Combined Nasoseptal and Inferior Turbinate Flap for Reconstruction of Large Skull Base Defect After Expanded Endonasal Approach: Operative Technique

International audienceBACKROUND:Increasing indications for endoscopic endonasal approaches have led neurosurgeons to develop new reconstruction techniques for larger skull base defects. Vascularized grafts have been a great adjunction to reduce the rate of cerebrospinal fluid leak and can also be used to cover exposed critical structures such as the internal carotid artery. The nasoseptal flap and the inferior or middle turbinate flap are thus widely used in endoscopic skull base surgery, but may be insufficient for very large defects.OBJECTIVE:To present a new mucosal flap used to cover large skull base defects in which the mucosa of the inferior turbinate, inferior meatus, nasal floor, and nasal septum is harvested in 1 piece keeping both vascular pedicles intact (inferior turbinate and septal arteries).METHODS:We describe a surgical technique to harvest a combined inferior turbinate-nasoseptal flap.RESULTS:Technical pearls and surgical pitfalls are described through 2 clinical cases in which the nasoseptal mucosa was partially damaged during a previous surgery, rendering the nasoseptal flap insufficient by itself. The flap is harvested thanks to 2 mucosal cuts: a first circular cut around the choanal arch and the junction between the hard and the soft palate, and a second one combining classical cuts of the nasoseptal flap and the inferior turbinate flap.CONCLUSION:The inferior turbinate-nasoseptal flap can be a useful alternative in patients whose septal mucosa was partially damaged and/or with very large postoperative skull base defects

sGCα1β1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGCα1-deficient (sGCα1−/−) mice to unequivocally determine the role of sGCα1β1 in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGCα1−/− mice on the C57BL/6 background (sGCα1−/−B6 mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGCα1−/−B6 than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca2+ handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGCα1−/−B6 than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGCα1−/−B6 compared with WT mice. Together, these findings suggest that cGMP generated by sGCα1β1 protects against cardiac dysfunction and mortality in murine inflammatory shock models

Dramatic In Vivo Efficacy of the EZH2-Inhibitor Tazemetostat in PBRM1-Mutated Human Chordoma Xenograft

Chordomas are rare neoplasms characterized by a high recurrence rate and a poor long-term prognosis. Considering their chemo-/radio-resistance, alternative treatment strategies are strongly required, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complexes are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this pathology. Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p = 0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed. Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1 variant supports further evaluation for EZH2-inhibitors in this subgroup of chordomas