Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma.

BACKGROUND: Prior studies characterized the association of molecular alterations with treatment-specific outcomes in KRAS-mutant (KRASMUT) lung adenocarcinoma (LUAD). Less is known about the prognostic role of molecular alterations and their associations with metastatic disease. PATIENTS AND METHODS: We analyzed clinicogenomic data from 1817 patients with KRASMUT LUAD sequenced at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC). Patients with metastatic (M1) and nonmetastatic (M0) disease were compared. Transcriptomic data from The Cancer Genome Atlas (TCGA) were investigated to characterize the biology of differential associations with clinical outcomes. Organ-specific metastasis was associated with overall survival (OS). RESULTS: KEAP1 (DFCI: OR = 2.3, q = 0.04; MSKCC: OR = 2.2, q = 0.00027) and SMARCA4 mutations (DFCI: OR = 2.5, q = 0.06; MSKCC: OR = 2.6, q = 0.0021) were enriched in M1 versus M0 tumors. On integrative modeling, NRF2 activation was the genomic feature most associated with OS. KEAP1 mutations were enriched in M1 versus M0 tumors independent of STK11 status (KEAP1MUT/STK11WT: DFCI OR = 3.0, P = 0.0064; MSKCC OR = 2.0, P = 0.041; KEAP1MUT/STK11MUT: DFCI OR = 2.3, P = 0.0063; MSKCC OR = 2.5, P = 3.6 × 10-05); STK11 mutations without KEAP1 loss were not associated with stage (KEAP1WT/STK11MUT: DFCI OR = 0.97, P = 1.0; MSKCC OR = 1.2, P = 0.33) or outcome. KEAP1/KRAS-mutated tumors with and without STK11 mutations exhibited high functional STK11 loss. The negative effects of KEAP1 were compounded in the presence of bone (HR = 2.3, P = 4.4 × 10-14) and negated in the presence of lymph node metastasis (HR = 1.0, P = 0.91). CONCLUSIONS: Mutations in KEAP1 and SMARCA4, but not STK11, were associated with metastatic disease and poor OS. Functional STK11 loss, however, may contribute to poor outcomes in KEAP1MUT tumors. Integrating molecular data with clinical and metastatic-site annotations can more accurately risk stratify patients.

Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. PATIENTS AND METHODS: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. RESULTS: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. CONCLUSIONS: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.

EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.

BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

Effect of elongation rate on the failure properties of the rabbit anterior cruciate ligament.

The effect of elongation rate on the failure properties of the rabbit femur-anterior crucicate ligament-tibia were investigated. Paired limbs were elongated to failure at rates of 0.0001 m s(-1) and 0.92 m s(-1). Two distinct types of tibial avulsion injury reflecting rate-dependent areas of weakness were noted. 'Bony avulsions' formed by the junction between cortical and trabecular bone comprised the predominant injury observed at the faster elongation rate. 'Fibrous avulsions' between the zones of mineralized fibrocartilage and bone occurred predominantly at the slower elongation rate. The faster rate significantly increased ultimate load (74%) and stiffness (615%) on average, relative to the slow rate. In contrast to what has been previously described, there was a significant decrease in failure deformation (79%) at the faster rate.

On the understanding of clinical instability.

STUDY DESIGN: Three-dimensional flexibility changes due to the application of an external fixator at C4-C5 were studied in cervical spine specimens. OBJECTIVES: To evaluate the biomechanical effects of applying a cervical external fixator to a patient using an in vitro model. SUMMARY OF BACKGROUND DATA: There is controversy regarding the relationship between the changes in spinal motion and clinical instability. METHODS: Using fresh cadaveric C4-C7 specimens, multidirectional flexibility was measured at all vertebral levels, before and after the fixator application at C4-C5, C5-C6, and C4-C6. RESULTS: The average ranges of motion for flexion, extension, lateral bending, and axial rotation were 8.3 degrees, 7.2 degrees, 5.3 degrees, and 5.6 degrees, which decreased by 40%, 27%, 32%, and 58%, respectively, because of the fixator application. The corresponding neutral zones were 3.4 degrees, 3.4 degrees, 3.0 degrees, and 2.0 degrees, which decreased by 76%, 76%, 54% and 69%, respectively. The decreases with the fixation at C4-C5 were similar to those for fixation at C5-C6. CONCLUSIONS: This in vitro study documented that the application of an external fixator to the cervical spine decreases the intervertebral motion in general, and decreases flexion, extension and torsional neutral zones in particular. The findings help explain the clinical instability of the spine and support the hypothesis that the neutral zone is more closely associated with the clinical instability than is the range of motion.

[The unstable spine--an "in vitro" and "in vivo study" on better understanding of clinical instability]. / Die instabile Wirbelsäule--eine "In-vitro-" und "In-vivo-Studie" zum besseren Verständnis der klinischen Instabilität.

In cases of suspected painful instability of a cervical segment, temporary external fixation by means of external fixator was applied. The segmental immobilization caused immediate relief of pain. The pain reoccurred after removal of the immobilization. The effect of immobilization by external fixation was investigated in biomechanical tests using fresh cadaveric C4-7 specimens. Multidirectional flexibility was measured before and after application of the fixator at C4/C5, C5/C6 and C4-6. We measured the reduction in motion between the different segments. In every situation the neutral zone decreased more than the range of motion. The findings are helpful to understand the clinical instability of the spine and support the hypothesis that the neutral zone is more closely associated with clinical instability than range of motion. The combination of clinical application and biomechanical investigation allowed us to establish a direct correlation between instability and pain.

Anular incision technique on the strength and multidirectional flexibility of the healing intervertebral disc.

STUDY DESIGN: This study used a sheep model to biomechanically analyze the healing strength of the anulus fibrosus after two types of anular incisions. OBJECTIVE: This study evaluated whether the type of anular incision made at the time of lumbar discectomy plays a role in the subsequent healing strength of the anulus and the biomechanical flexibility of the corresponding motion segment. METHODS: Two types of anular incision, a full thickness removal of a box or window of anulus and a full thickness straight transverse slit through the anulus, were made in the intervertebral discs of 18 adult sheep. After healing times of 2, 4, and 6 weeks, the intervertebral discs were tested versus control levels for strength of anular healing and biomechanical flexibility of the corresponding motion segment. RESULTS: The box incised discs showed a significantly greater loss in strength during the early healing phase (2 to 4 weeks) and a longer response before recovering anular strength when compared with the slit-incised discs. The type of incision also affected the multidirectional flexibility of the motion segments in a differentiated manner. Larger amounts of motion were seen with the box incision when compared with the slit incision at all time periods and in all pure moments. CONCLUSION: The technique of anular incision plays a definite role in the timing and strength of subsequent anular healing. The box incision through the anulus led to significantly weaker healing than did the slit incision in the early healing phase (2-4 weeks). Also, larger amounts of motion were seen in the vertebral motion segments of those discs undergoing box incision when compared with slit or control levels.