ANTIFUNGAL ACTIVITY OF BIPHENYL-2,6-DIETHANONE DERIVATIVES

Objective: The objective of the study was to evaluate the antifungal activity of biphenyl-2,6-diethanone derivatives against Cryptococcus neoformans.Methods: Antifungal activity of biphenyl derivatives were evaluated against C. neoformans. Zone of inhibition by disc diffusion method and minimum inhibitory concentration (MIC) using micro-broth dilution method was performed as per clinical and laboratory standard institute (CLSI). Melanin was extracted using 1M KOH, purified using 6M HCL and its reduction was assayed spectrophotometrically at 530 nm. Laccase activity was measured using L-DOPA as substrate and was assayed spectrophotometrically at 480 nm. Time kill assay was also performed to compare the antifungal potency of the test compound against azole drug.Results: Zone of inhibition of 12 mm diameter was estimated against C. neoformans. MIC80 of compound 1e was calculated as 50µg/ml. 63.67% decrease in melanization and 57.44% laccase activity reduction was determined. The Time-kill assay illustrated that the compound 1e inhibited the growth of C. neoformans cells in almost the same duration as observed in fluconazole.Conclusion: The outcome of in vitro antifungal studies indicated that compound 1e demonstrated maximum reduction of melanin and laccase activity in C. neoformans. In conclusion, biphenyl-2,6-diethanone derivatives possess significant antifungal property which can be explored further for lead generation.Â

A Single-Institution Retrospective Series of SARS-CoV-2 Infection in Adult Glioma Patients

A subset of cancer patients is particularly vulnerable to SARS-CoV-2 infection; however, real-world outcomes-based data on primary central nervous system tumor patients is sparse. This retrospective series describes a cohort of adult glioma patients seen at Stanford Cancer Center between January 1, 2020, and June 30, 2022 who contracted SARS-CoV-2, which, to our knowledge, currently represents the largest single-institution comprehensive analysis of this patient population. We performed a retrospective search of patients seen in the Stanford Neuro-Oncology clinic, identifying 29 cases of COVID-19 amongst glioma patients and extracted clinical data via individual chart review. At the time of COVID-19 diagnosis, 15 patients had been vaccinated against SARS-CoV-2, 8 patients were taking dexamethasone, and 8 were undergoing cancer-specific treatment. Obesity, prior tobacco use, and diabetes were the most common comorbidities. Cough, sore throat, and congestion were the most common symptoms. Five patients were admitted to the hospital and two received COVID-19-specific treatment. None died from COVID-related causes or complications. Our data suggest that glioma patients seen at Stanford Cancer Center do not experience an exceptionally high COVID-19 infectivity, hospitalization, or mortality rate, especially when compared to other vulnerable populations such as lung cancer patients. High vaccination rates, adherence to COVID-19 guidelines, and low prevalence of comorbidities may have contributed to these results

High-throughput quantitation of amino acids and acylcarnitine in cerebrospinal fluid: identification of PCNSL biomarkers and potential metabolic messengers

Background: Due to the poor prognosis and rising occurrence, there is a crucial need to improve the diagnosis of Primary Central Nervous System Lymphoma (PCNSL), which is a rare type of non-Hodgkin’s lymphoma. This study utilized targeted metabolomics of cerebrospinal fluid (CSF) to identify biomarker panels for the improved diagnosis or differential diagnosis of primary central nervous system lymphoma (PCNSL).Methods: In this study, a cohort of 68 individuals, including patients with primary central nervous system lymphoma (PCNSL), non-malignant disease controls, and patients with other brain tumors, was recruited. Their cerebrospinal fluid samples were analyzed using the Ultra-high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS) technique for targeted metabolomics analysis. Multivariate statistical analysis and logistic regression modeling were employed to identify biomarkers for both diagnosis (Dx) and differential diagnosis (Diff) purposes. The Dx and Diff models were further validated using a separate cohort of 34 subjects through logistic regression modeling.Results: A targeted analysis of 45 metabolites was conducted using UHPLC-MS/MS on cerebrospinal fluid (CSF) samples from a cohort of 68 individuals, including PCNSL patients, non-malignant disease controls, and patients with other brain tumors. Five metabolic features were identified as biomarkers for PCNSL diagnosis, while nine metabolic features were found to be biomarkers for differential diagnosis. Logistic regression modeling was employed to validate the Dx and Diff models using an independent cohort of 34 subjects. The logistic model demonstrated excellent performance, with an AUC of 0.83 for PCNSL vs. non-malignant disease controls and 0.86 for PCNSL vs. other brain tumor patients.Conclusion: Our study has successfully developed two logistic regression models utilizing metabolic markers in cerebrospinal fluid (CSF) for the diagnosis and differential diagnosis of PCNSL. These models provide valuable insights and hold promise for the future development of a non-invasive and reliable diagnostic tool for PCNSL

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

BackgroundOfranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.MethodsThis pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).ResultsEnrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.ConclusionsIn this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.Clinical trials registrationNCT02511405

History and current state of immunotherapy in glioma and brain metastasis

Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit

The Incidence and Significance of Multiple Lesions in Glioblastoma

The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances