Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

RETROSPECTIVE REVIEW OF PROPOFOL ANESTHESIA IN MULTIPLE ELASMOBRANCH SPECIES AT GEORGIA AQUARIUM, 2010-2022.

General anesthesia is often required in elasmobranch species for medical procedures. A variety of anesthetic drugs have been administered to elasmobranchs with wide variability in efficacy and safety. A retrospective review of 47 anesthetic procedures using IV propofol in eight different elasmobranch species at the Georgia Aquarium from 2010 to 2022 was performed. Cases involving seven sand tiger sharks (Carcharias taurus), four largetooth sawfish (Pristis perotteti), one longcomb sawfish (Pristis zijsron), four blacktip reef sharks (Carcharhinus melanopterus), three silvertip sharks (Carcharhinus albimarginatus), one sandbar shark (Carcharhinus plumbeus), five cownose rays (Rhinoptera bonasus), and one blotched fantail stingray (Taeniura meyeni) were evaluated. Induction dose of IV propofol (median: 2.5; 25-75%: 2.3-3.0; range: 1.7-4.0 mg/kg), time to desired effect (median: 4.0; 25-75%: 2.0-5.0; range: 0.5-15.0 min) and anesthetic duration (median: 76.0; 25-75%: 61.5-119.0; range: 27-216 min) were reported in all species. In six procedures (12.7%), maintenance of desired anesthetic plane required a supplemental dose of propofol IV (1 mg/kg) or addition of tricaine methanesulfonate (70 mg/L) as an immersion bath. The most common side effects were apnea and prolonged recovery. The IV propofol was efficacious and provided a procedural plane of anesthesia for a clinically relevant period of time in the majority of elasmobranch species, but observation for and management of complications is warranted.

Neoadjuvant Gene-Mediated Cytotoxic Immunotherapy for Non-Small-Cell Lung Cancer: Safety and Immunologic Activity.

Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 1012 viral particles) was performed during diagnostic staging, followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 1 week later. Twelve patients participated after appropriate informed consent. Vector-related adverse events were minimal. Immune biomarkers were evaluated in tumor and blood before and after GMCI. Significantly increased infiltration of CD8+ T cells was found in resected tumors. Expression of activation, inhibitory, and proliferation markers, such as human leukocyte antigen (HLA)-DR, CD38, Ki67, PD-1, CD39, and CTLA-4, were significantly increased in both the tumor and peripheral CD8+ T cells. Thus, intratumoral AdV-tk injection into non-small-cell lung cancer (NSCLC) proved safe and feasible, and it effectively induced CD8+ T cell activation. These data provide a foundation for additional clinical trials of GMCI for lung cancer patients with potential benefit if combined with other immune therapies.

Leveraging external data in the design and analysis of clinical trials in neuro-oncology.

Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma.

Phase I Study of Intrapleural Gene-Mediated Cytotoxic Immunotherapy in Patients with Malignant Pleural Effusion.

Gene-mediated cytotoxic immunotherapy (GMCI) is an immune strategy implemented through local delivery of an adenovirus-based vector expressing the thymidine kinase gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug valacyclovir. A phase I dose escalation trial of GMCI followed by chemotherapy was conducted in patients with malignant pleural effusion (MPE). AdV-tk was administered intrapleurally (IP) in three cohorts at a dose of 1 × 1012 to 1013 vector particles. Primary endpoint was safety; secondary endpoints included response rate, progression-free survival, and overall survival. Nineteen patients were enrolled: median age 67 years; 14 with malignant mesothelioma, 4 non-small-cell lung cancer (NSCLC), and 1 breast cancer. There were no dose limiting toxicities. All 3 patients in cohort 2 experienced transient cytokine release syndrome (CRS). Addition of celecoxib in cohort 3 reduced the incidence and severity of CRS (none > grade 2). Three patients are alive (23-33 months after GMCI), and 3 of 4 NSCLC patients had prolonged disease stabilization; one is alive 29 months after GMCI, 3.6 years after initial diagnosis. GMCI was safe and well tolerated in combination with chemotherapy in patients with MPE and showed encouraging response. Further studies are warranted to determine efficacy.

Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr).

INTRODUCTION: A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1. METHODS: We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing. RESULTS: Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03). DISCUSSION: Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a "mini-population bottleneck" and subsequent emergence of a rare dominant mutation.

Anti-GK1 antibodies damage Taenia crassiceps cysticerci through complement activation.

Taeniasis-cysticercosis, a zoonosis caused by Taenia solium, is prevalent in underdeveloped countries, where marginalization promotes its continued transmission. Pig cysticercosis, an essential stage for transmission, is preventable by vaccination. An efficient multiepitope vaccine against pig cysticercosis, S3Pvac, was developed. Previous studies showed that antibodies against one of the S3Pvac components, GK-1, are capable of damaging T. solium cysticerci, inhibiting their ability to transform into the adult stage in golden hamster gut. This study is aimed to evaluate one of the mechanisms that could mediate anti-GK-1 antibody-dependent protection. To this end, pig anti-GK-1 antibodies were produced and purified by using protein A. Proteomic analysis showed that the induced antibodies recognized the respective native cysticercal protein KE7 (Bobes et al. Infect Immun 85:e00395-17, 2017) and two additional T. solium proteins (endophilin B1 and Gp50). A new procedure to evaluate cysticercus viability, based on quantifying the cytochrome c released after parasite damage, was developed. Taenia crassiceps cysticerci were cultured in the presence of differing amounts of anti-GK-1 antibody and complement in a saturating concentration, along with the respective controls. Cysticercus viability was assessed by recording parasite motility, trypan blue exclusion, and cytochrome c levels in cysticercal soluble extract. Anti-GK-1 antibody significantly increased cysticercus damage as measured by all three methods. Parasite evaluation by electron microscopy after treatment with anti-GK-1 antibody plus complement demonstrated cysticercus damage as shorter, capsule-severed microtrichia; a decrease in glycocalyx length with respect to untreated cysts; and disaggregated desmosomes. These results demonstrate that anti-GK-1 antibodies damage cysticerci through classic complement activation.

Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma.

BACKGROUND: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer. METHODS: Four dose levels (3 × 10(10) to 1 × 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug. RESULTS: Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration. CONCLUSIONS: AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

Public interest in drug-related problems reflected in information search trends: an infodemiological study.

BACKGROUND: The analysis of how people search and "navigate" the internet to obtain health-related information and how they communicate and share this information can provide valuable knowledge about the disease patterns behaviour and health habits of populations. OBJECTIVE: To determine the population's interest in drug-related problems through information search trends. METHOD: A descriptive ecological correlational study, based on obtaining Google Trends data. VARIABLES STUDIED: relative search volume (RSV), evolution over time, milestones and seasonality. RESULTS: The most searched topic was drug overdose, with mean RSV of 56.25 ± 0.65. The highest increase occurred in the contraindication topic (R2 = 0.87, p < 0.001). The main milestone was observed in the drug overdose topic in July 2018 (RSV = 100). A very close relationship was found between adverse drug reaction and contraindication (R = 0.89, p < 0.001). Slight seasonality was noted in the adverse drug reaction (augmented Dickey-Fuller test [ADF] = -1.96), contraindication (ADF = -2.66) and drug interaction (ADF = -1.67) topics, but did not show an epidemiological trend. CONCLUSIONS: The greatest public interest was found in the drug overdose and contraindication topics, which showed a stronger upward trend, although the seasonality study did not show any very notable data or demonstrate epidemiological information search behaviour. The main milestone observed was due to media factors related to the consumption of narcotics. There was a clear difference in English-speaking countries in the use of the drug overdose topic. A correlation between the adverse drug reaction and contraindication topics was confirmed.

Implementation of a vascular access team and an intravenous therapy programme: A first-year activity analysis.

