Role of gut microbiota in regulating immune checkpoint inhibitor therapy for glioblastoma.

Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong patient survival. With the deepening of research, it has been found that gut microbiota plays a certain role in GBM, and can directly or indirectly affect the efficacy of immune checkpoint inhibitors (ICIs) in various ways. (1) The metabolites produced by gut microbiota directly affect the host's immune homeostasis, and these metabolites can affect the function and distribution of immune cells, promote or inhibit inflammatory responses, affect the phenotype, angiogenesis, inflammatory response, and immune cell infiltration of GBM cells, thereby affecting the effectiveness of ICIs. (2) Some members of the gut microbiota may reverse T cell function inhibition, increase T cell anti-tumor activity, and ultimately improve the efficacy of ICIs by targeting specific immunosuppressive metabolites and cytokines. (3) Some members of the gut microbiota directly participate in the metabolic process of drugs, which can degrade, transform, or produce metabolites, affecting the effective concentration and bioavailability of drugs. Optimizing the structure of the gut microbiota may help improve the efficacy of ICIs. (4) The gut microbiota can also regulate immune cell function and inflammatory status in the brain through gut brain axis communication, indirectly affecting the progression of GBM and the therapeutic response to ICIs. (5) Given the importance of gut microbiota for ICI therapy, researchers have begun exploring the use of fecal microbiota transplantation (FMT) to transplant healthy or optimized gut microbiota to GBM patients, in order to improve their immune status and enhance their response to ICI therapy. Preliminary studies suggest that FMT may enhance the efficacy of ICI therapy in some patients. In summary, gut microbiota plays a crucial role in regulating ICIs in GBM, and with a deeper understanding of the relationship between gut microbiota and tumor immunity, it is expected to develop more precise and effective personalized ICI therapy strategies for GBM, in order to improve patient prognosis.

Discussion on the relationship between gut microbiota and glioma through Mendelian randomization test based on the brain gut axis.

BACKGROUND: In the realm of Gut-Brain axis research, existing evidence points to a complex bidirectional regulatory mechanism between gut microbiota and the brain. However, the question of whether a causal relationship exists between gut microbiota and specific types of brain tumors, such as gliomas, remains unresolved. To address this gap, we employed publicly available Genome-Wide Association Study (GWAS) and MIOBEN databases, conducting an in-depth analysis using Two-Sample Mendelian Randomization (MR). METHOD: We carried out two sets of MR analyses. The preliminary analysis included fewer instrumental variables due to a high genome-wide statistical significance threshold (5×10-8). To enable a more comprehensive and detailed analysis, we adjusted the significance threshold to 1×10-5. We performed linkage disequilibrium analysis (R2 <0.001, clumping distance = 10,000kb) and detailed screening of palindromic SNPs, followed by MR analysis and validation through sensitivity analysis. RESULTS: Our findings reveal a causal relationship between gut microbiota and gliomas. Further confirmation via Inverse Variance Weighting (IVW) identified eight specific microbial communities related to gliomas. Notably, the Peptostreptococcaceae and Olsenella communities appear to have a protective effect, reducing glioma risk. CONCLUSION: This study not only confirms the causal link between gut microbiota and gliomas but also suggests a new avenue for future glioma treatment.

Glioma and temozolomide induced alterations in gut microbiome.

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. Recently, in immune-oncology, specific microbial taxa have been described to enhance the effects of therapeutic modalities. However, the effects of microbial dysbiosis on glioma are still unknown. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. C57BL/6 mice were implanted with GL261/Sham and given TMZ/Saline. Fecal samples were collected longitudinally and analyzed by 16S rRNA sequencing. Fecal samples were collected from healthy controls as well as glioma patients at diagnosis, before and after chemoradiation. Compared to healthy controls, mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. TMZ treatment in the non-tumor bearing mouse-model diminished the F/B ratio, increase Muribaculaceae family and decrease Ruminococcaceae family. Nevertheless, there were no changes in Verrucomicrobia/Akkermansia. Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study.

Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma.

Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.

Gut microbiota alterations affect glioma growth and innate immune cells involved in tumor immunosurveillance in mice.

Glioma is a CNS tumor with few therapeutic options. Recently, host microbiota has been involved in the immune modulation of different tumors, but no data are available on the possible effects of the gut-immune axis on brain tumors. Here, we investigated the effect of gut microbiota alteration in a syngeneic (GL261) mouse model of glioma, treating mice with two antibiotics (ABX) and evaluating the effects on tumor growth, microbe composition, natural killer (NK) cells and microglia phenotype. We report that ABX treatment (i) altered the intestinal microbiota at family level, (ii) reduced cytotoxic NK cell subsets, and (iii) altered the expression of inflammatory and homeostatic proteins in microglia. All these findings could contribute to the increased growth of intracranial glioma that was observed after ABX treatment. These results demonstrate that chronic ABX administration alters microbiota composition and contributes to modulate brain immune state paving the way to glioma growth.

Nocardia farcinica Meningitis Masquerading as Central Nervous System Metastasis in a Child With Cerebellar Pilocytic Astrocytoma.

Juvenile pilocytic astrocytoma, the most common pediatric central nervous system (CNS) neoplasm, characteristically displays an indolent growth pattern and rarely demonstrates metastatic dissemination. Reports of infections mimicking CNS metastatic disease are also rare and can impact treatment. We report the youngest known case of a child with a CNS Nocardia farcinica infection who had a known cerebellar pilocytic astrocytoma, review other infections that may masquerade as CNS neoplasms, and discuss N. farcinica CNS infections.

Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that is especially difficult to treat. The tumor's ability to withstand hypoxia leads to enhanced cancer cell survival and therapy resistance, but also yields a microenvironment that is in many aspects unique within the human body, thus offering potential therapeutic opportunities. The spore-forming anaerobic bacterium Clostridium novyi-NT(C. novyi-NT) has the ability to propagate in tumor-generated hypoxia, leading to oncolysis. Here, we show that intravenously injected spores of C. novyi-NT led to dramatic tumor destructions and significant survival increases in implanted, intracranial syngeneic F98 and human xenograft 060919 rat GBM models. C. novyi-NT germination was specific and confined to the neoplasm, with sparing of the normal brain parenchyma. All animals tolerated the bacteriolytic treatment, but edema and increased intracranial pressure could quickly be lethal if not monitored and medically managed with hydration and antibiotics. These results provide pre-clinical data supporting the development of this therapeutic approach for the treatment of patients with GBM.

Tumor-targeting Salmonella typhimurium A1-R arrests growth of breast-cancer brain metastasis.

Brain metastasis is a morbid, treatment-resistant, end-stage frequent occurrence in breast cancer patients. The aim of this study was to evaluate the efficacy of tumor-targeting Salmonella typhimurium A1-R on breast cancer brain metastases. High brain-metastatic variants of murine 4T1 breast cancer cells expressing red fluorescent protein (RFP) were injected orthotopically in the mammary fat pad in non-transgenic nude mice or in the left ventricle of non-transgenic nude mice and transgenic nude mice expressing nestin-driven green fluorescent protein (ND-GFP). ND-GFP mice express GFP in nascent blood vessels. In the orthotopically-injected mice, the primary tumor was surgically-resected in order to allow brain metastasis to develop. At various time points, the tumors and vasculature in the brain were imaged by confocal and stereo fluorescence microscopy. Some of the breast cancer cells that reached the brain extravasated and grew perivascularly and some of the cells proliferated within the vasculature. S. typhimurium A1-R significantly inhibited brain metastasis in both metastatic models and increased survival of the orthotopically-transplanted, primary-tumor-resected mice (p<0.05). The results of the present study suggest the clinical potential of bacterial therapy of breast cancer brain metastasis.

Salmonella as a biological "Trojan horse" for neoplasia: future possibilities including brain cancer.

This manuscript considers available evidence that a specific Salmonella strain could be used as an effective orally-administered option for cancer therapy involving the brain. It has been established that Salmonella preferentially colonizes neoplastic tissue and thrives as a facultative anaerobe in the intra-tumor environment. Although Salmonella accumulates in tumors by passive processes, it is still possible for lipopolysaccharide to cause sepsis and endotoxic shock during the migration of bacteria to the tumor site. An LPS-free version of a recently identified Salmonella isolate may have the capability to circumvent the blood brain barrier and provide a safer method of reaching brain tumors. This isolate merits further research as a "Trojan horse" for future oral biotherapy of brain cancer.

Usefulness of McRAPD for typing and importance of biofilm production in a case of nosocomial ventriculoperitoneal shunt infection caused by Candida lusitaniae.

A case report of ventriculoperitoneal shunt infection caused by Candida lusitaniae in a 6-year-old patient with cerebral astrocytoma and obstructive hydrocephalus is presented briefly with emphasis on the course of antifungal treatment. Seven isolates recovered subsequently from the cerebrospinal fluid were studied retrospectively. To confirm identity, isolates were typed using pulsed-field gel electrophoresis and melting curve of random amplified polymorphic DNA (McRAPD). Further, the ability to form biofilm and its susceptibility to systemic antifungals were evaluated. Using McRAPD, identity of C. lusitaniae isolates showing slight microevolutionary changes in karyotypes was undoubtedly confirmed; successful application of numerical interpretation of McRAPD for typing is demonstrated here for the first time. The strain was also recognized as a strong biofilm producer. Moreover, minimum biofilm inhibitory concentrations were very high, in contrast to low antifungal minimum inhibitory concentrations of isolates. It can be concluded that McRAPD seems to be a simple and reliable method not only for identification but also for typing of yeasts. A ventriculoperitoneal shunt colonized by C. lusitaniae was revealed as the source of this nosocomial infection, and the ability of the strain to form biofilm on its surface likely caused treatment failure.

Concomitant presentation of a glioblastoma multiforme with superimposed abscess.

BACKGROUND: The coexistence of a primary brain tumor such as high-grade glioma and superimposed abscess is a rare entity and can present a diagnostic and therapeutic challenge. The concomitant abscess may not be recognized until surgery, and the overall course of treatment may require adjustment in the presence of a coinciding infection. In the present report we evaluate the diagnosis and treatment of a glioblastoma multiforme with an intratumoral abscess. METHODS: A patient was diagnosed with a glioblastoma multiforme with a concomitantly superimposed multimicrobial abscess containing coagulase-negative Staphylococcus, Acinetobacter iwofii, and Propionibacterium species. The suspected infectious source was a dental abscess with presumed secondary seeding. The patient underwent a left anterior temporal lobectomy with debulking of the lesion. Although the adjuvant therapy schedule was adjusted to accommodate the course of antibiotics, the existence of a concurrent abscess did not preclude adjuvant radiation and chemotherapy. RESULTS: The patient responded well to antibiotic treatment with no evidence of recurrent infection. He underwent a second operation for additional debulking of the lesion approximately half a year after his initial surgery. The patient died 2 years after the initial diagnosis. CONCLUSIONS: There are insufficient guidelines on the treatment of a primary brain tumor with intratumoral abscess. In this report we present our therapeutic decisions in this rare case.

Central nervous system marginal zone B-cell lymphoma associated with Chlamydophila psittaci infection.

Extranodal marginal zone B-cell lymphomas are linked to bacterial infections that vary according to the anatomical site. The occurrence of these lymphomas in the central nervous system is a very rare event, and the identification of specific bacteria in this setting has not been previously addressed. Herein, we report for the first time a case of primary central nervous system marginal zone B-cell lymphoma involving the choroid plexus associated with Chlamydophila psittaci infection. No concomitant ocular involvement was detected. C psittaci was identified with 3 independent methods, and through immunohistochemistry, it was visualized in the cytoplasm of monocytes/macrophages present within lymphomatous tissues. This observation points toward the opportunity to investigate the prevalence of C psittaci infection in central nervous system lymphomas, particularly in those with low-grade histologic features.

