Characterization of industry relationships in oncology.

BACKGROUND: Collaborative relationships between academic oncology and industry (pharmaceutical, biotechnology, "omic," and medical device companies) are essential for therapeutic development in oncology; however, limited research on engagement in and perceptions of these relationships has been done. METHODS: Survey questions were developed to evaluate relationships between academic oncology and industry. An electronic survey was delivered to 1000 randomly selected members of the American Society of Clinical Oncology, a professional organization for oncologists, eliciting respondents' views around oncology-industry collaborations. The responses were analyzed according to prespecified plans. RESULTS: There were 225 survey respondents. Most were from the United States (70.0%), worked at an academic institution (60.1%), worked in medical oncology (81.2%), and had an active relationship with industry (85.8%). One quarter (26.7%) of respondents reported difficulty establishing a relationship with industry collaborators, and most respondents (75%) did not report having had mentorship in developing these relationships. The majority (85.3%) of respondents considered these collaborations important to their careers. Respondents generally thought that scientific integrity was preserved (92%), and most respondents (95%) had little concern over the quality of the collaborative product. Many (60%) shared concerns over potential conflict of interest if an individual with a compensated relationship promoted an industry product for clinical care/research, yet most respondents (67%) stated these relationships did not shape their interactions with patients. CONCLUSIONS: This study provides novel data characterizing the nature of collaborative relationships between clinicians, researchers, and industry in oncology. Although respondents considered these collaborations an important part of clinical and academic oncology, formal education or mentorship around these relationships was rare. Conflicting findings around conflict of interest highlight the importance of more dedicated research in this area. PLAIN LANGUAGE SUMMARY: Business enterprises in health care play a central role in cancer research and care, driving the development of new medical testing, drugs, and devices. Effective working relationships among clinicians, researchers, and these industry partners can promote innovative research and enhance patient care. Study of these collaborations has been limited to date. Through distribution of a questionnaire to cancer clinicians and researchers, we found that most participants consider these relationships valuable, though they find establishing such relationships challenging partly because of gaps in educational programs in this area. Our findings also highlight the need for further policy around the potential bias these relationships can introduce.

Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis.

BACKGROUND: Glioma is one of the leading types of brain tumor, but few etiologic factors of primary glioma have been identified. Previous observational research has shown an association between viral infection and glioma risk. In this study, we used Mendelian randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infection and glioma. METHODS: We conducted a two-sample bidirectional MR analysis using genome-wide association study (GWAS) data. Summary statistics data of glioma were collected from the largest meta-analysis GWAS, involving 12,488 cases and 18,169 controls. Single-nucleotide polymorphisms (SNPs) associated with exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed. RESULTS: After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted herpes zoster (caused by Varicella zoster virus (VZV) infection) significantly decreased risk of low-grade glioma (LGG) development (OR = 0.85, 95% CI: 0.76-0.96, P = 0.01, FDR = 0.04). No causal effects of the other eleven viral infections on glioma and reverse causality were detected. CONCLUSIONS: This is one of the first and largest studies in this field. We show robust evidence supporting that genetically predicted herpes zoster caused by VZV infection reduces risk of LGG. The findings of our research advance understanding of the etiology of glioma.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Targeted Therapy for BRAF Mutant Brain Tumors.

OPINION STATEMENT: Molecular heterogeneity has confounded attempts to target individual pathways in brain tumors. However, gliomas with BRAF mutations have been identified as being uniquely vulnerable to targeted therapies. Such mutations are predominantly seen in brain tumors of the adolescent and young adult population. Given that accurate and timely identification of such mutations is essential for offering appropriate treatment, treatment centers should offer both immunohistochemical and sequencing methods for detection of these mutations to guide treatment. Additional studies of these tumors at recurrence would also allow identification of breakthrough resistance mechanisms that may also be targetable for treatment. Due to the relative rarity of these tumors, multicenter collaborative studies will be essential in achieving long term control of these tumors.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Early imaging marker of progressing glioblastoma: a window of opportunity.