BACKGROUND: Creating Vascular Access Teams (VAT) provides an expert nursing role that contributes to the training and continuous improvement of healthcare personnel. They can offer greater clinical safety, reducing complications and costs. Peripherally inserted central catheters (PICCs) and midline catheters (ML) can be safe and cost-effective alternatives to other types of venous access (VA). The aim of the study was to analyse our centre's VAT first 12 months of activity. The primary outcome was reported complications. Secondary outcomes were cause of catheter removal, consultancy activity and economic impact of VAT implantation. METHODOLOGY: A longitudinal, descriptive study was carried out from March 2019 to March 2020. Using consecutive sampling, all VA inserted, and all consults received were included. Patients under 18 years of age were excluded. RESULTS: The VAT inserted 1257 catheters into 1056 patients (291 MLs, 966 PICCs). The mean dwell time was 14.9 days for MLs and 59.07 days for PICCs. The main reason for removing VA was end of treatment (80.7%). During VA follow-up confirmed infection was detected in 1 ML (0.3%) and nine PICCs (0.9%). Symptomatic thrombosis was reported in 2 MLs (0.7%) and 16 PICCs (1.7%). The VAT received 367 consultations, and the main reason for consultation was to resolve doubts regarding the management of VA (80.9%). The insertion of ML and PICC catheters represented annual estimated economic savings of €867,688.44€. CONCLUSIONS: Our study provides a detailed analysis of VAT's activity, its relevance to clinical safety, and to efficient resource management within our hospital. It demonstrates how VAT establishment can be a safe and efficient intervention that enhances care quality.

Reduction of Ca2+ Entry by a Specific Block of KCa3.1 Channels Optimizes Cytotoxic Activity of NK Cells against T-ALL Jurkat Cells.

Degranulation mediated killing mechanism by NK cells is dependent on store-operated Ca2+ entry (SOCE) and has optimum at moderate intracellular Ca2+ elevations so that partial block of SOCE optimizes the killing process. In this study, we tested the effect of the selective blocker of KCa3.1 channel NS6180 on SOCE and the killing efficiency of NK cells from healthy donors and NK-92 cells against T-ALL cell line Jurkat. Patch-clamp analysis showed that only one-quarter of resting NK cells functionally express KCa3.1 current, which increases 3-fold after activation by interleukins 15 and 2. Nevertheless, blockage of KCa3.1 significantly reduced SOCE and intracellular Ca2+ rise induced by IL-15 or target cell recognition. NS6180 (1 µM) decreased NK degranulation at zero time of coculture with Jurkat cells but already after 1 h, the degranulation reached the same level as in the control. Monitoring of target cell death by flow cytometry and confocal microscopy demonstrated that NS6180 significantly improved the killing ability of NK cells after 1 h in coculture with Jurkat cells and increased the Jurkat cell fraction with apoptotic and necrotic markers. Our data evidence a strong dependence of SOCE on KCa3.1 activity in NK cells and that KCa3.1 specific block can improve NK cytotoxicity.

Suitability of indexing terms in the MEDLINE bibliographic database on drug-related problems.

BACKGROUND: For years, there has been controversy about the meaning of medication-related problems (MRPs). This has led several authors to attempt to redefine and classify this term with the aim of using it correctly in the healthcare setting. So far without achieving the desired objective, resulting in erroneous results in the sources of information and thus in malpractice in the sector. OBJECTIVE: To describe and analyze the appropriateness of the existing indexing of scientific publications in the MEDLINE bibliographical database with respect to drug-related problems (DRPs) and to determine whether the descriptors used fulfilled the function of suitably representing this concept. METHODS: A descriptive study was conducted, using the following search terms: Medication Errors; Drug Interactions; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Contraindications, Drug. The sample size was calculated by estimating population parameters in an infinite population (expected value = 0.05; precision of interval = 0.05; level of confidence = 0.95) and the selection method was simple random sampling without replacement, taking the total number of bibliographical references in the database as the basis. The agreement of the indexing with DRPs was evaluated with the coefficient of determination (R2), and the Cohen kappa coefficient was used for the association between the definition of the descriptors and the objective of the article. RESULTS: The 1930 records analyzed showed a total of 2888 different major topics. These major topics were present, with at least one of the five descriptors studied, in 482 (25.0%; 95% CI 23.0-27.0) documentary files, with statistically significant differences between the two phases analyzed (χ2 = 183.8; degrees of freedom (df) = 1; p < 0.001): 1st phase, 295 (13.3%; 95% CI 13.7-16.9) and 2nd phase, 187 (9.7%; 95% CI 8.4-11.0). Overall scientific output with the five descriptors showed a coefficient of determination (R2) of 0.9 (p < 0.001) and the relationship between the objective of the study and the definitions of the five descriptors was 0.9 (p < 0.001). CONCLUSIONS: There was a very good direct exponential trend of the overall scientific output retrieved with the terms associated with DRPs, although the progression of the five descriptors separately did not show a growth model conforming to expectations. There was a moderate agreement between the objective of the study and the definition of each of the five descriptors used and a low relationship between the objective of the study and the concept of DRPs used for this investigation. It is essential to have a descriptor that unifies the terminological diffusion that has existed up till now, since process (causes) and effects (outcomes) have been mixed together under the various definitions and classifications of DRPs found in the studies.

