•Because of a favorable toxicity profile, mycophenolate mofetil is frequently used as long-term immunosuppressive therapy for various autoimmune disorders.•Immunocompromised subjects are prone to ...develop Epstein Barr virus (EBV)-associated primary central nervous system lymphoma (ePCNSL).•We report the first case of ePCNSL in a patient with diffuse cutaneous systemic sclerosis receiving long-term mycophenolate mofetil.•Patients on long-term mycophenolate mofetil should undergo regular surveillance for neurological deficits so that prompt evaluation and management can be initiated.
Epstein Barr virus (EBV)-associated primary central nervous system lymphoma (ePCNSL) is increasingly recognized in immunocompromised subjects, including patients receiving systemic immunosuppressive therapy. Here, we report the first case of primary CNS lymphoma associated with EBV in a patient with diffuse cutaneous systemic sclerosis (dcSSc) receiving long-term mycophenolate mofetil (MMF).
A 51-year-old female with dcSSc had been on MMF 2 grams daily, which was initiated for a rapidly rising modified Rodnan skin score (mRSS), severe pruritus, and progressive joint contractures. She had an impressive response to this therapy with a significant decrease in her mRSS. Her condition remained stable for the next five years, after which she developed worsening headaches for 2–3 weeks, associated with dizziness, gait instability, and left homonymous hemianopia. MRI scan of the brain revealed a solitary 2.4cm peripherally enhancing right parietal lobe mass. Excised tissue from the right parietal lobe mass showed EBV-associated diffuse large B cell lymphoma. She received four cycles of chemotherapy (high dose methotrexate and rituximab). Currently, her condition is being monitored. Her left homonymous hemianopia persists.
Because of a favorable toxicity profile, MMF is increasingly being used as long-term immunomodulatory therapy for a wide variety of autoimmune disorders. Nevertheless, patients on long-term MMF should still undergo regular CNS surveillance, not only for opportunistic infections but also for opportunistic malignancies such as PCNSL. Progressive focal or non-focal neurological deficits should always raise the alarm. Prompt evaluation and management can prevent irreversible neurological sequelae.
Steroids are often utilized to manage patients with non-small cell lung cancer brain metastases (NSCLCBM). Steroids and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with ...decreased overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI). We retrospectively investigated patients treated with ICI after the diagnosis of NSCLCBM at a single tertiary care institution examing the impact of steroids and NLR. Overall survival (OS) and intracranial progression-free survival (PFS) were analyzed. 171 patients treated with ICI for NSCLCBM were included. Thirty-six received steroids within 30 days of the start of ICI, and 53 patients had an NLR ≥ 5 before the start of ICI. Upfront steroids was associated with decreased OS on multivariable analysis (median OS 10.5 vs. 17.9 months, p = .03) and intracranial PFS (5.0 vs. 8.7 months, p = .045). NLR ≥ 5 was indicative of worse OS (10.5 vs. 18.4 months, p = .04) but not intracranial PFS (7.2 vs. 7.7 months, p = .61). When NLR and upfront steroids are modeled together, there is a strong interaction (p = .0008) indicating that the impact of steroids depended on the patient's NLR. In a subgroup analysis, only in patients with NLR < 4 was there a significant difference in OS with upfront steroids (26.1 vs. 15.6 months, p = .032). The impact of steroids on the efficacy of ICI in patients with NSCLCBM is dependent on the patient's NLR underscoring its importance in these patients. Patients with a low NLR, steroid use decreases the efficacy of ICI. These results can inform clinicians about the impact of steroids in patients treated with ICI.
Glioblastoma (GBM), the most common primary malignant brain tumor, remains difficult to treat and shares phenotypes, including an aberrant immune response, with other neurological disorders. ...Understanding the cellular and molecular mechanisms underlying this pathological immune response remains a priority, particularly as standard of care for advanced cancers evolves to include immunotherapies, which have yet to show strong clinical efficacy in GBM. Epidemiological evidence supports a sex difference in GBM, with increased prevalence in males, and recent studies identified differences between males and females ranging from genetic aberrations to cellular programs. Sex differences have also been identified in immune response, and in this mini-review, we present these differences to highlight potential sex-specific cellular and molecular mechanisms that underly GBM growth and response to immunotherapies. These sex differences offer an opportunity to understand GBM pathogenesis and extend beyond GBM to other tumors and neurological disorders to inform the development of next-generation therapies.
Targeted Therapies for Brain Metastases Niranjan, Ajay; Lunsford, L Dade; Ahluwalia, Manmeet S
Progress in neurological surgery,
2019, Volume:
34
Journal Article
Peer reviewed
The most common primary cancers that metastasize to the brain are lung cancer, breast cancer, and melanoma. The established management approaches for brain metastasis include stereotactic ...radiosurgery, fractionated radiation therapy, and surgical resection. In the past the role of medical therapies in brain metastases was limited. In the last decade, our understanding of molecular drivers of brain metastases and CNS penetration of drugs across the blood-brain barrier has improved. The molecular targeted tyrosine kinase inhibitors have shown effectiveness in brain metastases with activating mutations from non-small cell lung cancer, breast cancer, and melanoma. More recently, immunotherapies have also shown efficacy in the management of these patients. These agents can be effective for both intracranial as well as extracranial disease and are being actively employed in this patient population.
