Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy’s history,efficacy and application in humans

Hyperthermia therapy (HT) is the exposure of a region of the body to elevated temperatures to achieve a therapeutic effect. HT anticancer properties and its potential as a cancer treatment have been studied for decades. Techniques used to achieve a localised hyperthermic effect include radiofrequency, ultrasound, microwave, laser and magnetic nanoparticles (MNPs). The use of MNPs for therapeutic hyperthermia generation is known as magnetic hyperthermia therapy (MHT) and was first attempted as a cancer therapy in 1957. However, despite more recent advancements, MHT has still not become part of the standard of care for cancer treatment. Certain challenges, such as accurate thermometry within the tumour mass and precise tumour heating, preclude its widespread application as a treatment modality for cancer. MHT is especially attractive for the treatment of glioblastoma (GBM), the most common and aggressive primary brain cancer in adults, which has no cure. In this review, the application of MHT as a therapeutic modality for GBM will be discussed. Its therapeutic efficacy, technical details, and major experimental and clinical findings will be reviewed and analysed. Finally, current limitations, areas of improvement, and future directions will be discussed in depth.     

Effect of cumulus cell mass and follicle quality on in-vitro maturation of cynomolgus monkey oocytes

Cynomolgus monkey oocytes were recovered from healthy or atreticfollicles > 1000 µm in diameter at day 8 of gonadotrophinstimulated cycles and cultured in vitro, cumulus enclosed orcumulus free, for 2 days. Germinal vesicle breakdown (GVBD)occurred in 26.7% of healthy cumulus enclosed oocytes (n= 60)compared to 52.6% of atretic cumulus enclosed oocytes (n = 38).The mechanical removal of the cumulus cell mass increased theGVBD rate of the healthy oocytes (56.5%, n = 23) and acceleratedthe passage of the atretic oocytes (n = 23) from metaphase I(4.3%) to metaphase II (47.8%). In the healthy primate follicle,the dktyate stage could be maintained by aninhibitory substancesecreted by the cumulus; foUicular atresia could either decreasethe synthesis of this substance and/or induce the metabolismof a stimulatory substance.     

Beneficial effects of coculture with cumulus cells on blastocyst formation in a prospective trial with supernumerary human embryos

Purpose: We reported previously on the use of coculture with cumulus cells in insemination medium for the development of human embryos in vitro. Here we describe a prospective trial to determine if this procedure has a significant beneficial effect. Methods: On the day after insemination, zygotes were randomized for culture in either a fresh drop of medium without (– cum) or were left in their insemination drop with (+ cum) cumulus cells. Embryos with the best morphological quality were replaced on the third day of development at the eight-cell stage. The remaining embryos were cultured for a further 3 days and cryopreserved if they reached the fully expanded blastocyst (FEB) stage. Three different culture media were used over the period of this study. Results: In 11 patients, supernumerary embryos were available only for continued culture in + cum and three patients had embryos cultured in only – cum. Thirty-nine other patients had embryos assigned to both + cum and – cum treatments. In the + cum group, 98 blastocysts developed from 216 embryos cultured for 6 days (45%), and this was significantly greater (P<0.01) than the 48 blastocysts from 156 embryos (31%) developing in the absence of cumulus cells. In basal HTF medium (HTF medium with EDTA and glutamine) and basal XI HTF medium (similar to basal HTF but devoid of glucose and phosphate), culture of embryos with cumulus cells produced significantly more FEBs than in the absence of cumulus cells. There was no significant difference between the two culture treatments when regular HTF medium was used. Preliminary results indicate that pronectin-coated dishes provide a good substratum for cumulus cell attachment and embryo development. Conclusions: The culture of human embryos with their cumulus cells in insemination drops of medium produces a significantly greater proportion of FEBs than when the zygotes are transferred to fresh culture drops devoid of cumulus cells. This is the first report of a significantly higher blastocyst rate with coculture in which a real comparison has been made between two culture treatments which differ only in the presence or absence of homologous cumulus cells in insemination drops.Presented in part at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction. Vienna, Austria. April 3–7, 1995.     

Apoptosis in human cumulus cells in relation to zona pellucida thickness variation, maturation stage, and cleavage of the corresponding oocyte after intracytoplasmic sperm injection

OBJECTIVE: To assess the degree of apoptosis in the cumulus cells and the variation of the zona pellucida and the maturity and fertilization of the corresponding oocyte. DESIGN: Retrospective study. SETTING: Private fertility clinic. PATIENT(S): Fifty couples undergoing ICSI. INTERVENTION(S): ICSI. MAIN OUTCOME MEASURE(S): Correlation between apoptosis in the cumulus cells and the zona pellucida thickness variation, maturation stage, fertilization rate, and embryo score. RESULT(S): This study demonstrated no correlation between apoptosis in cumulus cells and the thickness and variation of the zona pellucida in oocytes and embryos. The incidence of apoptosis was significantly higher in cumulus cells from empty zona pellucidas and germinal vesicle stage and metaphase I oocytes compared with metaphase II oocytes. Non-fertilized metaphase II oocytes showed significantly higher incidence of apoptosis compared with fertilized metaphase II oocytes. There was a correlation between embryo score and the zona pellucida thickness variation. CONCLUSION(S): Apoptosis in cumulus cells had no impact on the zona pellucida thickness and variation in oocytes and embryos. The zona pellucida thickness variation was positively correlated to good embryo score. A higher degree of apoptosis was seen in cumulus cells from immature oocytes compared with mature oocytes. Furthermore, apoptosis in cumulus cells impaired the fertilization rate of metaphase II oocytes after ICSI.     

