Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation.

BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study. METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety. RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug discontinuation in 6.9% of patients. CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; ClinicalTrials.gov number, NCT03785249.).

Acquired Resistance to KRASG12C Inhibition in Cancer.

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).

Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors.

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer.

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.

Methods Used to Maximize Follow-Up: Lessons Learned From the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials.

OBJECTIVES: To describe telephone interview completion rates among 12-month cardiac arrest survivors enrolled in the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials, identify key characteristics of the completed follow-up interviews at both 3- and 12-month postcardiac arrest, and describe strategies implemented to promote follow-up. SETTING: Centralized telephone follow-up interviews. DESIGN: Retrospective report of data collected for Therapeutic Hypothermia after Pediatric Cardiac Arrest trials, and summary of strategies used to maximize follow-up completion. PATIENTS: Twelve-month survivors (n = 251) from 39 Therapeutic Hypothermia after Pediatric Cardiac Arrest PICU sites in the United States, Canada, and United Kingdom. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The 3- and 12-month telephone interviews included completion of the Vineland Adaptive Behavior Scales, Second Edition. Vineland Adaptive Behavior Scales, Second Edition data were available on 96% of 3-month survivors (242/251) and 95% of 12-month survivors (239/251) with no differences in demographics between those with and without completed Vineland Adaptive Behavior Scales, Second Edition. At 12 months, a substantial minority of interviews were completed with caregivers other than parents (10%), after calls attempts were made on 6 or more days (18%), and during evenings/weekends (17%). Strategies included emphasizing the relationship between study teams and participants, ongoing communication between study team members across sites, promoting site engagement during the study's final year, and withholding payment for work associated with the primary outcome until work had been completed. CONCLUSIONS: It is feasible to use telephone follow-up interviews to successfully collect detailed neurobehavioral outcome about children following pediatric cardiac arrest. Future studies should consider availability of the telephone interviewer to conduct calls at times convenient for families, using a range of respondents, ongoing engagement with site teams, and site payment related to primary outcome completion.

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes.

BACKGROUND: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study. METHODS: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. RESULTS: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [Cmax ] after TIW dosing of 0.2 ng/mL/mg). CONCLUSIONS: To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.

Extracorporeal Cardiopulmonary Resuscitation: One-Year Survival and Neurobehavioral Outcome Among Infants and Children With In-Hospital Cardiac Arrest.

OBJECTIVE: To describe neurobehavioral outcomes and investigate factors associated with survival and survival with good neurobehavioral outcome 1 year after in-hospital cardiac arrest for children who received extracorporeal cardiopulmonary resuscitation. DESIGN: Secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital trial. SETTING: Thirty-seven PICUs in the United States, Canada, and the United Kingdom. PATIENTS: Children (n = 147) resuscitated with extracorporeal cardiopulmonary resuscitation following in-hospital cardiac arrest. INTERVENTIONS: Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition, at prearrest baseline and 12 months postarrest. Norms for Vineland Adaptive Behavior Scales, Second Edition, are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival, 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. MEASUREMENTS AND MAIN RESULTS: Of 147 children receiving extracorporeal cardiopulmonary resuscitation, 125 (85.0%) had a preexisting cardiac condition, 75 (51.0%) were postcardiac surgery, and 84 (57.1%) were less than 1 year old. Duration of chest compressions was greater than 30 minutes for 114 (77.5%). Sixty-one (41.5%) survived to 12 months, 32 (22.1%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 39 (30.5%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. On multivariable analyses, open-chest cardiac massage was independently associated with greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Higher minimum postarrest lactate and preexisting gastrointestinal conditions were independently associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. CONCLUSIONS: About one third of children survived with good neurobehavioral outcome 1 year after receiving extracorporeal cardiopulmonary resuscitation for in-hospital arrest. Open-chest cardiac massage and minimum postarrest lactate were associated with survival with good neurobehavioral outcome at 1 year.

Cardiac Arrest Outcomes in Children With Preexisting Neurobehavioral Impairment.