The spectrum of vaccine therapies for patients with glioblastoma multiforme.

OPINION STATEMENT: Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system (CNS) and one of the most lethal cancers in adults and children. Despite aggressive treatment with surgery, radiation, and chemotherapy, median survival is less than 15 months and overall survival is less than 10 % at 5 years. Development of therapeutics for malignant gliomas has been hampered by their natural complexity as well as protective mechanisms unique to the CNS. Better understanding of the pathogenesis of GBM is opening the path to novel, specific-targeted therapies. Recently, multiple immunotherapy approaches have been acquiring substantial indication of therapeutic efficacy with a very safe profile. Examples of the leading clinical approaches for GBM will be discussed in detail in this review.

Buckling Susceptibility of a K-File during the Initial Negotiations of Narrow and Curved Canals Using Different Manual Techniques.

(1) Background: One possible way to investigate the potential impact or susceptibility of buckling on different manual techniques is to measure compressive loads during canal negotiation. The higher their values, the easier and quicker the critical load level to buckling is reached, leading to possible instrument lateral deformation. The objective of the present study was to investigate the impacts of compressive loads on a small K-file manipulated with different techniques for canal negotiation in simulated narrow and curved canals. (2) Methods: The tooth model selected was a plastic double-curved premolar 23 mm long (DRSK Group AB, Kasernvagen 2, SE-281 35, Hassleholm, Sweden) with an extremely narrow canal lumen to mimic a very difficult anatomical scenario. An experienced endodontist performed the negotiation of 90 of these artificial teeth randomly assigned to 3 different groups of 30 blocks each, respectively, using 3 different techniques: Group A: watch winding/pull (WW) motion; Group B: balanced forces (BF) technique; Group C: envelope of motion (EOM). The measurement system was based on the use of a dynamometer, Instron, Ltd. (model 2525-818 2kN f.s.), linked to a data acquisition unit HBM MGC+ to test all the compression and tensile loads, including all the peaks. (3) Results: All data acquired were processed by the CATMAN AP HBM software. Multiple comparisons for the highest compressive loads estimated the mean difference between WW vs. BF techniques of 3.60 [95% confidence interval (CI): 2.85 to 4.35, p < 0.001], WW vs. EOM of −1.76 (95% CI: −2.11 to 1.40, p < 0.001), and BF vs. EOM −5.36 (95% CI: −6.04 to −4.67, p < 0.001). (4) Conclusions: In conclusion, among the tested manual motions, the BF technique (Group B) was the most susceptible to buckling with the highest compressive load. WW motion (Group A) and EOM (Group C) were less susceptible to buckling than the BF technique. Therefore, a pressure-free manipulation of manual files, such as WW motion or EOM, can help reduce the susceptibility to buckling during the negotiation of narrow-curved canals.

Systemic high-dose dexamethasone treatment may modulate the efficacy of intratumoral viral oncolytic immunotherapy in glioblastoma models.