•Assay developed and validated for terameprocol over the range of 5–1000 ng/mL.•Validated according to the FDA guidance.•Plasma stability documented for 20 months at − 70 °C.•Applied to a clinical ...trial to assess the bioavailability of an oral formulation.
The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5–1000 ng/mL was demonstrated to be accurate (92.7–107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at −70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.
Abstract
BACKGROUND
Cancer stem-like cells are a major cause of resistance to therapy in patients with glioblastoma (GBM) as well as other cancers. Tumor cells are maintained in a stem-like ...proliferative state in large part through the Notch signaling pathway. The function of this pathway in turn depends on gamma secretase activity. Inhibition of this enzyme therefore inhibits the Notch pathway and tumor growth as measured by a reduction in the formation of brain tumor neurospheres in murine models. RO4929097 is an oral gamma secretase inhibitor.
OBJECTIVE
To estimate the 6-mo progression-free survival rate (PFS6) in patients with progressive GBM and to inhibit by 50% the generation of neurospheres in fresh tissue resected from patients treated with RO4929097.
METHODS
In this phase II and pharmacodynamic study, patients with recurrent GBM received RO4929097 in a study of 2 groups. Group A patients had unresectable disease and received drug in a standard phase II design. Group B patients had resectable disease and received drug before and after surgical resection. Endpoints included PFS6 and the inhibition of neurosphere formation in the resected tumor samples.
RESULTS
A total of 47 patients received treatment, 7 of whom had tumor resection. The PFS6 was 4%, and the inhibition of neurosphere formation occurred in 1 of 7 patient samples.
CONCLUSION
RO4929097 was inactive in recurrent GBM patients and demonstrated minimal inhibition of neurosphere formation in fresh tissue samples.
Graphical Abstract
Graphical Abstract
The coordination of complex tumor processes requires cells to rapidly modify their phenotype and is achieved by direct cell-cell communication through gap junction channels composed of connexins. ...Previous reports have suggested that gap junctions are tumor suppressive based on connexin 43 (Cx43), but this does not take into account differences in connexin-mediated ion selectivity and intercellular communication rate that drive gap junction diversity. We find that glioblastoma cancer stem cells (CSCs) possess functional gap junctions that can be targeted using clinically relevant compounds to reduce self-renewal and tumor growth. Our analysis reveals that CSCs express Cx46, while Cx43 is predominantly expressed in non-CSCs. During differentiation, Cx46 is reduced, while Cx43 is increased, and targeting Cx46 compromises CSC maintenance. The difference between Cx46 and Cx43 is reflected in elevated cell-cell communication and reduced resting membrane potential in CSCs. Our data demonstrate a pro-tumorigenic role for gap junctions that is dependent on connexin expression.
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•Gap junction targeting potently inhibits GBM growth•Gap junctions have a pro-tumorigenic role that depends on connexin expression•CSCs express Cx46, which is required for self-renewal•Connexin expression dictates intercellular communication and membrane potential
Hitomi et al. demonstrate that glioblastoma cancer stem cells possess functional gap junctions that can be targeted to attenuate self-renewal and tumor growth. The authors also identify connexin 46 as a novel glioblastoma cancer stem cell regulator that is required for stem cell maintenance.
Abstract
Background
Recent epidemiological studies have suggested that sexual dimorphism influences treatment response and prognostic outcome in glioblastoma (GBM). To this end, we sought to (i) ...identify distinct sex-specific radiomic phenotypes—from tumor subcompartments (peritumoral edema, enhancing tumor, and necrotic core) using pretreatment MRI scans—that are prognostic of overall survival (OS) in GBMs, and (ii) investigate radiogenomic associations of the MRI-based phenotypes with corresponding transcriptomic data, to identify the signaling pathways that drive sex-specific tumor biology and treatment response in GBM.
Methods
In a retrospective setting, 313 GBM patients (male = 196, female = 117) were curated from multiple institutions for radiomic analysis, where 130 were used for training and independently validated on a cohort of 183 patients. For the radiogenomic analysis, 147 GBM patients (male = 94, female = 53) were used, with 125 patients in training and 22 cases for independent validation.
Results
Cox regression models of radiomic features from gadolinium T1-weighted MRI allowed for developing more precise prognostic models, when trained separately on male and female cohorts. Our radiogenomic analysis revealed higher expression of Laws energy features that capture spots and ripple-like patterns (representative of increased heterogeneity) from the enhancing tumor region, as well as aggressive biological processes of cell adhesion and angiogenesis to be more enriched in the “high-risk” group of poor OS in the male population. In contrast, higher expressions of Laws energy features (which detect levels and edges) from the necrotic core with significant involvement of immune related signaling pathways was observed in the “low-risk” group of the female population.
Conclusions
Sexually dimorphic radiogenomic models could help risk-stratify GBM patients for personalized treatment decisions.
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