Exposure to low intensity ultrasound removes paclitaxel cytotoxicity in breast and ovarian cancer cells.

BACKGROUND: Paclitaxel (Taxol) is a microtubule-stabilizing drug used to treat several solid tumors, including ovarian, breast, non-small cell lung, and pancreatic cancers. The current treatment of ovarian cancer is chemotherapy using paclitaxel in combination with carboplatin as a frontline agent, and paclitaxel is also used in salvage treatment as a second line drug with a dose intensive regimen following recurrence. More recently, a dose dense approach for paclitaxel has been used to treat metastatic breast cancer with success. Paclitaxel binds to beta tubulin with high affinity and stabilizes microtubule bundles. As a consequence of targeting microtubules, paclitaxel kills cancer cells through inhibition of mitosis, causing mitotic catastrophes, and by additional, not yet well defined non-mitotic mechanism(s). RESULTS: In exploring methods to modulate activity of paclitaxel in causing cancer cell death, we unexpectedly found that a brief exposure of paclitaxel-treated cells in culture to low intensity ultrasound waves prevented the paclitaxel-induced cytotoxicity and death of the cancer cells. The treatment with ultrasound shock waves was found to transiently disrupt the microtubule cytoskeleton and to eliminate paclitaxel-induced rigid microtubule bundles. When cellular microtubules were labelled with a fluorescent paclitaxel analog, exposure to ultrasound waves led to the disassembly of the labeled microtubules and localization of the signals to perinuclear compartments, which were determined to be lysosomes. CONCLUSIONS: We suggest that ultrasound disrupts the paclitaxel-induced rigid microtubule cytoskeleton, generating paclitaxel bound fragments that undergo degradation. A new microtubule network forms from tubulins that are not bound by paclitaxel. Hence, ultrasound shock waves are able to abolish paclitaxel impact on microtubules. Thus, our results demonstrate that a brief exposure to low intensity ultrasound can reduce and/or eliminate cytotoxicity associated with paclitaxel treatment of cancer cells in cultures.

The Ventilatory Ratio as a Predictor of Successful Weaning from a Veno-Venous Extracorporeal Membrane Oxygenator.

Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a critical intervention for patients with severe lung failure, especially acute respiratory distress syndrome (ARDS). The weaning process from ECMO relies largely on expert opinion due to a lack of evidence-based guidelines. The ventilatory ratio (VR), which correlates with dead space and mortality in ARDS, is calculated as [minute ventilation (mL/min) x arterial pCO2 (mmHg)]/[predicted body weight × 100 × 37.5]. Objectives: The aim of this study was to determine whether the VR alone can serve as a reliable predictor of safe or unsafe liberation from VV-ECMO in critically ill patients. Methods: A multicenter retrospective analysis was conducted, involving ARDS patients undergoing VV-ECMO weaning at Massachusetts General Hospital (January 2016 - December 2020) and at the University Hospital Aachen (January 2012-December 2021). Safe liberation was defined as no need for ECMO recannulation within 48 h after decannulation. Clinical parameters were obtained for both centers at the same time point: 30 min after the start of the SGOT (sweep gas off trial). Results: Of the patients studied, 83.3% (70/84) were successfully weaned from VV-ECMO. The VR emerged as a significant predictor of unsafe liberation (OR per unit increase: 0.38; CI: 0.17-0.81; p = 0.01). Patients who could not be safely liberated had longer ICU and hospital stays, with a trend towards higher mortality (38% vs. 13%; p = 0.05). Conclusions: The VR may be a valuable predictor for safe liberation from VV-ECMO in ARDS patients, with higher VR values associated with an elevated risk of unsuccessful weaning and adverse clinical outcomes.