Releasing the brake: CTLA-4 loss turbocharges CAR T cells.

Immune checkpoint receptor-induced T cell dysfunction is a major cause of CAR T cell treatment failure. In this issue, Agarwal et al. report that CRISPR/Cas9 deletion of CTLA4, but not PDCD1 or CTLA4 and PDCD1, enhances CD28 signaling, restoring fitness and antitumor function of CAR T cells, including those derived from patients who failed CAR T cell therapy.

Influence of limited examination conditions on contrast-enhanced sonography for characterising liver lesions.

AIM: To assess the influence of difficult examination conditions onto the diagnostic performance of CEUS (contrast-enhanced ultrasound) in focal liver lesions (FLL). METHODS: 77 liver CEUS examinations of 75 patients were analysed retrospectively. CEUS was performed as the first diagnostic procedure by one experienced sonographer after bolus injection of 1.0 up to 2.4 ml sulphur hexafluoride microbubbles using a high-end ultrasound device with a high resolution multifrequency probe (1-6 MHz). The combination of complementary imaging (CT or MRI), histology and CEUS follow up of at least 6 months was considered. Cross tables were used to define the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy. Chi-Square Test analysed categorical data. RESULTS: The patients were between 18 and 84 years old (mean 62±11 years). 26 patients suffered from liver cirrhosis (33.8%). 52 patients (67.5%) received therapy for an oncological disease. The final diagnosis showed 52 malignant FLLs including 24 hepatocellular carcinomas (HCCs), 9 cholangiocellular carcinomas (CCCs) and 19 metastases from different primary tumors. In the other 25 patients no malignant lesions could be detected, three of them presenting however liver haemangioma and two of them liver cysts. The overall lesions' size according to the CEUS findings ranged from 7 to 100 mm (mean 31.1±22.6 mm). Under good examination conditions the malignant potential of a tumor was diagnosed correctly by CEUS in 98.0% of cases (Sensitivity 97.1%, Specificity 100%, PPV 100%, NPV 94.1%, diagnostic accuracy 98.0%). Limited examination conditions (e.g. obesity, meteorism) were present in 35.1% of cases with a decrease of the diagnostic accuracy to 92.6% (Sensitivity 100%, Specificity 77.8%, PPV 90.0%, NPV 100%). CONCLUSION: Despite the influence of difficult examination conditions, CEUS is - in the hands of an experienced sonographer - an excellent diagnostic procedure for the assessment of liver lesions.