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Background Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. Objectives To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy. Methods A multicentre, retrospective, observational study of CPI-associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019. Results In total, 7391 patients were identified. CPI-associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%. Conclusions CPI-associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)-associated bullous pemphigoid is a rare dermatological immune-related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%.Clinical presentation is variable, with one-quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom.The median time to diagnosis is 12 months and irAEs rarely present after cessation of treatment. Time to onset of symptoms is longer with a single CPI, but with a shorter duration of symptoms compared with combination CPI therapy.Most patients had cutaneous melanoma, of which 81% were BRAF wildtype.

Background Expression of neuron-glial antigen 2 (NG2) identifies an aggressive malignant phenotype in glioblastoma (GBM). Mouse models have implicated NG2 in the genesis, evolution, and maintenance of glial cancers and have highlighted potential interactions between NG2 and epidermal growth factor receptor (EGFR). However, it is unknown whether the lineage relationship of NG2+ and NG2− cells follows a hierarchical or stochastic mode of growth. Furthermore, the interaction between NG2 and EGFR signaling in human GBM is also unclear. Methods Single GBM NG2+ and NG2− cells were studied longitudinally to assess lineage relationships. Short hairpin RNA knockdown of NG2 was used to assess the mechanistic role of NG2 in human GBM cells. NG2+ and NG2− cells and NG2 knockdown (NG2-KD) and wild type (NG2-WT) cells were analyzed for differential effects on EGFR signaling. Results Expression of NG2 endows an aggressive phenotype both at single cell and population levels. Progeny derived from single GBM NG2− or GBM NG2+ cells consistently establish phenotypic equilibrium, indicating the absence of a cellular hierarchy. NG2 knockdown reduces proliferation, and mice grafted with NG2-KD survive longer than controls. Finally, NG2 promotes EGFR signaling and is associated with EGFR expression. Conclusions These data support a dynamic evolution in which a bidirectional relationship exists between GBM NG2+ and GBM NG2− cells. Such findings have implications for understanding phenotypic heterogeneity, the emergence of resistant disease, and developing novel therapeutics.

BACKGROUND Brain metastasis (BM) and leptomeningeal disease (LMD) are typified by a poor prognosis and are an area of unmet clinical need. Historically, patients with central nervous system (CNS) disease have been excluded from systemic therapy clinical trials, particularly with active/leptomeningeal disease. However, increasing prevalence of CNS metastasis is leading to greater interest in BM/LMD. We performed a descriptive analysis of clinical studies investigating BM/LMD management, published between Jan 2010 to Mar 2020. METHODS A comprehensive, customised search strategy was devised for 12 online bibliographic databases, using the following concepts: “clinical study”, “brain metastasis”, “leptomeningeal disease”, “intervention”, “patient-related outcome”. Double screening for inclusion/exclusion was performed on the Rayyan QCRI web application. Published abstracts were also screened for inclusion from ASCO, ESMO, SNO and EANO between 2015–2020. Following full text screening, conflicts were resolved by consensus and data were extracted using an online standardised tool. Data analysis and data visualisation were performed on the R statistical package. RESULTS Overall, 33118 published studies were double screened; 2632 full publications and 628 abstracts were included. Of these, 14.7% reported on unique interventional clinical trials (phase 2 = 267; phase 3 = 80). More than three times the number of clinical trials investigating systemic agents as the sole therapy for BM/LMD were published in Q1 2020 compared to the whole of 2010 (16 vs 5). 42.5% of clinical trials employed a form of local therapy (brain targeted radiotherapy or neurosurgery). Studies reported on patients with BM (n = 2738), LMD (n = 110) or both (n = 119). The majority of studies were performed in North America, Europe or East Asia (88.5% vs 11.5% rest of the world). The top 3 nations involved in published studies were the USA (n = 1155), China (n = 351) and Germany (n = 334). Network analysis demonstrated increasing links between countries. In line with expected BM prevalence, the main tumour sites studied were lung (23.4%), gastrointestinal (17.5%), breast (15%) and melanoma (12.5%). A rising trend of published BM/LMD studies over time was noted, with 83 observational studies/10 clinical trials in 2010 vs. 454 observational studies/80 clinical trials in 2019. CONCLUSION These findings demonstrate that over the last decade there has been a growth in BM/LMD research; likely reflecting an increasing disease prevalence, availability of novel and potentially CNS active agents, as well as more advanced local therapy modalities. BM/LMD clinical research is dominated by a few geographical regions and nations; however, there is an apparent shift to more international collaboration. This comprehensive mapping exercise will enable targeted systematic reviews of the existing evidence base on BM/LMD management.