BACKGROUND: Intratumoral viral oncolytic immunotherapy is a promising new approach for the treatment of a variety of solid cancers. CAN-2409 is a replication-deficient adenovirus that delivers herpes simplex virus thymidine kinase to cancer cells, resulting in local conversion of ganciclovir or valacyclovir into a toxic metabolite. This leads to highly immunogenic cell death, followed by a local immune response against a variety of cancer neoantigens and, next, a systemic immune response against the injected tumor and uninjected distant metastases. CAN-2409 treatment has shown promising results in clinical studies in glioblastoma (GBM). Patients with GBM are usually given the corticosteroid dexamethasone to manage edema. Previous work has suggested that concurrent dexamethasone therapy may have a negative effect in patients treated with immune checkpoint inhibitors in patients with GBM. However, the effects of dexamethasone on the efficacy of CAN-2409 treatment have not been explored. METHODS: In vitro experiments included cell viability and neurosphere T-cell killing assays. Effects of dexamethasone on CAN-2409 in vivo were examined using a syngeneic murine GBM model; survival was assessed according to Kaplan-Meier; analyses of tumor-infiltrating lymphocytes were performed with mass cytometry (CyTOF - cytometry by time-of-flight). Data were analyzed using a general linear model, with one-way analysis of variance followed by Dunnett's multiple comparison test, Kruskal-Wallis test, Dunn's multiple comparison test or statistical significance analysis of microarrays. RESULTS: In a mouse model of GBM, we found that high doses of dexamethasone combined with CAN-2409 led to significantly reduced median survival (29.0 days) compared with CAN-2409 treatment alone (39.5 days). CyTOF analyses of tumor-infiltrating immune cells demonstrated potent immune stimulation induced by CAN-2409 treatment. These effects were diminished when high-dose dexamethasone was used. Functional immune cell characterization suggested increased immune cell exhaustion and tumor promoting profiles after dexamethasone treatment. CONCLUSION: Our data suggest that concurrent high-dose dexamethasone treatment may impair the efficacy of oncolytic viral immunotherapy of GBM, supporting the notion that dexamethasone use should be balanced between symptom control and impact on the therapeutic outcome.

Perturbing DDR signaling enhances cytotoxic effects of local oncolytic virotherapy and modulates the immune environment in glioma.

CAN-2409 is a replication-deficient adenovirus encoding herpes simplex virus (HSV) thymidine kinase (tk) currently in clinical trials for treatment of glioblastoma. The expression of tk in transduced cancer cells results in conversion of the pro-drug ganciclovir into a toxic metabolite causing DNA damage, inducing immunogenic cell death and immune activation. We hypothesize that CAN-2409 combined with DNA-damage-response inhibitors could amplify tumor cell death, resulting in an improved response. We investigated the effects of ATR inhibitor AZD6738 in combination with CAN-2409 in vitro using cytotoxicity, cytokine, and fluorescence-activated cell sorting (FACS) assays in glioma cell lines and in vivo with an orthotopic syngeneic murine glioma model. Tumor immune infiltrates were analyzed by cytometry by time of flight (CyTOF). In vitro, we observed a significant increase in the DNA-damage marker γH2AX and decreased expression of PD-L1, pro-tumorigenic cytokines (interleukin-1ß [IL-1ß], IL-4), and ligand NKG2D after combination treatment compared with monotherapy or control. In vivo, long-term survival was increased after combination treatment (66.7%) compared with CAN-2409 (50%) and control. In a tumor re-challenge, long-term immunity after combination treatment was not improved. Our results suggest that ATR inhibition could amplify CAN-2409's efficacy in glioblastoma through increased DNA damage while having complex immunological ramifications, warranting further studies to determine the ideal conditions for maximized therapeutic benefit.

Pulmonary injury as a predictor of cerebral hypoxia in traumatic brain injury: from physiology to physiopathology.

Traumatic brain injury is caused by mechanical forces impacting the skull and its internal structures and constitutes one of the main causes of morbidity and mortality in the world. Clinically, severe traumatic brain injury is associated with the development of acute lung injury and so far, few studies have evaluated the cellular, molecular and immunological mechanisms involved in this pathophysiological process. Knowing and investigating these mechanisms allows us to correlate pulmonary injury as a predictor of cerebral hypoxia in traumatic brain injury and to use this finding in decision making during clinical practice. This review aims to provide evidence on the importance of the pathophysiology of traumatic brain injury-acute lung injury, and thus confirm its role as a predictor of cerebral hypoxia, helping to establish an appropriate therapeutic strategy to improve functional outcomes and reduce mortality.