ABSTRACT
OBJECTIVE@#To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy.@*METHODS@#Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms.@*RESULTS@#(1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline.@*CONCLUSION@#Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient's natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.
Subject(s)
Humans , Carcinoma, Hepatocellular , Graft vs Host Disease , Killer Cells, Natural , Leukocytes, Mononuclear , Liver NeoplasmsABSTRACT
OBJECTIVE@#To explore the value and significance of the clinical application of whole exome sequencing (WES) in monogenic hereditary disorders in critically ill newborns.@*METHODS@#The critically ill newborns in the neonatal intensive care unit with suspected hereditary diseases or unclear clinical diagnosis from June 2016 to December 2018 were enrolled. The whole blood samples from both newborns and parents were collected for WES. The detected genetic mutations were classified, the mutations associated with clinical phenotypes were searched for, and Sanger sequencing was performed to verify the mutations.@*RESULTS@#A total of 45 newborns were enrolled, including 22 males and 23 females, and the median age of onset was 2.0 days. Of the 45 newborns, 12 (27%) were confirmed with monogenic hereditary disorders by molecular diagnostics, and the median age at diagnosis was 31.5 days. Of the 12 newborns with monogenic hereditary disorders, 5 (42%) were partially associated with clinical phenotypes but confirmed with monogenic hereditary disorders by additional information supplement and analysis. The improvement rate of newborns with monogenic hereditary disorders was 67% (8/12) after treatment.@*CONCLUSIONS@#WES technology is a powerful tool for finding genetic mutations in monogenic hereditary disorders in critically ill newborns and can play a crucial role in clinical decision-making. However, a comprehensive interpretation of sequence data requires physicians to take the clinical phenotypes and the results of WES into consideration simultaneously.