Glioblastoma, the most common and aggressive adult brain tumor, is characterized by extreme phenotypic diversity and treatment failure. Through fluorescence-guided resection, we identified fluorescent tissue in the sub-ependymal zone (SEZ) of patients with glioblastoma. Histologic analysis and genomic characterization revealed that the SEZ harbors malignant cells with tumor-initiating capacity, analogous to cells isolated from the fluorescent tumor mass (T). We observed resistance to supramaximal chemotherapy doses along with differential patterns of drug response between T and SEZ in the same tumor. Our results reveal novel insights into glioblastoma growth dynamics, with implications for understanding and limiting treatment resistance. Cancer Res; 75(1); 194–202. ©2014 AACR.

The neurosurgical management of patients with intrinsic glial cancers is one of the most rapidly evolving areas of practice. This has been fuelled by advances in surgical technique not only in cytoreduction but also in drug delivery. Further innovation will depend on a deeper understanding of the biology of the disease and an appreciation of the limitations of current knowledge. Here we review the controversial topic of cancer stem cells applied to glioma to provide neurosurgeons with a working overview. It is now recognised that the adult human brain contains regionally specified cell populations capable of self-renewal that may contribute to tumour growth and maintenance following accumulated mutational change. Tumour cells adapted to maintain growth demonstrate some stem-like characteristics and as such constitute a legitimate therapeutic target. Cellular reprogramming technologies raise the potential of developing stem cells as novel surgical tools to target disease and possibly ameliorate some of the consequences of treatment. Achieving these goals remains a significant challenge to neurosurgical oncologists, not least in challenging how we think about treating brain cancer. This review will briefly examine our understanding of adult stem cells within the brain, the evidence that they contribute to the development of brain tumours as tumour-initiating cells, and the potential implications for therapy. It will also look at the role stem cells may play in the future management of glioma.

Temozolomide (TMZ) is the primary chemotherapeutic agent for treatment of glioblastoma multiforme (GBM) yet it has a fast rate of degradation under physiological conditions to the 'active' MTIC, which has poor penetration of the blood-brain barrier and cellular absorption. Herein we have demonstrated binding of TMZ within the cavity of nano-container cucurbit[7]uril, resulting in a decreased rate of drug degradation. Prolonging the lifetime of the TMZ under physiological conditions through encapsulation dramatically improved the drug's activity against primary GBM cell lines as more TMZ could be absorbed by the cells before degradation. This work can potentially lead to increases in the drug's propensity for crossing the blood-brain barrier and absorption into the GBM cells, thereby increasing the efficacy of this chemotherapy.

Glioblastoma (GB), the most common and aggressive adult brain tumor, is characterized by phenotypic diversity and ultimately treatment failure. Using fluorescence-guided sampling we integrated copy number aberration, gene expression and molecular clock data to show that the sub-ependymal zone (SEZ) contains precursor cells of the corresponding mass. The genetically distinct tumor margin contains non self-renewing cells that retain the potential to regenerate the tumor. Functional assays confirmed that SEZ and marginal disease were less clinically aggressive compared to the mass compartment in the same tumor. However, resistance to supra-maximal chemotherapy doses and differential patterns of drug response were observed between compartments. These data provide novel insights into the basis of clinical diversity, poor treatment response and emergence of resistant disease in GB patients. Citation Format: Sara Grazia Maria Piccirillo, Inma Spiteri, Andrea Sottoriva, Anestis Touloumis, Suzan Ber, Stephen J. Price, Richard Heywood, Nicola-Jane Francis, Vincent P. Collins, Ashok R. Venkitaraman, Christina Curtis, John C. Marioni, Simon Tavare’, Colin Watts. The human sub-ependymal zone harbors glioblastoma precursors and represents a distinct therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5016. doi:10.1158/1538-7445.AM2013-5016