PURPOSE: Therapeutic intervention at glioblastoma (GBM) progression, as defined by current assessment criteria, is arguably too late as second-line therapies fail to extend survival. Still, most GBM trials target recurrent disease. We propose integration of a novel imaging biomarker to more confidently and promptly define progression and propose a critical timepoint for earlier intervention to extend therapeutic exposure. METHODS: A retrospective review of 609 GBM patients between 2006 and 2019 yielded 135 meeting resection, clinical, and imaging inclusion criteria. We qualitatively and quantitatively analyzed 2000+ sequential brain MRIs (initial diagnosis to first progression) for development of T2 FLAIR signal intensity (SI) within the resection cavity (RC) compared to the ventricles (V) for quantitative inter-image normalization. PFS and OS were evaluated using Kaplan-Meier curves stratified by SI. Specificity and sensitivity were determined using a 2 × 2 table and pathology confirmation at progression. Multivariate analysis evaluated SI effect on the hazard rate for death after adjusting for established prognostic covariates. Recursive partitioning determined successive quantifiers and cutoffs associated with outcomes. Neurological deficits correlated with SI. RESULTS: Seventy-five percent of patients developed SI on average 3.4 months before RANO-assessed progression with 84% sensitivity. SI-positivity portended neurological decline and significantly poorer outcomes for PFS (median, 10 vs. 15 months) and OS (median, 20 vs. 29 months) compared to SI-negative. RC/V ratio ≥ 4 was the most significant prognostic indicator of death. CONCLUSION: Implications of these data are far-reaching, potentially shifting paradigms for glioma treatment response assessment, altering timepoints for salvage therapeutic intervention, and reshaping glioma clinical trial design.

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Impact of provider level, training and gender on the utilization of palliative care and hospice in neuro-oncology: a North-American survey.

Specialized palliative care (PC) services have emerged to address symptoms and provide end-of-life management for patients with brain tumors. The utilization patterns of PC in neuro-oncology are unknown. A 22-question survey was distributed to participants of the society for neuro-oncology annual meeting 2012 (n = 4487). Nonparametric methods including Wilcoxon two-sample and Kruskal-Wallis tests were used to assess differences in responses. 239 (5.3 %) evaluable responses were received; 79 % of respondents were physicians, and 17 % were nurses or midlevel providers. Forty-seven percent were medical or neuro-oncologists, 31 % neurosurgeons and 11 % radiation oncologists. Forty percent had no formal training in PC, 57 % had some formal training and 3 % completed a PC fellowship. Seventy-nine percent practiced in an academic setting. Of the respondents, 57 % referred patients to PC when symptoms required treatment and 18 % at end of life. Only 51 % of all providers felt comfortable dealing with end-of-life issues and symptoms, while 33 % did not. Fifty-one percent preferred a service named "Supportive Care" rather than "Palliative Care" (MDs > midlevel providers, p < 0.001), and 32 % felt that patient expectations for ongoing therapy hindered their ability to make PC referrals. Female gender, formal training in neuro-oncology and PC, and medical versus surgical neuro-oncology training were significantly associated with hospice referral, comfort in dealing with end-of-life issues, and ease of access to PC services. Provider level, specialty, gender, training in PC and neuro-oncology have significant impact on the utilization of PC and hospice in neuro-oncology.

Outcome of patients with malignant glioma and synchronous or metachronous non-central nervous system primary neoplasms.

Patients with malignant glioma who are also diagnosed with one or more primary neoplasms of other organs present a unique challenge in both determining prognosis and clinical management. The overlapping impact of the malignancies and their treatment result in confounding variables that may adversely affect optimal management of such patients. Additionally, the glioma-related characteristics and survival outcome of these patients is not well-defined. In this retrospective chart and data review from our longitudinal database, we identified patients with malignant glioma including anaplastic glioma and glioblastoma, diagnosed between January 2005 and June 2011, who were also diagnosed with other non-CNS primary neoplasms. Patients with known genetic syndromes were excluded. The data was analyzed to determine the clinical characteristics and glioma-related survival. A total of 204 patients with malignant glioma (165 glioblastoma and 39 anaplastic glioma) were identified. There was no significant difference in the overall survival or progression-free survival between patients with malignant glioma plus non-CNS primary neoplasm when compared with patients with malignant glioma only. In patients with glioblastoma and non-CNS malignancy, the duration between diagnosis of glioblastoma and non-CNS neoplasms did not significantly alter glioma-related survival. Patients with malignant glioma who were diagnosed with other non-CNS malignancy have survival outcome comparable to those with malignant glioma only. The duration between diagnosis of glioblastoma and diagnosis of non-CNS neoplasms did not affect survival. Further prospective studies specifically addressing survival and molecular characteristics of patients with malignant glioma plus non-CNS cancers are recommended.

A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma.

Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.

Characterization of pseudoprogression in patients with glioblastoma: is histology the gold standard?

