cells

Glioblastoma multiforme (GBM) is one of the most highly vascularized of all human tumors. Our objective was to characterize a 3-dimensional (3-D) in vitro angiogenesis model by co-culturing HUVEC and GBM cells, and to study the role of VEGF in mediating capillary tubule formation in this model. HUVEC-coated dextran beads were suspended in fibrin gel with human glioma cells on top. The number of sprouts and the length of the processes were measured. HUVEC can be induced to form sprouts and longer processes with lumens, in co-culture with glioma cells that secrete VEGF. Addition of exogenous VEGF enhances this effect. In the absence of glioma cells, many single HUVEC migrate away from the beads, without significant tubule formation. Hypoxia further stimulated sprout formation by 50–100%. Anti-VEGF neutralizing antibody suppressed HUVEC sprouting by 75% in co-culture with glioma cells. This 3-D in vitro co-culture system provides a robust and useful model for analysis of the major steps of glioma-induced angiogenesis.