OBJECTIVES: To describe survival and 3-month and 12-month neurobehavioral outcomes in children with preexisting neurobehavioral impairment enrolled in one of two parallel randomized clinical trials of targeted temperature management. DESIGN: Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials data. SETTING: Forty-one PICUs in the United States, Canada, and United Kingdom. PATIENTS: Eighty-four participants (59 in-hospital cardiac arrest and 25 out-of-hospital cardiac arrest), 49 males, 35 females, mean age 4.6 years (SD, 5.36 yr), with precardiac arrest neurobehavioral impairment (Vineland Adaptive Behavior Scales, Second Edition composite score < 70). All required chest compressions for greater than or equal to 2 minutes, were comatose and required mechanical ventilation after return of circulation. INTERVENTIONS: Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting precardiac arrest status), and at 3 and 12 months postcardiac arrest, followed by on-site cognitive evaluation. Vineland Adaptive Behavior Scales, Second Edition norms are 100 (mean) ± 15 (SD); higher scores indicate better function. Analyses evaluated survival, changes in Vineland Adaptive Behavior Scales, Second Edition, and cognitive functioning. MEASUREMENTS AND MAIN RESULTS: Twenty-eight of 84 (33%) survived to 12 months (in-hospital cardiac arrest, 19/59 (32%); out-of-hospital cardiac arrest, 9/25 [36%]). In-hospital cardiac arrest (but not out-of-hospital cardiac arrest) survival rate was significantly lower compared with the Therapeutic Hypothermia after Pediatric Cardiac Arrest group without precardiac arrest neurobehavioral impairment. Twenty-five survived with decrease in Vineland Adaptive Behavior Scales, Second Edition less than or equal to 15 (in-hospital cardiac arrest, 18/59 (31%); out-of-hospital cardiac arrest, 7/25 [28%]). At 3-months postcardiac arrest, mean Vineland Adaptive Behavior Scales, Second Edition scores declined significantly (-5; SD, 14; p < 0.05). At 12 months, Vineland Adaptive Behavior Scales, Second Edition declined after out-of-hospital cardiac arrest (-10; SD, 12; p < 0.05), but not in-hospital cardiac arrest (0; SD, 15); 43% (12/28) had unchanged or improved scores. CONCLUSIONS: This study demonstrates the feasibility, utility, and challenge of including this population in clinical neuroprotection trials. In children with preexisting neurobehavioral impairment, one-third survived to 12 months and their neurobehavioral outcomes varied broadly.

Therapeutic hypothermia after out-of-hospital cardiac arrest in children.

BACKGROUND: Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS: We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS: A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS: In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy.

Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon γ (IFN-γ) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy.

Cross-Participant EEG-Based Assessment of Cognitive Workload Using Multi-Path Convolutional Recurrent Neural Networks.

Applying deep learning methods to electroencephalograph (EEG) data for cognitive state assessment has yielded improvements over previous modeling methods. However, research focused on cross-participant cognitive workload modeling using these techniques is underrepresented. We study the problem of cross-participant state estimation in a non-stimulus-locked task environment, where a trained model is used to make workload estimates on a new participant who is not represented in the training set. Using experimental data from the Multi-Attribute Task Battery (MATB) environment, a variety of deep neural network models are evaluated in the trade-space of computational efficiency, model accuracy, variance and temporal specificity yielding three important contributions: (1) The performance of ensembles of individually-trained models is statistically indistinguishable from group-trained methods at most sequence lengths. These ensembles can be trained for a fraction of the computational cost compared to group-trained methods and enable simpler model updates. (2) While increasing temporal sequence length improves mean accuracy, it is not sufficient to overcome distributional dissimilarities between individuals’ EEG data, as it results in statistically significant increases in cross-participant variance. (3) Compared to all other networks evaluated, a novel convolutional-recurrent model using multi-path subnetworks and bi-directional, residual recurrent layers resulted in statistically significant increases in predictive accuracy and decreases in cross-participant variance.

The effect of propensity to trust and perceptions of trustworthiness on trust behaviors in dyads.

Research on trust has burgeoned in the last few decades. Despite the growing interest in trust, little is known about trusting behaviors in non-dichotomous trust games. The current study explored propensity to trust, trustworthiness, and trust behaviors in a new computer-mediated trust relevant task. We used multivariate multilevel survival analysis (MMSA) to analyze behaviors across time. Results indicated propensity to trust did not influence trust behaviors. However, trustworthiness perceptions influenced initial trust behaviors and trust behaviors influenced subsequent trustworthiness perceptions. Indeed, behaviors fully mediated the relationship of trustworthiness perceptions over time. The study demonstrated the utility of MMSA and the new trust game, Checkmate, as viable research methods and stimuli for assessing the loci of trust.

Crizotinib in ROS1-rearranged non-small-cell lung cancer.

BACKGROUND: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. RESULTS: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Acquired resistance to crizotinib from a mutation in CD74-ROS1.

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Functional Outcome Trajectories After Out-of-Hospital Pediatric Cardiac Arrest.

