STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC. MATERIALS AND METHODS: This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62). RESULTS: Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local. CONCLUSION: In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

Radiation Therapy Without Anesthesia for a 2-Year-Old Child Using Audio-Visual Assisted Therapeutic Ambience in Radiation Therapy (AVATAR).

PURPOSE: Radiation therapy (RT) is essential to managing many pediatric malignancies but can provoke anxiety, fear, and discomfort for children owing to prolonged treatment time, extended course, and restrictive immobilization. Patients younger than 10 years frequently require daily general anesthesia (GA), which is resource intensive, expensive, potentially toxic, and anxiety and fear provoking. Audio-Visual Assisted Therapeutic Ambience in Radiation Therapy (AVATAR), a video streaming device, has been proposed as an alternative to anesthesia in patients aged 3 to 10 years. A pilot study evaluating the efficacy of this novel innovation is accruing, but patients younger than 3 years are ineligible. METHODS AND MATERIALS: We simulated a 2-year-old with stage IV Wilms tumor for bilateral whole-lung and left-flank irradiation without GA. Using AVATAR, we attempted to deliver RT to this patient without sedation. Patient anxiety at the time of simulation and at the beginning, middle, and end of the treatment course was characterized using the validated Modified Yale Preoperative Anxiety Score (mYPAS) measurement tool. RESULTS: Although the patient tolerated computed tomography simulation without GA or AVATAR use, his mYPAS of 14 out of 18 indicated significant anxiety. Using AVATAR, all treatments were delivered without GA; his mYPASs were 5 and 4 (the lowest possible) and 4 at the first, midcourse, and final treatments, indicating no significant anxiety and a decrease from the pre-AVATAR baseline. Without GA, the time to deliver RT decreased by 66% from 90 to 30 minutes. CONCLUSIONS: We describe an expanded, previously unreported indication for AVATAR by demonstrating the feasibility of this approach to reduce or omit anesthesia in appropriate younger patients currently excluded from ongoing trials. The financial and quality-of-life benefits (including decreased stress, anxiety, toxic effects, cost, and appointment time) of AVATAR use may be extendable to a younger patient population than previously thought. In older children, prospective validation is ongoing, but additional study in patients younger than 3 years is needed.

Differential involvement of toll-like receptors 2 and 4 in the host response to acute respiratory infections with wild-type and mutant Haemophilus influenzae strains.

We used a mouse model of acute respiratory infections to investigate the role of Toll-like receptor 2 (TLR2) and TLR4 in the host response to Haemophilus influenzae. Acute aerosol exposures to wild-type strains of H. influenzae showed that TLR4 function was essential for TNF-alpha induction, neutrophil influx, and bacterial clearance. To determine how lipooligosaccharide (LOS) modifications would affect the role of TLR4 in inducing the host response, we used acute infections with an H. influenzae strain expressing a mutation in the htrB gene. This mutant strain expresses an LOS subunit with decreased acylation. In response to H. influenzae htrB infection, tumor necrosis factor alpha (TNF-alpha) secretion remained TLR4 dependent. But the decrease in LOS acylation made the neutrophil influx and the bacterial clearance also dependent on TLR2, as shown by the decreased host response elicited in TLR2 knockout mice compared to C57BL/6 mice. A subsequent analysis of TLR2 and TLR4 gene expression by quantitative PCR indicated that TLR4 function induces TLR2 expression and vice versa. These results indicate that some changes in the LOS subunit of H. influenzae can favor signaling through non-TLR4 receptors, such as TLR2. The results also indicate a close interaction between TLR4 and TLR2 that tightly regulates the expression of both receptors.