Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Normative reference values for the timed up-and-go test in Indian children aged four to 11 years old and their correlation with demographic characteristics: A cross-sectional study.

BACKGROUND: The timed up-and-go test (TUGT) is a quick, reliable, and valid assessment tool for evaluating functional mobility or dynamic balance. AIMS: The purpose of this study was to establish the normative values for TUGT in children aged 4 to 11 years old in Surat, India. METHODS: A total of 420 children (210 boys and 210 girls) were included. Subjects were divided into seven age groups. In each age group, 60 (30 males and 30 females) subjects were included. Subjects were randomly recruited from primary schools and underwent three trials of the TUGT. Then, the mean of the three TUGT trials was calculated for each participant. RESULTS: We formulated normative reference values for each of the seven age groups. The mean and standard deviation of the TUGT score across the total population was 6.00 ± 1.15 seconds. TUGT scores were compared between age groups and genders. Between boys and girls, we found no significant differences. Among the age groups, however, we found significant differences, with a P value of less than 0.001. Thus, only age showed a moderate negative correlation with TUGT score. CONCLUSIONS: This study provides normative reference values for the TUGT among Indian children aged four to 11 years old. We found that no differences existed between the TUGT results according to genders. Conversely, age had a moderate negative correlation: a comparison of TUGT scores among the ages revealed significant differences between the age groups.

Annealing effects on capacitance-voltage characteristics of a-Si/SiN(x) multilayer prepared using hot-wire chemical vapour deposition.

Post-deposition annealing of a-Si/SiN(x) multilayer films at different temperature shows varying shift in high frequency (1 MHz) capacitance-voltage (HFCV) characteristics. Various a-Si/SiN(x) multilayer films were deposited using hot wire chemical vapor deposition (HWCVD) and annealed in the temperature range of 800 to 900 degrees C to precipitate Si quantum dots (Si-QD) in a-Si layers. HFCV measurements of the as-deposited and annealed films in metal-insulator-semiconductor (MIS) structures show hysterisis in C-V curves. The hysteresis in the as-deposited films and annealed films is attributed to charge trapping in Si-dangling bonds in a-Si layer and in Si-QD respectively. The charge trapping density in Si-QD increases with temperature while the interface defects density (D(it)) remains constant.

Acute hibernation decreases myocardial pyruvate carboxylation and citrate release.

In the well-perfused heart, pyruvate carboxylation accounts for 3-6% of the citric acid cycle (CAC) flux, and CAC carbon is lost via citrate release. We investigated the effects of an acute reduction in coronary flow on these processes and on the tissue content of CAC intermediates. Measurements were made in an open-chest anesthetized swine model. Left anterior descending coronary artery blood flow was controlled by a extracorporeal perfusion circuit, and flow was decreased by 40% for 80 min to induce myocardial hibernation (n = 8). An intracoronary infusion of [U-(13)C(3)]lactate and [U-(13)C(3)]pyruvate was given to measure the entry of pyruvate into the CAC through pyruvate carboxylation from the (13)C-labeled isotopomers of CAC intermediates. Compared with normal coronary flow, myocardial hibernation resulted in parallel decreases of 65% and 79% in pyruvate carboxylation and net citrate release by the myocardium, respectively, and maintenance of the CAC intermediate content. Elevation of the arterial pyruvate concentration by 1 mM had no effect. Thus a 40% decrease in coronary blood flow resulted in a concomitant decrease in pyruvate carboxylation and citrate release as well as maintenance of the CAC intermediates.

Alterations in enzymes involved in fat metabolism after acute and chronic altitude exposure.