Pseudoprogression (psPD) refers to an increase in size or appearance of new areas of MRI contrast enhancement soon after completing chemoradiation, timely diagnosis of which has been a challenge. Given that tissue sampling of the MRI changes would be expected to accurately distinguish psPD from true progression when MRI changes are first seen, we examined the utility of surgery in diagnosing psPD and influencing patient outcome. We retrospectively reviewed data from adults with GBM who had MRI changes suggestive of progression within 3 months of chemoRT; of these, 34 underwent surgical resection. Three subsets-tumor, psPD or mixed-were identified based on histology and immunohistochemistry in the surgical group and by imaging characteristics in the nonsurgical group. A cohort of patients with stable disease post-chemoRT served as control. PFS and OS were determined using the Kaplan-Meier method and log rank analysis. Concordance for psPD between radiological interpretation and subsequent histological diagnosis was seen in only 32% of cases (11/34) 95%CI 19-49%. A large proportion of patients had a histologically "mixed" pattern with tumor and treatment effect. No significant differences in PFS or OS were seen among the three subtypes. Surgical sampling and histologic review of MRI changes after chemoRT may not serve as a gold standard to distinguish psPD from true progression in GBM patients. Refinement of the histological criteria, careful intraoperative selection of regions of interest and advanced imaging modalities are needed for early differentiation of PsPD from progression to guide clinical management.

A multi-resolution textural approach to diagnostic neuropathology reporting.

We present a computer aided diagnostic workflow focusing on two diagnostic branch points in neuropathology (intraoperative consultation and p53 status in tumor biopsy specimens) by means of texture analysis via discrete wavelet frames decomposition. For intraoperative consultation, our methodology is capable of classifying glioblastoma versus metastatic cancer by extracting textural features from the non-nuclei region of cytologic preparations based on the imaging characteristics of glial processes, which appear as anisotropic thin linear structures. For metastasis, these are homogeneous in appearance, thus suitable and extractable texture features distinguish the two tissue types. Experiments on 53 images (29 glioblastomas and 24 metastases) resulted in average accuracy as high as 89.7 % for glioblastoma, 87.5 % for metastasis and 88.7 % overall. For p53 interpretation, we detect and classify p53 status by classifying staining intensity into strong, moderate, weak and negative sub-classes. We achieved this by developing a novel adaptive thresholding for detection, a two-step rule based on weighted color and intensity for the classification of positively and negatively stained nuclei, followed by texture classification to classify the positively stained nuclei into the strong, moderate and weak intensity sub-classes. Our detection method is able to correctly locate and distinguish the four types of cells, at 85 % average precision and 88 % average sensitivity rate. These classification methods on the other hand recorded 81 % accuracy in classifying the positive and negative cells, and 60 % accuracy in further classifying the positive cells into the three intensity groups, which is comparable with neuropathologists' markings.

Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance.

Glioblastoma is a devastating disease, and there is an urgent need to develop novel therapies, such as oncolytic HSV1 (OV) to effectively target tumor cells. OV therapy depends on tumor-specific replication leading to destruction of neoplastic tissues. Host responses that curtail virus replication limit its efficacy in vivo. We have previously shown that cysteine-rich 61 protein (CCN1) activates a type 1 IFN antiviral defense response in glioblastoma cells. Incorporating TCGA data, we found CCN1 expression to be a negative prognostic factor for glioblastoma patients. Based on this, we used neutralizing antibodies against CCN1 to investigate its effect on OV therapy. Use of an anti-CCN1 antibody in mice bearing glioblastomas treated with OV led to enhanced virus expression along with reduced immune cell infiltration. OV-induced CCN1 increases macrophage migration toward infected glioblastoma cells by directly binding macrophages and also by enhancing the proinflammatory activation of macrophages inducing MCP-1 expression in glioblastoma cells. Activation of macrophages by CCN1 also increases viral clearance. Neutralization of integrin αMß2 reversed CCN1-induced macrophage activation and migration, and reduced MCP-1 expression by glioblastoma cells. Our findings reveal that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors.

Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition-induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy.

Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma.

Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma. It is not known if there are differences in outcome between early versus delayed BEV treatment of recurrent glioblastoma. We examined the relationship between the time of starting BEV treatment and outcomes in patients with recurrent glioblastoma. In this retrospective chart review, we identified patients with recurrent glioblastoma diagnosed between 2005 and 2011 who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of starting BEV. A total of 298 patients were identified, 112 patients received early BEV, 133 patients received delayed BEV, and 53 patients were excluded because they either progressed within 3 months of radiation or received BEV at the time of diagnosis. There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.2 vs. 4.3 months, p = 0.2). Patients treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 vs. 20.8 months, p = 0.005). In patients with recurrent glioblastoma, there was no significant difference in PFS from the time of starting BEV between early and delayed BEV. Although patients treated with delayed BEV seemed to have longer OS, a conclusion regarding OS outcome requires further prospective trials. These results may indicate that delaying treatment with BEV is not detrimental for survival of patients with recurrent glioblastoma.

Protocol for real-time assessment of mitochondrial and glycolytic ATP production in patient-derived glioma stem-like cells.

