Thomas Carter

Ipilimumab and Bevacizumab in Glioblastoma

The median survival in glioblastoma is just over a year, with no standard second-line therapy. Ipilimumab is an immune checkpoint inhibitor that activates the anti-tumour immune response by cytotoxic T-lymphocyte antigen-4 blockade. There is significant evidence supporting its role in the treatment of malignant melanoma, including in patients with brain metastases. The addition of the anti-angiogenesis agent, bevacizumab, seems to offer additional benefit and limit the immune-related side-effects of ipilimumab in melanoma. To date there have been no clinical trials investigating this combination in glioblastoma. In this single practice case series, 20 patients with glioblastoma were consented for and treated with ipilimumab and bevacizumab in combination. Safety, tolerability and the response to treatment were reviewed for all patients. Three patients were treated after palliative first-line radiotherapy, one patient after first-line chemoradiation and 16 patients were treated with recurrent disease. Sixty-five per cent of patients completed four cycles of 3 weekly ipilimumab therapy, administered with 2 weekly bevacizumab. Radiographic responses for patients with recurrent disease were evaluated by Response Assessment in Neuro-oncology (RANO) criteria; 31% of patients showed a partial response, 31% had stable disease and 38% had disease progression. The treatment combination was well tolerated, with treatment terminated before completion due to adverse events in two patients. Autoimmune toxicity was manageable with systemic corticosteroid therapy. Ipilimumab and bevacizumab in combination show promising activity with a predictable and manageable toxicity profile, warranting further clinical studies.

Dabrafenib in BRAFV600-mutated anaplastic pleomorphic xanthoastrocytoma

Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor. Anaplastic features are found in 20-30% of cases of PXA and are associated with poor outcomes. Typical treatment is with gross total resection, followed by radiation therapy and cytotoxic chemotherapy at relapse. BRAFV600 mutations have been identified in 38-60% of patients with PXA. Several case reports and small case series have identified clinical benefit with BRAF inhibition in patients with BRAFV600-mutated PXA. We report the second published case of successful treatment with the BRAF inhibitor dabrafenib in a female patient with relapsed anaplastic PXA with a BRAFV600 mutation, and the first published case of dabrafinib treatment following intolerance to vemurafenib.

Antibody-targeted nanoparticles for cancer treatment

Nanoparticles (NPs) are diverse and versatile with physical properties that can be employed for use in cancer medicine. Targeting NPs using antibodies and antibody fragments could overcome some of the limitations seen with current targeted therapies. This review will discuss the role of antibody-targeted NPs in the treatment of cancer: as delivery vehicles, targeted theranostic agents and in the evolving field of cancer hyperthermia.

Dabrafenib and trametinib in BRAFV600E mutated glioma

BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib.

Fucoidan Prolongs the Circulation Time of Dextran-Coated Iron Oxide Nanoparticles

The magnetic properties and safety of dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) have facilitated their clinical use as MRI contrast agents and stimulated research on applications for SPIONs in particle imaging and magnetic hyperthermia. The wider clinical potential of SPIONs, however, has been limited by their rapid removal from circulation via the reticuloendothelial system (RES). We explored the possibility of extending SPION circulatory time using fucoidan, a seaweed-derived food supplement, to inhibit RES uptake. The effects of fucoidan on SPION biodistribution were evaluated using ferucarbotran, which in its pharmaceutical formulation (Resovist) targets the RES. Ferucarbotran was radiolabeled at the iron oxide core with technetium-99m (99mTc; t1/2 = 6 h) or zirconium-89 (89Zr; t1/2 = 3.3 days). Results obtained with 99mTc-ferucarbotran demonstrated that administration of fucoidan led to a 4-fold increase in the circulatory half-life (t1/2 slow) from 37.4 to 150 min (n = 4; P < 0.0001). To investigate whether a longer circulatory half-life could lead to concomitant increased tumor uptake, the effects of fucoidan were tested with 89Zr-ferucarbotran in mice bearing syngeneic subcutaneous (GL261) tumors. In this model, the longer circulatory half-life achieved with fucoidan was associated with a doubling in tumor SPION uptake (n = 5; P < 0.001). Fucoidan was also effective in significantly increasing the circulatory half-life of perimag-COOH, a commercially available SPION with a larger hydrodynamic size (130 nm) than ferucarbotran (65 nm). These findings indicate successful diversion of SPIONs away from the hepatic RES and show realistic potential for future clinical applications.

