Medical treatment of pulmonary nontuberculous mycobacteria (NTM) disease has highly variable outcomes. Despite the use of multiple antibiotics, sputum clearance is often difficult to achieve, especially in cases with macrolide resistant NTM infection. Immunocompromised patients and those with structural lung disease are at increased risk, although occurrence in immunocompetent patients without structural lung disease is well recognised. Most pulmonary NTM disease involves Mycobacterium avium complex (MAC), but with enhanced identification multiple species have now been recognised as opportunistic pathogens. The observed increase in NTM disease, especially infection with multidrug-resistant Mycobacterium abscessus complex, is probably multifactorial. Surgery has been used as adjuvant treatment in patients with 1) focal disease that can be removed or 2) bothersome symptoms despite medical treatment that can be ameliorated. Early post-surgical mortality is low, but long-term morbidity and mortality are highly dependent on the degree of lung involvement and the residual lung function, the potency of medical treatment and the type of surgical intervention. In conjunction with antibiotic therapy, reported post-surgical sputum clearance was excellent, although publication bias should be considered. Bronchopleural fistulae were problematic, especially in pneumonectomy cases. Study results support the use of minimal resection surgery, in a carefully selected subgroup of patients with focal disease or persistent symptoms.Educational aimsTo critically review the literature describing the use of surgery in the treatment of pulmonary disease caused by nontuberculous mycobacteria (NTM).To assess the outcomes and complications observed with different surgical approaches used in the treatment of pulmonary NTM disease.
<div>Abstract<p>The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients.</p>Significance:<p>These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.</p></div>
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