Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Left atrial appendage occlusion with the Amulet device: to tug or not to tug?

Journal of Interventional Cardiac Electrophysiology - Left atrial appendage occlusion (LAAO) involves a “tug test,” in which implanters pull on the device delivery cable to ensure...     

Correction to: Left atrial appendage occlusion with the Amulet device: to tug or not to tug?

Journal of Interventional Cardiac Electrophysiology - For Fig. 4, an internal working draft of the image depicting the device placed in the heart was erroneously provided during the...     

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity. One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30- to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.     

Proliferation and cytogenetic analysis of hairy cell leukemia upon stimulation via the CD40 antigen

Using the CD40 system, in vitro proliferation of hairy cell leukemia (HCL) was examined in 43 patients. In this culture system, cells were stimulated by interleukin-4 (IL-4) and anti-CD40 monoclonal antibodies (MoAbs) that were added in soluble form or were cross-linked via their Fc part using Fc gamma RII-transfected mouse fibroblast cells. Proliferation was induced and confirmed by 3H-thymidine incorporation in 14 cases and by the presence of metaphases in 42 cases. 3H-thymidine incorporation showed a heterogeneous pattern: cross-linking of anti- CD40 gave the highest proliferation in 8 cases; in 11 cases, stimulation with anti-CD40 MoAbs alone, without cross-linking also resulted in proliferation; the addition of IL-4 further enhanced 3H- thymidine incorporation in 5 cases, but suppressed this phenomenon in 5 other cases. The CD40 system proved to be very effective in obtaining cytogenetic data. With a success rate of 42 of 43 patients tested, we found clonal abnormalities in 8 cases (19%) and nonclonal abnormalities with involvement of one or two abnormal metaphases in another 7 cases. The chromosomes most frequently involved in the abnormal karyotypes, both structurally and numerically, were chromosomes 5, 7, and 14. By fluorescence-activated cell-sorting analysis of the cultured cells, and by immunophenotypic analysis of metaphase spreads, T-cell growth could be excluded and the HCL-lineage confirmed. Stimulation via the CD40 antigen is an excellent tool for growing hairy cell leukemia cells.     

Inhibition and complexation of activated protein C by two major inhibitors in plasma

To determine the major physiologic inhibitors of activated protein C (APC), plasma was incubated with APC or with Protac C and subjected to immunoblotting. APC:inhibitor complexes gave two major bands reacting with antiprotein C antibodies when immunoblotted on nondenaturing gels, and additional minor bands that varied between serum and plasma. Formation of one of the two major bands of APC:inhibitor complex, but not the other, was stimulated by heparin and only this band reacted with antibodies to the previously described APC inhibitor that is here designated PCI-1. Plasma immunodepleted of PCI-1 formed complexes with APC as visualized with antiprotein C but not anti-PCI-1 antibodies, and exhibited heparin-independent inhibition of APC activity, providing evidence for the existence of a second major physiologic APC inhibitor, PCI-2. Formation of APC:PCI-2 complexes in PCI-1-depleted plasma paralleled inhibition of APC amidolytic activity. PCI-2 was separated from PCI-1 and partially purified using column chromatography. PCI-2 formed inactive complexes of approximately 110,000 molecular weight (mol wt) with APC suggesting PCI-2 has an approximate mol wt of 50,000. Thus, inhibition of APC in plasma involves two major distinct 50,000 mol wt inhibitors, the heparin-dependent PCI-1 and the heparin- independent PCI-2.     

Nature and extent of histological changes induced by argon laser photocoagulation in canine gastric mucosa.

The tissue changes in canine gastric mucosa caused by exposure to an argon laser beam vary from mild mucosal oedema to complete cell destruction. Intermediate degrees of damage cause an inflammatory cell response with the formation of granulation tissue, particularly in the submucosa. The rate of healing is similar to that after other forms of injury to the gastric mucosa. Cell destruction at the surface of the mucosa starts with energies greater than 8 Joules on any one spot, and occurs at greater depths as the energy is increased but, unless cells are actually destroyed, the extent of histological damage is limited to a zone 1 mm lateral to, or below, the area exposed to the laser beam. Haemostasis is achieved by thermal contraction of bleeding vessels and of the surrounding tissue, thrombosis only occurring as a secondary effect.     

Recurrent posterior scleritis and orbital myositis as extra-intestinal manifestations of Crohn's disease: Case report and systematic literature review

BackgroundOcular episcleritis and uveitis are well-recognised extra-intestinal manifestations of Crohn's disease. Orbital myositis is rare: to our knowledge it has been associated with Crohn's disease in thirteen cases. Posterior scleritis, orbital myositis and Crohn's disease have been reported as coexisting in only two cases.Methods and resultsWe describe a third case, that of a 31-year old female with Crohn's colitis for 8 years, complicated by enteropathic arthritis and pyoderma gangrenosum. She presented with intense and intractable periorbital pain, particularly at night and worse on eye movements. B-scan ultrasonography confirmed posterior scleritis and treatment with high dose oral steroids (up to 60 mg prednisolone) was initially effective, but subsequently failed to control the inflammation. There was only a partial response to infliximab. Five months after presentation, diplopia developed, with failure of abduction of the left eye. MRI scan of the orbits confirmed orbital myositis involving the left lateral and medial rectus muscles. Pulsed intravenous methylprednisolone and six cycles of intravenous cyclophosphamide over a three month period resulted in complete resolution of inflammatory symptoms.ConclusionsThis case highlights a rare combination of ocular abnormality secondary to Crohn's disease and reports successful resolution with aggressive immunosuppressive therapy.     

Argon laser photocoagulation in the dog stomach.

Laser photocoagulation is one of a number of methods currently under investigation for the endoscopic treatment of gastrointestinal haemorrhage. The Argon ion and Neodymium Yttrium Aluminium Garnet (Nd YAG) lasers are theoretically suitable as the beam from each may be transmitted via a flexible fibre. Argon laser photocoagulation has been shown to be effective and we have elucidated which factors determine its safety and efficacy. Studies on normal canine gastric mucosa showed that the depth of tissue damage depended chiefly on the total incident laser energy on any one spot, and that below 50 J the risk of perforation was extremely low. The energy density was much less important. The haemostatic effect depended more on the laser power. In artificial bleeding gastric ulcers in heparinised dogs the most effective level was 7--9 W, at which 22 out of 23 ulcers (96%) stopped bleeding completely, compared with one out of 12 controls. Photocoagulation was achieved in these cases with energies well within the safe limits. The procedure was effective endoscopically, and these results justify early clinical studies in man.