Adjuvant Chemotherapy is Indicated in Patients with Lower Grade Glioma

The addition of chemotherapy to radiotherapy (RT) following surgery in patients with low grade glioma prolongs survival. In the recently published long-term follow-up of a randomised phase 3 trial, Buckner et. al reported 254 patients with high-risk WHO Grade II oligodendroglioma, oligoastrocytoma, or astrocytoma, randomised to either receive RT alone or RT followed by 12 months of procarbazine, vincristine and lomustine (PCV) chemotherapy [1]. In this study, high-risk was defined as patients aged 40 and over, or patients under 40 who had undergone subtotal resection or biopsy. Median follow up was 11.9 years by which time 67% had disease progression and 55% of patients had died. The addition of PCV to RT improved median overall survival (mOS) from 7.8 to 13.3 years (HR 0.59 p=0.003), and 10-year survival increased from 40% to 60%. Survival benefit was seen in all histological subtypes, although not statistically significant in astrocytomas (oligodendroglioma: HR 0.43 [95% CI 0.23-0.82] p=0.009; oligoastrocytoma: HR 0.56 [0.32-1.00] p=0.05; astrocytoma: HR 0.73 [0.401.34] p=0.31). Patients with isocitrate dehydrogenase 1 (IDH1) R132 mutation also had significant survival benefit from the addition of PCV (HR 0.42 [0.20-0.86] p=0.02), but conclusions were not made for patients with 1p19q co-deletion or with IDH wild-type tumours. Of note, patients who were randomised to RT alone were more likely to receive further treatment, but only 56% received chemotherapy, reasons for which are unclear.

Regional-Local Executive Branch Conflict in El’tsin’s Russia: the role of boundary control in Sverdlovsk Oblast

Download this article from UCL Discovery. Conflicts between regional executive leaders and the executive heads of regional capital cities were a frequent occurrence in El’tsin’s Russia, and were consequences of the rapid decentralization of power that occurred in the first half of the 1990s. This article focuses on the political competition that emerged in Sverdlovsk Oblast between the regional governor Eduard Rossel’ and his counterpart at the local level, Ekaterinburg Mayor Arkadii Chernetskii. It evaluates the key network relationships held by these two actors during the 1990s, and asks how these networks influenced the balance of regional power prior to the federal recentralisation processes of the 2000s. The article applies the strategy of boundary control, as previously applied by Edward Gibson to the study of subnational regional regimes in Latin America under conditions of national democratization;1 in so doing, it considers Rossel’’s hold over regional power as being determined by his approach to representing regional elite interests, both political and economic, which thereby insulated his power from challengers.

Combining Ipilimumab and Bevacizumab in Glioblastoma: Is it Really Safe and Effective? Author Response

Madam d We thank Tini and Pirtoli [1] for their interest in our article ‘Ipilimumab and bevacizumab in glioblastoma’ [2] and we are grateful for the opportunity to respond to their comments. We reported a retrospective review of all glioblastoma patients treated with the immune checkpoint inhibitor ipilimumab and the anti-VEGF agent bevacizumab within a single institution. The article provides information on toxicity and tolerability, including in patients who concurrently received temozolomide (eight patients) or lomustine (six patients). Individual patient data are presented in table format. In the radiographic response analysis only patients with recurrent disease were included. These data may be helpful for the design of future clinical trials using ipilimumab and bevacizumab in glioblastoma. This article was prepared to generate interest in the use of immunotherapeutic agents in glioblastoma. We reported 31% partial response, 31% stable disease and 38% disease progressionwith combination treatment, with performance status maintained or improved for 12 of the 14 patients with either partial response or stable disease. It is noted within the conclusions that these data were nonrandomised, involve small patient numbers but warrant further investigation in formal prospective clinical trials. Although responses were assessed using RANO criteria, the recently reported iRANO guidelines [3] could usefully contribute to future analyses. Toxicity data were reported regardless of causality. The grade 3 or above adverse event rate of seven in 20 patients (35%) compares with rates of 46% for ipilimumab alone in advanced melanoma [4], 46.4% for bevacizumab alone in recurrent glioblastoma [5] and 32.5% for bevacizumab in newly diagnosed glioblastoma [6,7]. Two patients had treatment terminated early due to adverse events (10%). Hence, ipilimumab and bevacizumab in combination show promising activity with a predictable and manageable toxicity profile, warranting further clinical studies.

Optical nanoparticles: general discussion

Hedi Mattoussi responded: The use of a multi-coordinating polymer ligand having several histidine groups for surface coordination may be benecial for gold nanorods (AuNRs). These NRs tend to have large surface areas, and a polymer structure provides stronger binding and better interactions with the hydrophilic surrounding medium. Multi-thiol polymer coating would also provide stronger affinity, nonetheless. I should also stress the importance of using a PEGrich polymer for these systems.