Glioma cells switch between energetic pathways to adapt and resist therapies. We present a protocol for measuring mitochondrial and glycolytic ATP rates in patient-derived glioma stem-like cells using a Seahorse XF ATP rate assay. We describe steps for growing 3D glioma stem-like cells, attaching cells to the assay plate, preparing drugs, and running the ATP rate assay. We also detail procedures for imaging viable cell numbers and normalization, with tips to overcome pitfalls in Agilent Seahorse assays.

Triethylammonium Salts of Dicoumarol: Synthesis, Characterization, Human Antiglioblastoma, Antimicrobial and Antioxidant Studies.

The most typical primary brain tumor, glioblastoma multiforme (GBM), has a dismal prognosis. They are removed through arduous, potentially fatal operations. The primary cause of tumor recurrence following surgery is glioblastoma stem cells (GSCs). In order to combat the recurrent glioblastoma malignant cells, medications have been developed. Chemotherapies now in use are expensive and encounter resistance. To combat inherent and developed resistance, new and powerful chemotherapeutics are being synthesized. In this regard, dicoumarols were deprotonated by triethylamine to produce corresponding salts which are reported and used for the first time for human antiglioblastoma activity. Spectroscopic characterizations like 1H and 13C-NMR were carried out. The cytotoxicity of normal human astrocytes (NHA) and human glioblastoma cells (A172 and LN229) were both examined in terms of dose and time dependence. The range of the IC50 value for all the deprotonated derivatives against A172 was found to be 2.81-0.24 µM, whereas the range against LN229 was found to be 2.50-0.85 µM. According to cytotoxicity results, malignant cell death was seen in GBM cells treated with triethylamine salts of dicoumarols compared to the control group, which suggested that salts may cause apoptosis in GBM cells. Antimicrobial and antifungal activities were also investigated for all the triethylamine salts of dicoumarols suggesting that salt formation enhances antimicrobial potentials manyfolds compared to the standard drug used. Free radical activities were also investigated using DPPH free radicals.

Accelerated tumor progression after COVID-19 infection in patients with glioblastoma: A retrospective case-control study.

Background: We observed rapid tumor progression following COVID-19 infection among patients with glioblastoma and sought to systematically characterize their disease course in a retrospective case-control study. Methods: Using an institutional database, we retrospectively identified a series of COVID-19-positive glioblastoma cases and matched them by age and sex 1:2 to glioblastoma controls who had a negative COVID-19 test during their disease course. Demographic and clinical data were analyzed. Hyperprogression was defined using modified response evaluation criteria in solid tumors criteria. Time to progression and overall survival were estimated using the Kaplan-Meier method. Results: Thirty-two glioblastoma cases with positive COVID-19 testing were matched to 64 glioblastoma controls with negative testing; age, sex, and molecular profiles did not differ between groups. Progression events occurred in 27 cases (84%) and 46 controls (72%). Of these, 14 cases (52%) presented with multifocal disease or leptomeningeal disease at progression compared with 10 controls (22%; P = .0082). Hyperprogression was identified in 13 cases (48%) but only 4 controls (9%; P = .0001). Cases had disease progression at a median of 35 days following COVID-19 testing, compared with 164 days for controls (P = .0001). Median survival from COVID-19 testing until death was 8.3 months for cases but 17 months for controls (P = .0016). Median overall survival from glioblastoma diagnosis was 20.7 months for cases and 24.6 months for controls (P = .672). Conclusions: Patients with glioblastoma may have accelerated disease progression in the first 2 months after COVID-19 infection. Infected patients should be monitored vigilantly. Future investigations should explore tumor-immune microenvironment changes linking tumor progression and COVID-19.

A first-in-human phase 1 study of BXQ-350, a first-in-class sphingolipid metabolism regulator, in patients with advanced/recurrent solid tumors or high-grade gliomas.

PURPOSE: BXQ-350, a nanovesicle formulation of Saposin C, is an allosteric sphingolipid metabolism regulator that increases pro-apoptotic ceramide and decreases oncogenic sphingosine-1-phosphate (S1P) levels. We conducted a first-in-human, phase 1 study of BXQ-350. PATIENTS AND METHODS: Adults (≥18 years old) with advanced/recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7-2.4 mg/kg) in a 3+3 dose-escalation and expansion design. Primary endpoints during dose escalation were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD); primary objective in expansion parts was assessment of anti-tumor activity (RECIST v1.1/RANO criteria). RESULTS: Eighty-six patients were enrolled. DLTs were not observed during dose escalation (n=18), and a MTD was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events (AEs). The most common treatment-related AEs were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival (PFS) ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with PFS ≥6 months, seven remained on study for >12 months, five for >24 months, and after seven years, two remained on study without disease progression. CONCLUSIONS: BXQ-350 was well tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic S1P/ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard-of-care for advanced solid tumors.