Exhaled Volatile Organic Compounds during Inflammation Induced by TNF-α in Ventilated Rats.

Systemic inflammation alters the composition of exhaled breath, possibly helping clinicians diagnose conditions such as sepsis. We therefore evaluated changes in exhaled breath of rats given tumor necrosis factor-alpha (TNF-α). Thirty male Sprague-Dawley rats were randomly assigned to three groups (n = 10 each) with intravenous injections of normal saline (control), 200 µg·kg-1 bodyweight TNF-α (TNF-α-200), or 600 µg·kg-1 bodyweight TNF-α (TNF-α-600), and were observed for 24 h or until death. Animals were ventilated with highly-purified synthetic air to analyze exhaled air by multicapillary column-ion mobility spectrometry. Volatile organic compounds (VOCs) were identified from a database. We recorded blood pressure and cardiac output, along with cytokine plasma concentrations. Control rats survived the 24 h observation period, whereas mean survival time decreased to 22 h for TNF-α-200 and 23 h for TNF-α-600 rats. Mean arterial pressure decreased in TNF-α groups, whereas IL-6 increased, consistent with mild to moderate inflammation. Hundreds of VOCs were detected in exhalome. P-cymol increased by a factor-of-two 4 h after injection of TNF-α-600 compared to the control and TNF-α-200. We found that 1-butanol and 1-pentanol increased in both TNF-α groups after 20 h compared to the control. As breath analysis distinguishes between two doses of TNF-α and none, we conclude that it might help clinicians identify systemic inflammation.

Leptomeningeal dissemination of low-grade neuroepithelial CNS tumors in adults: a 15-year experience.

BACKGROUND: Leptomeningeal dissemination (LD) in adults is an exceedingly rare complication of low-grade neuroepithelial CNS tumors (LGNs). We aimed to determine relative incidence, clinical presentation, and predictors of outcome. METHODS: We searched the quality control database of the Section of Neuro-Oncology, Yale Cancer Center, for patients with LGN (WHO grade I/II) seen between 2002 and 2017. For cases complicated by LD, we recorded demographics, clinical signs, histopathological diagnosis, and imaging findings. A comprehensive literature review was performed. RESULTS: Eleven consecutive patients with LD were identified, representing 2.3% of individuals with LGN seen at our institution between 2002 and 2017 (n = 475). Ependymoma was the predominant histological entity. Mean time interval from diagnosis of LGN to LD was 38.6 ± 10 months. Symptoms were mostly attributed to communicating hydrocephalus. Tumor deposits of LD were either nodular or linear with variable enhancement (nonenhancing lesions in 4 of 11 patients). Localized (surgery, radiosurgery, involved-field, or craniospinal radiation therapy) or systemic treatments (chemotherapy) were provided. All patients progressed radiographically. Median overall survival after LD was 102 months. Survival was prolonged when a combination of localized and systemic therapies was administered (188.5 vs 25.5 months; P = .03). Demographics and tumor spectrum reported in the literature were similar to our cohort. CONCLUSIONS: LD is a rare complication of LGNs. A high level of suspicion is required for timely diagnosis as early symptoms are nonspecific and commonly do not occur until years after initial tumor diagnosis. Repeated aggressive treatment appears to be beneficial in improving survival.

Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell-mediated neurotoxicity warrants evaluation in prospective clinical trials.