The purpose of this study was to examine the effect of acute (24 h) and chronic (5 wk) hypobaric hypoxic exposure equivalent to a simulated altitude of 4,300 m (446 mmHg) on the enzymes of fat metabolism. Heart, liver, and skeletal muscle were taken from 32 male Sprague-Dawley rats. Altitude exposure did not affect the activity of citrate synthase in any of the tissues, suggesting that mitochondrial content was unchanged. Carnitine palmitoyltransferase-I (CPT-I) activity was significantly reduced in the heart by both acute and chronic high altitude exposure compared with controls. A similar reduction was found for CPT-I activity in extensor digitorum longus after acute and chronic exposure compared with control animals. CPT-I activity was not affected by altitude exposure in the soleus muscle or the liver. 3-Hydroxyacyl-CoA dehydrogenase (beta-HAD) activity was significantly depressed in the hearts of chronically exposed animals compared with controls. No difference between acute and control animals was found in the heart for beta-HAD activity. Liver beta-HAD activity was also significantly decreased in the acclimatized as well as in the acute animals compared with the control group. Quadriceps beta-HAD activity was reduced for the chronic animals only compared with controls. These data suggest that acclimatization to high altitude selectively decreases key enzymes in fat utilization and oxidation in the heart, liver, and select skeletal muscles.

Partitioning of pyruvate between oxidation and anaplerosis in swine hearts.

The goal of this study was to measure flux through pyruvate carboxylation and decarboxylation in the heart in vivo. These rates were measured in the anterior wall of normal anesthetized swine hearts by infusing [U-(13)C(3)]lactate and/or [U-(13)C(3)] pyruvate into the left anterior descending (LAD) coronary artery. After 1 h, the tissue was freeze-clamped and analyzed by gas chromatography-mass spectrometry for the mass isotopomer distribution of citrate and its oxaloacetate moiety. LAD blood pyruvate and lactate enrichments and concentrations were constant after 15 min of infusion. Under near-normal physiological concentrations of lactate and pyruvate, pyruvate carboxylation and decarboxylation accounted for 4.7 +/- 0.3 and 41.5 +/- 2.0% of citrate formation, respectively. Similar relative fluxes were found when arterial pyruvate was raised from 0.2 to 1.1 mM. Addition of 1 mM octanoate to 1 mM pyruvate inhibited pyruvate decarboxylation by 93% without affecting carboxylation. The absence of M1 and M2 pyruvate demonstrated net irreversible pyruvate carboxylation. Under our experimental conditions we found that pyruvate carboxylation in the in vivo heart accounts for at least 3-6% of the citric acid cycle flux despite considerable variation in the flux through pyruvate decarboxylation.

Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure.

BACKGROUND: Pharmacological inhibition of carnitine palmitoyl transferase I (CPT-I), the enzyme controlling the rate of fatty acid transport into the mitochondria, prevents the contractile dysfunction, myosin isozyme shift and deterioration in sarcoplasmic reticulum Ca2+ handling that occurs in rat models of left ventricular hypertrophy. In this study we examine whether the improved cardiac function with beta blockade therapy in heart failure is associated with an alteration in CPT-I activity. METHODS AND RESULTS: We examined dogs with coronary microembolism-induced heart failure treated for 12 weeks with metoprolol (25 mg twice daily). Myocardial activities of CPT-I, medium-chain acyl co-enzyme A dehydrogenase (MCAD, a beta-oxidation enzyme), citrate synthase, and triglyceride content were measured. The progressive decrease in cardiac function was prevented by treatment with metoprolol, as reflected by an improved ejection fraction over 12 weeks in the metoprolol group (from 35% to 40%) compared to the untreated heart failure dogs (decrease from 36% to 26%). Dogs treated with metoprolol had a marked decrease in CPT-I activity (0.46 +/- 0.03 vs. 0.64 +/- 0.02 micromol min(-1) g(-1) wet weight; P < .02) along with an increase in triglyceride concentration compared to untreated heart failure dogs (3.9 +/- 0.3 v 4.9 +/- 0.2 micromol/g wet weight, respectively; P < .003). By contrast, MCAD and citrate synthase activities did not change. CONCLUSION: Metoprolol induced a decrease in CPT-I activity and an increase in triglyceride content. These results suggest that the improved function observed with beta blockers in heart failure could be due, in part, to a decrease in CPT-I activity and less fatty acid oxidation by the heart.

Role of electron microscopy in interstitial lung disease.

