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.     

Current status of bone graft options for anterior interbody fusion of the cervical and lumbar spine

Anterior cervical discectomy and fusion (ACDF) and anterior lumbar interbody fusion (ALIF) are common surgical procedures for degenerative disc disease of the cervical and lumbar spine. Over the years, many bone graft options have been developed and investigated aimed at complimenting or substituting autograft bone, the traditional fusion substrate. Here, we summarise the historical context, biological basis and current best evidence for these bone graft options in ACDF and ALIF.     

3D-printed spine surgery implants: a systematic review of the efficacy and clinical safety profile of patient-specific and off-the-shelf devices

Three-dimensional printing (3DP), or additive manufacturing, is an emergent fabrication technology for surgical devices. As a production method, 3DP enables physical realisation of surgical implants from geometrically complex digital-models in computer-aided design. Spine surgery has been an innovative adopter of 3DP technology for both patient-specific (PS) and market-available ‘Off-The-Shelf’ (OTS) implants. The present study assessed clinical evidence for efficacy and safety of both PS and OTS 3DP spinal implants through review of the published literature. The aim was to evaluate the clinical utility of 3DP devices for spinal surgery. A systematic literature review of peer-reviewed papers featured on online medical databases evidencing the application of 3DP (PS and OTS) surgical spine implants was conducted in accordance with PRISMA guidelines. Twenty-two peer-reviewed articles and one book-chapter were eligible for systematic review. The published literature was limited to case reports and case series, with a predominant focus on PS designs fabricated from titanium alloys for surgical reconstruction in cases where neoplasia, infection, trauma or degenerative processes of the spine have precipitated significant anatomical complexity. PS and 3DP OTS surgical implants have demonstrated considerable utility for the surgical management of complex spine pathology. The reviewed literature indicated that 3DP spinal implants have also been used safely, with positive surgeon- and patient-reported outcomes. However, these conclusions are tentative as the follow-up periods are still relatively short and the number of high-powered studies was limited. Single case and small case series reporting would benefit greatly from more standardised reporting of clinical, radiographic and biomechanical outcomes. These slides can be retrieved under Electronic Supplementary Material.     

Successful cranio-cervical fusion in a patient with Down syndrome

We present a patient with Down syndrome with neck pain and severe cervical myelopathy. Imaging revealed occipito-atlantal and atlanto-axial instability with severe spinal cord compression. There are no standardized radiological or clinical guidelines to aid in managing this unique subset of patients. We demonstrate a successful occiput–C3 internal fixation and fusion without complication. Due to the largely unknown natural history and ongoing management difficulties in this population, we demonstrate a case that may aid future decision making for this specialized field. We also discuss an approach to reduce this deformity, which, to our knowledge, has not been published before.     

Estrogen receptor messenger RNA expression in rat hypothalamus as a function of genetic sex and estrogen dose

Previously, we showed that estrogen receptor (ER) messenger RNA (mRNA) levels are decreased in cells of the mediobasal hypothalamus of ovariectomized (OVX) female rats following an acute estradiol treatment. Here, we examined whether the level of ER mRNA remains depressed in the continued long-term presence of estradiol, and questioned if there is a systematic relationship between the concentration of estradiol and the decrease in ER mRNA level. OVX female rats were implanted for 2 weeks with silastic capsules containing various concentrations of estradiol. Tissue sections were hybridized with a [3H] single-stranded DNA probe prepared from the region of the rat ER complementary DNA corresponding to the steroid binding domain, and relative mRNA level was assessed by counting grains over cells in specific hypothalamic nuclei. Estradiol induced a dose-dependent decrease in ER mRNA levels. Message levels declined in the ventrolateral aspect of the ventromedial nucleus (VLVM) by 57% and in the arcuate nucleus by 62% at the highest hormone concentrations used. Thus, ER mRNA down-regulation in female rat hypothalamus exhibits orderly dose dependence at a time following hormone treatment which ensures the system is at steady state. A second study determined if there exist differences in basal levels of ER mRNA expression between castrated (CAS) females and males, and if estradiol can down-regulate ER mRNA levels in male hypothalamus. CAS rats of both sexes were exposed acutely to estradiol benzoate (EB) for different periods of time. Again, in females, EB significantly decreased ER mRNA levels in VLVM by 55% (18 h) and in the arcuate nucleus by 74% (18 h). Interestingly, control CAS males had significantly lower basal ER mRNA levels than OVX females (52% lower than female levels in VLVM; 56% in arcuate), suggesting a sex difference in constitutive expression levels. Moreover, EB failed to down-regulate significantly ER message levels in males. There was no significant effect of sex or EB treatment on ER mRNA levels in medial amygdala. Thus, the second study shows sex differences and brain-region specificity in hormonal regulation of ER mRNA. These findings show that differences in basal levels and regulation of ER mRNA could be a substrate for sex differences in ER concentrations in the hypothalamus of the rat, and further raise the possibility of sex differences in concentrations of nuclear proteins related to the control of ER gene expression.     

Immunohistochemical characterization of a 183 KD myeloid-specific-DNA- binding protein in B5 fixed, paraffin-embedded tissues, and bone marrow aspirates by monoclonal antibody BM-1

A monoclonal antibody, designated BM-1, which is reactive in B5 formalin-fixed, paraffin-embedded tissues, has been generated against a cytoplasmic and nuclear antigen expressed in human myeloid precursor cells and derived leukemias. Using the avidin-biotin-complex immunoperoxidase procedure, BM-1 was found to stain selectively myeloid precursor cells in normal bone marrow and mature granulocytes in the blood. In a screen of 26 normal adult and fetal human organs fixed in B5 formalin, BM-1 was negative in all nonhematopoietic tissues with the exception of tissue granulocytes and scattered cells in the peripheral cortex of the thymus. Likewise a screen of 30 solid tumor cell lines including a spectrum of carcinomas, sarcomas, and neural-derived tumors was negative. BM-1 was also negative with 21 T and B cell lymphomas and 11 Hodgkin's disease tumors. A preliminary study of tumors of the hematopoietic system revealed that BM-1 was reactive with M2 and M3 acute myelogenous leukemias (AML), chronic myelogenous leukemias (CML) and myelomonocytic leukemias, and granulocytic sarcomas. M1, M4, M5, and M6 AML clot preparations were negative in this study, indicating that BM-1 may have a role in the histopathologic diagnosis of myelogenous leukemia. Myeloid leukemic cell lines HL-60, ML-2, KG1, and TPH-1-O showed BM-1 nuclear and/or cytoplasmic reactivity in a subpopulation of cells, but erythroid and lymphoid leukemias and all lymphoma cell lines were negative. Immunoperoxidase studies of a panel of fetal tissues showed BM-1 positive cells in the peripheral cortex of the thymus and portal myelopoietic regions of the liver at 18 weeks gestation. Finally, DNA-cellulose and solid phase radioimmunoassay (RIA) techniques developed in our laboratory demonstrate that the BM-1 antigenic domain is reactive only after binding to eukaryotic but not prokaryotic single- or double-stranded DNA. Immunoblot techniques using a DNA-cellulose purified protein sample revealed that BM-1 recognizes a 183 kD protein. These studies indicate that BM-1 is recognizing a myeloid-specific antigen that, because of its DNA binding characteristics, may have an important role in the differentiation of myeloid cells at the molecular level.