Convection enhanced delivery for the treatment of malignant gliomas: symposium review

Summary In January 2003 a symposium was held to discuss the current state of progress and future challenges for the recently described technique of convection enhanced delivery (CED). The focus of the CED symposium was on the potential use of this novel drug delivery technology to enhance the delivery of chemotherapy to malignant brain tumors. The international panel of invited speakers included individuals who had a significant role in pioneering the concept of CED, were actively pursuing new areas of investigation into the uses of CED and/or who were directing the first clinical trials using CED in patients with malignant brain tumors. Topics covered included the physiology of the blood brain barrier, basic principles of CED, application of CED to the treatment of brain tumors, and research models that have been developed to further refine the technique of CED. Each speakers talk has been abstracted and a list of relevant references has been compiled.     

Pregnancies resulting from in vitro matured oocytes collected from women with regular menstrual cycle

Purpose: To demonstrate that human immature oocytes retrieved from women with regular menstrual cycles can undergo maturation and fertilization, and that the resulting embryos can establish pregnancies.Methods: Immature oocytes (n = 568) were retrieved from women with regular menstrual cycle. The intact immature oocytes (n = 506) were allowed to mature in YS medium supplemented with 70% human follicular fluid (hFF); the matured oocytes were fertilized with husband sperm. Two pronuclei oocytes were cocultured with cumulus cells in YS medium supplemented with 10% hFF until 2 or 3 days after insemination. The cleaved embryos were transferred in uteri.Results: Follicles were aspirated on Day 9.2 ± 5.3 of 63 natural cycles from 51 patients (mean age = 34.8 ± 4.0 years). The average number of retrieved immature oocytes was 9.0. The maturation rate was 74.3% (376/506). The two PN and cleavage rates were 72.6% (273/376) and 89.0% (243/273), respectively. Embryo transfer was achieved in 51 cycles and clinical pregnancy rate was 17.6% (9/51).Conclusions: The results suggest that in vitro matured oocytes can undergo fertilization and the resulting embryos may successfully lead to pregnancies. However, further research is needed to improve IVM technique to achieve success rate comparable to gonadotrophin stimulated cycles.     

Leukemia Inhibitory Factor Decreases the Arylamine N-Acetyltransferase Activity in Human Cumulus Granulosa Cells

Purpose: To evaluate the activities of acetyl coenzyme A (AcCoA): arylamine N-acetyltransferase (NAT) of intact cumulus granulosa cells and the role of leukemia inhibitory factor (LIF) upon their NAT activities. Methods: Thirty women accepted controlled ovarian hyperstimulation (COH) and oocyte retrievals. Human cumulus granulosa cells were obtained during oocyte retrievals. Using 2-aminofluorene (2-AF) and p-aminobenzoic acid (PABA) as substrates, NAT activity of all samples was determined by high pressure liquid chromatography. After the incubation with different time and concentrations of 2-AF, PABA, and LIF, 2-acetyl-aminofluorene (2-AAF) and N-acetyl-PABA (N-Ac-PABA) were measured. Results: After incubation with 2.812, 5.625, 11.25, and 22.5 M of 2-AF/PABA, their product concentrations (2-AAF/N-Ac-PABA) were 0.42/0.32, 0.76/0.58, 1.29/1.04, and 1.94/1.26 nmol/10⁶ cells, respectively. After 6, 12, 18, and 24 h incubation with 11.25 M of 2-AF/PABA, their product concentrations were 0.19/0.12, 0.56/0.4, 0.98/0.79, and 1.3/1.0 nmol/10⁶ cells, respectively. After incubation with 0, 5, and 50 M of LIF, the 2-AAF/N-Ac-PABA concentrations were 0.98/0.80, 0.70/0.52, and 0.49/0.30 nmol/10⁶ cells, respectively. Conclusion: Intact human cumulus granulosa cells could acetylate arylamine carcinogen (2-AF) and noncarcinogens drug (PABA). LIF decreased the NAT activities. It provides a model for monitoring the effects of COH and LIF upon the oocytes.     

Effect of removal of cumulus cells from one-cell mouse embryos on in vitro development

The effects of the removal of cumulus cells from fertilized mouse oocytes (one-cell embryos) and the presence of streptomycin in culture medium on in vitro development were studied. Ham's F-10 medium with (0.075 g/liter) or without streptomycin was supplemented with human serum (15%). Cumulus-intact embryos were harvested from oviducts after mice were superovulated with pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). Hyaluronidase (300 IU/ml) was used to remove the cumuli. Embryos were cultured (i) with cumulus/without streptomycin (n=238), (ii) with cumulus/with streptomycin (n=185), (iii) without cumulus/with streptomycin (n=210), and (iv) without cumulus/without streptomycin (n=218). Embryonic development was assessed 24, 96, and 120 hr after initiation of culture. Percentage two cells and percentage small or expanded blastocysts were not different (P>0.05) among experimental groups. Percentages hatched blastocysts for the four groups were (i) 36±8 and 54±7, (ii) 35±8 and 55±6, (iii) 19±5 and 42±6, (iv) 23±5 and 47±5 at 96 and 120 hr, respectively. Percentages all (small, expanded, and hatched combined) blastocysts were (i) 74±5 and 74±5, (ii) 74±9 and 72±5, (iii) 56±6 and 63±5, and (iv) 61±5 and 63±5 at 96 and 120 hr, respectively. A greater (P<0.05) percentage of embryos developed to blastocysts and hatched by 96 and 120 hr, when they were cultured with the cumulus intact. There was no effect of streptomycin on embryonic development. Cumulus cells may act as nurse cells during a critical stage of the development of the embryo.