Frequency of use and adequacy of Cochrane risk of bias tool 2 in non-Cochrane systematic reviews published in 2020: Meta-research study.

Risk of bias (RoB) assessment is essential to the systematic review methodology. The new version of the Cochrane RoB tool for randomized trials (RoB 2) was published in 2019 to address limitations identified since the first version of the tool was published in 2008 and to increase the reliability of assessments. This study analyzed the frequency of usage of the RoB 2 and the adequacy of reporting the RoB 2 assessments in non-Cochrane reviews published in 2020. This meta-research study included non-Cochrane systematic reviews of interventions published in 2020. For the reviews that used the RoB 2 tool, we analyzed the reporting of the RoB 2 assessment. Among 3880 included reviews, the Cochrane RoB 1 tool was the most frequently used (N = 2228; 57.4%), followed by the Cochrane RoB 2 tool (N = 267; 6.9%). From 267 reviews that reported using the RoB 2 tool, 213 (79.8%) actually used it. In 26 (12.2%) reviews, erroneous statements were used to indicate the RoB 2 assessment. Only 20 (9.4%) reviews presented a complete RoB 2 assessment with a detailed table of answers to all signaling questions. The judgment of risk of bias by the RoB 2 tool was not justified by a comment in 158 (74.2%) reviews. Only in 33 (14.5%) of reviews the judgment in all domains was justified in the accompanying comment. In most reviews (81.7%), the RoB was inadequately assessed at the study level. In conclusion, the majority of non-Cochrane reviews published in 2020 still used the Cochrane RoB 1 tool. Many reviews used the RoB 2 tool inadequately. Further studies about the uptake and the use of the RoB 2 tool are needed.

CAR t-cell therapy in BOlogNa-NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON-NEUTRAL): proposed protocol and results from an Italian study.

OBJECTIVE: To investigate neurotoxicity clinical and instrumental features, incidence, risk factors, and early and long-term prognosis in lymphoma patients who received CAR T-cell therapy. METHODS: In this prospective study, consecutive refractory B-cell non-Hodgkin lymphoma patients who received CAR T-cell therapy were included. Patients were comprehensively evaluated (neurological examination, EEG, brain MRI, and neuropsychological test) before and after (two and twelve months) CAR T-cells. From the day of CAR T-cells infusion, patients underwent daily neurological examinations to monitor the development of neurotoxicity. RESULTS: Forty-six patients were included in the study. The median age was 56.5 years, and 13 (28%) were females. Seventeen patients (37%) developed neurotoxicity, characterized by encephalopathy frequently associated with language disturbances (65%) and frontal lobe dysfunction (65%). EEG and brain FDG-PET findings also supported a predominant frontal lobe involvement. The median time at onset and duration were five and eight days, respectively. Baseline EEG abnormalities predicted ICANS development in the multivariable analysis (OR 4.771; CI 1.081-21.048; p = 0.039). Notably, CRS was invariably present before or concomitant with neurotoxicity, and all patients who exhibited severe CRS (grade ≥ 3) developed neurotoxicity. Serum inflammatory markers were significantly higher in patients who developed neurotoxicity. A complete neurological resolution following corticosteroids and anti-cytokines monoclonal antibodies was reached in all patients treated, except for one patient developing a fatal fulminant cerebral edema. All surviving patients completed the 1-year follow-up, and no long-term neurotoxicity was observed. CONCLUSIONS: In the first prospective Italian real-life study, we presented novel clinical and investigative insights into ICANS diagnosis, predictive factors, and prognosis.

Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity.

Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.