Intracranial caseating granulomas with no infectious organism detected.

BACKGROUND: Caseating granuloma is a classic histopathological feature of mycobacterial infections. Occasionally, no infectious organism is demonstrated despite extensive examination of intracranial caseating granulomas. The pathogenesis and optimal management strategy for patients with such intracranial caseating granulomas with no detectable infectious organism (ICGNs) remain unclear. METHODS: The study was a retrospective case-series design in a referral hospital setting. Patients with intracranial caseating granulomas in whom no infectious etiology was identified after appropriate investigations were reviewed. RESULTS: Eight patients with ICGN (four females and four males) were identified in an eight-year-period. Average age on presentation was 46 years (range 21-69 years). Cerebrospinal fluid showed lymphocytic pleocytosis, elevated protein and decreased glucose. Neuroimaging showed multiple or single intraparenchymal and meningeal enhancements. Intracranial ICGN were demonstrated on biopsy. Immunomodulation was tried and resulted in improvement in five out of eight patients. In four patients, anti-mycobacterial treatment resulted in no improvement or worsening of clinical or radiological features. CONCLUSIONS: The response to therapy of intracranial caseating granulomas where no organism is identified after thorough investigations hints to non-infectious causes, and suggests current dogma regarding the significance of necrosis in granulomatous diseases should be re-evaluated. Our retrospective series suggests that patients may benefit from an early trial of immunomodulation therapy, a hypothesis to be tested in a randomized trial.

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

Early infection and risk of childhood brain tumors (Canada).

OBJECTIVE: Up to 15% of human cancers can be attributed to infections. Currently there are no known associations between infective agents and childhood brain tumors. We explored childhood brain tumor risk associated with a variety of indicators of infection during gestation and childhood. METHODS: Two hundred and seventy-two cases of childhood brain tumor diagnosed in children less then 15 years of age in the province of Quebec between 1980 and 1999 were included in the study. An equal number of sex and age matched population based controls were recruited from family allowance or provincial health insurance files. Conditional logistic regression was used to estimate the risk of developing childhood brain tumors associated with self-reported exposure to infection. RESULTS: Childhood brain tumor risk was weakly to moderately elevated after maternal reported exposure to several indicators of infection: use of antibiotics during gestation (OR = 1.7, 95% CI = 0.8-3.6) or childhood (OR = 1.4, 95% CI = 0.7-2.9), removal of tonsils, adenoids or appendix (OR = 1.2, 95% CI = 0.6-2.4), having siblings (OR = 1.4, 95% CI = 0.9-2.3), and being at least second born (OR = 1.7, 95% CI = 1.2-2.4). Moreover, childhood brain tumor risk was reduced for some subjects who were breastfed or attended daycare for more than 1 year. Risk varied by sex, age at diagnosis and tumor type. CONCLUSION: Childhood brain tumor risk may be associated with exposure to infective agents.

Nontuberculous mycobacterial infection of a metastatic brain neoplasm in an immunocompromised patient.

BACKGROUND: Nontuberculous mycobacterial infections occur in immunocompromised patients but so rarely involve the central nervous system (CNS) that they may not be included in a differential diagnosis of CNS lesions in such patients. OBJECTIVE: To illustrate a putative mechanism for nontuberculous mycobacterial infection of the CNS via breakdown of the blood-brain barrier by metastatic neoplasm. RESULTS: A 56-year-old man who had undergone renal transplantation in February 2003 and was taking an immunosuppressive regimen of mycophenolate mofetil and cyclosporine was seen in the emergency department after a syncopal episode. Head computed tomography revealed a single focal occipital lesion with vasogenic edema. Hospital admission and further workup led to diagnosis of metastatic carcinoma infected with nontuberculous mycobacteria in the setting of a disseminated nontuberculous mycobacterial infection. CONCLUSION: This case illustrates that breakdown of the blood-brain barrier by metastatic neoplasm may provide a route of access for a pathogen that is not normally seen in the CNS.