IL-8 correlates with nonresponse to neoadjuvant nivolumab in HPV positive HNSCC via a potential extracellular vesicle miR-146a mediated mechanism

Therapy using anti-PD-1 immune checkpoint inhibitors (ICI) has revolutionized the treatment of many cancers including head and neck squamous cell carcinomas (HNSCC), but only a fraction of patients respond. To better understand the molecular mechanisms driving resistance, we performed extensive analysis of plasma and tumor tissues before and after a 4-week neoadjuvant trial in which HNSCC patients were treated with the anti-PD-1 inhibitor, nivolumab. Luminex cytokine analysis of patient plasma demonstrated that HPV^pos nonresponders displayed high levels of the proinflammatory chemokine, interleukin-8 (IL-8), which decreased after ICI treatment, but remained higher than responders. miRNAseq analysis of tetraspanin-enriched small extracellular vesicles (sEV) purified from plasma of HPV^pos nonresponders demonstrated significantly lower levels of seven miRNAs that target IL-8 including miR-146a. Levels of the pro-survival oncoprotein Dsg2, which has been to down-regulate miR-146a, are elevated with HPV^pos tumors displaying higher levels than HPV^neg tumors. Dsg2 levels decrease significantly following ICI in responders but not in nonresponders. In cultured HPV^pos cells, restoration of miR-146a by forced expression or treatment with miR-146a-loaded sEV, reduced IL-8 level, blocked cell cycle progression, and promoted cell death. These findings identify Dsg2, miR-146a, and IL-8 as potential biomarkers for ICI response and suggest that the Dsg2/miR-146a/IL-8 signaling axis negatively impacts ICI treatment outcomes and could be targeted to improve ICI responsiveness in HPV^pos HNSCC patients.     

Simultaneous trans-hepatic portal and hepatic vein embolization before major hepatectomy: the liver venous deprivation technique

Purpose

To assess technical feasibility, safety, and efficacy of the liver venous deprivation (LVD) technique that combines both portal and hepatic vein embolization during the same procedure for liver preparation before major hepatectomy.

Materials and methods

Seven patients (mean age:63.6y[42-77y]) underwent trans-hepatic LVD for liver metastases (n?=?2), hepatocellular carcinoma (n?=?1), intrahepatic cholangiocarcinoma (n?=?3) and Klatskin tumour (n?=?1). Assessment of future remnant liver (FRL) volume, liver enzymes and histology was performed.

Results

Technical success was 100 %. No complication occurred before surgery. Resection was performed in 6/7 patients. CT-scan revealed hepatic congestion in the venous-deprived area (6/7 patients). A mean of 3 days (range: 1–8 days) after LVD, transaminases increased (AST: from 42?±?24U/L to 103?±?118U/L, ALT: from 45?±?25U/L to 163?±?205U/L). Twenty-three days (range: 13–30 days) after LVD, FRL increased from 28.2 % (range: 22.4–33.3 %) to 40.9 % (range: 33.6–59.3 %). During the first 7 days, venous-deprived liver volume increased (+13.4 %) probably reflecting vascular congestion, whereas it strongly decreased (-21.3 %) at 3-4 weeks. Histology (embolized lobe) revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy in all patients.

Conclusion

Trans-hepatic LVD technique is feasible, well tolerated and provides fast and important hypertrophy of the FRL. This new technique needs to be further evaluated and compared to portal vein embolization.

Key Points

? Twenty-three days after LVD, FRL increased from 28.2 % (range:22.4-33.3 %) to 40.9 % (range:33.6–59.3 %) ? During the first 7 days, venous-deprived liver volume increased (+13.4 %) ? Venous-deprived liver volume strongly decreased (mean atrophy:229 cc; -21.3 %) at 3-4 weeks ? Histology of venous-deprived liver revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy

     

A snapshot of some pLI score pitfalls

The pLI score reflects the tolerance of a given gene to the loss of function on the basis of the number of protein truncating variants, that is, the frameshift, splice donor, splice acceptor, and stop‐gain variants referenced for this gene in control databases weighted by the size of the gene and the sequencing coverage. It is frequently used to prioritize candidate genes when analyzing whole exome or whole genome data. We list here the main pitfalls to consider before using this score. Concrete illustrations are given for each of these pitfalls.     

Measurement of tracheal temperature is not a reliable index of total respiratory heat loss in mechanically ventilated patients

The forced oscillation technique (FOT) is a method for non-invasively assessing respiratory mechanics that is applicable both in paralysed and non-paralysed patients. As the FOT requires a minimal modification of the conventional ventilation setting and does not interfere with the ventilation protocol, the technique is potentially useful to monitor patient mechanics during invasive and noninvasive ventilation. FOT allows the assessment of the respiratory system linearity by measuring resistance and reactance at different lung volumes or end-expiratory pressures. Moreover, FOT allows the physician to track the changes in patient mechanics along the ventilation cycle. Applying FOT at different frequencies may allow the physician to interpret patient mechanics in terms of models with pathophysiological interest. The current methodological and technical experience make possible the implementation of portable and compact computerised FOT systems specifically addressed to its application in the mechanical ventilation setting.