Although electron microscopy no longer enjoys the important role in the diagnosis of interstitial lung diseases that it had in the 1960s and 1970s, it remains an important adjunct in the differential diagnosis of certain pulmonary diseases. Examples include various manifestations of systemic lupus erythematous pneumonitis, in which the presence of tubuloreticular structures and electron-dense deposits are useful for diagnosis; immotile cilia disorders, in which qualitative and now quantitative studies of the cilia of respiratory epithelial cells can help to establish the diagnosis; infections by viruses and other subcellular microorganisms as shown by the role played by electron microscopy in the initial diagnosis of the Hantavirus pulmonary syndrome; pneumoconioses, in which, in conjunction with elemental analysis probes, scanning electron microscopy is of critical importance in establishing the presence of offending foreign compounds in lung tissue or fluids; pulmonary fibrilloses, such as amyloidosis, light chain disease, and fibrillary glomerulonephritis, affecting the lung; and cases of alveolar proteinosis or Langerhans cell granulomatosis diagnosed from fluids such as bronchoalveolar lavages or small tissue samples. As important, electron microscopy remains of enormous usefulness in the study of early structural events leading to the pathogenesis of diseases. For example, recent uses of the technique have focused on the alveolar-capillary wall damage induced by alveolitis in hypersensitivity pneumonitis and sarcoidosis. In summary, electron microscopy remains a useful method in the study and diagnosis of some interstitial lung diseases, but because of its expense it is incumbent on the clinician to use good judgment in the selection of cases and diseases for study by this method.

Insulin, transforming growth factors, and substrates modulate growth of guinea pig pancreatic duct cells in vitro.

BACKGROUND & AIMS: Little is known of the physiological mechanisms that control cellular renewal in the pancreatic excretory duct system. This study investigated the effects of potential regulatory substances on the growth of cultured guinea pig pancreatic duct epithelial monolayers. METHODS: Pancreatic duct explants were cultured for 3 days on plastic and on permeable filters in the presence and absence of different substances. Growth of epithelial monolayers from these explants was measured by 5-bromo-2'-deoxyuridine incorporation and morphometric procedures. RESULTS: Epidermal growth factor and insulin both enhanced monolayer growth and together had an additive effect. Transforming growth factor alpha enhanced and transforming growth factor beta inhibited growth, whereas glucagon, somatostatin, pancreatic polypeptide, secretin, cerulein, bombesin, and dexamethasone had no significant effects. Monolayer growth on type 1 collagen-coated filters was enhanced when compared with that of monolayers grown on tissue culture plastic. Cell growth from explants on filters coated with type IV collagen and fibronectin was comparable with that on plastic, whereas growth on Matrigel- or laminin-coated filters was reduced. CONCLUSIONS: Insulin, transforming growth factors, and substrate components modulate growth of pancreatic duct epithelial cells in vitro, suggesting that they are important regulators of cell division in the excretory duct system of the intact pancreas.

3'-untranslated region of SP-B mRNA mediates inhibitory effects of TPA and TNF-alpha on SP-B expression.

Surfactant protein-B (SP-B) is a small hydrophobic polypeptide that enhances spreading and stability of surfactant phospholipids in the alveolus of the lung. Decreased expression of SP-B is associated with respiratory failure in premature infants and in adult patients with acute respiratory distress syndrome (ARDS). Tumor necrosis factor-alpha (TNF-alpha) and 12-O-tetradecanoylphorbol-13 acetate (TPA) cause ARDS-like lung injury in vivo. Inhibitory effects of TPA and TNF-alpha on SP-B mRNA expression in vitro were mediated by decreased SP-B mRNA stability rather than by decreased rate of SP-B gene transcription. In the present study, a human pulmonary adenocarcinoma cell line, NCI H441-4, was stably transfected with expression vectors consisting of the thymidine kinase (TK) promotor and human growth hormone (hGH) gene, in which the hGH 3'-untranslated region (3'-UTR) was replaced by the 2.0-kb human SP-B cDNA [pTKGH(SP-B2.0)] or the 837-bp human SP-B 3'-UTR [pTKGH(SP-B.837)]. The mRNAs and cellular growth hormone protein generated from the chimeric TKGH(SP-B2.0) and TKGH(SP-B.837) genes were each inhibited by approximately 50% by TPA and TNF-alpha. Dexamethasone decreased the inhibitory effects of TPA and TNF-alpha. The inhibition of steady-state hGH-SP-B mRNA by TPA and TNF-alpha was mediated by a cis-active element located in the 3-UTR region of SP-B mRNA.