OBJECTIVES: To analyze functional performance measures collected prospectively during the conduct of a clinical trial that enrolled children (up to age 18 yr old), resuscitated after out-of-hospital cardiac arrest, who were at high risk of poor outcomes. DESIGN: Children with Glasgow Motor Scale score less than 5, within 6 hours of resuscitation, were enrolled in a clinical trial that compared two targeted temperature management interventions (THAPCA-OH, NCT00878644). The primary outcome, 12-month survival with Vineland Adaptive Behavior Scale, second edition, score greater or equal to 70, did not differ between groups. SETTING: Thirty-eight North American PICUs. PARTICIPANTS: Two hundred ninety-five children were enrolled; 270 of 295 had baseline Vineland Adaptive Behavior Scale, second edition, scores greater or equal to 70; 87 of 270 survived 1 year. INTERVENTIONS: Targeted temperatures were 33.0°C and 36.8°C for hypothermia and normothermia groups. MEASUREMENTS AND MAIN RESULTS: Baseline measures included Vineland Adaptive Behavior Scale, second edition, Pediatric Cerebral Performance Category, and Pediatric Overall Performance Category. Pediatric Cerebral Performance Category and Pediatric Overall Performance Category were rescored at hospital discharges; all three were scored at 3 and 12 months. In survivors with baseline Vineland Adaptive Behavior Scale, second edition scores greater or equal to 70, we evaluated relationships of hospital discharge Pediatric Cerebral Performance Category with 3- and 12-month scores and between 3- and 12-month Vineland Adaptive Behavior Scale, second edition, scores. Hospital discharge Pediatric Cerebral Performance Category scores strongly predicted 3- and 12-month Pediatric Cerebral Performance Category (r = 0.82 and 0.79; p < 0.0001) and Vineland Adaptive Behavior Scale, second edition, scores (r = -0.81 and -0.77; p < 0.0001). Three-month Vineland Adaptive Behavior Scale, second edition, scores strongly predicted 12-month performance (r = 0.95; p < 0.0001). Hypothermia treatment did not alter these relationships. CONCLUSIONS: In comatose children, with Glasgow Motor Scale score less than 5 in the initial hours after out-of-hospital cardiac arrest resuscitation, function scores at hospital discharge and at 3 months predicted 12-month performance well in the majority of survivors.

Pediatric Out-of-Hospital Cardiac Arrest Characteristics and Their Association With Survival and Neurobehavioral Outcome.

OBJECTIVE: To investigate relationships between cardiac arrest characteristics and survival and neurobehavioral outcome among children recruited to the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial. DESIGN: Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial data. SETTING: Thirty-six PICUs in the United States and Canada. PATIENTS: All children (n = 295) had chest compressions for greater than or equal to 2 minutes, were comatose, and required mechanical ventilation after return of circulation. INTERVENTIONS: Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting prearrest status) and 12 months postarrest. U.S. norms for Vineland Adaptive Behavior Scales, Second Edition scores are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70. MEASUREMENT AND MAIN RESULTS: Cardiac etiology of arrest, initial arrest rhythm of ventricular fibrillation/tachycardia, shorter duration of chest compressions, compressions not required at hospital arrival, fewer epinephrine doses, and witnessed arrest were associated with greater 12-month survival and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70. Weekend arrest was associated with lower 12-month survival. Body habitus was associated with 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70; underweight children had better outcomes, and obese children had worse outcomes. On multivariate analysis, acute life threatening event/sudden unexpected infant death, chest compressions more than 30 minutes, and weekend arrest were associated with lower 12-month survival; witnessed arrest was associated with greater 12-month survival. Acute life threatening event/sudden unexpected infant death, other respiratory causes of arrest except drowning, other/unknown causes of arrest, and compressions more than 30 minutes were associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition greater than or equal to 70. CONCLUSIONS: Many factors are associated with survival and neurobehavioral outcome among children who are comatose and require mechanical ventilation after out-of-hospital cardiac arrest. These factors may be useful for identifying children at risk for poor outcomes, and for improving prevention and resuscitation strategies.

Family Burden After Out-of-Hospital Cardiac Arrest in Children.

OBJECTIVES: To describe family burden among caregivers of children who survived out-of-hospital cardiac arrest and who were at high risk for neurologic disability and examine relationships between family burden, child functioning, and other factors during the first year post arrest. DESIGN: Secondary analysis of data from the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial. SETTING: Thirty-six PICUs in the United States and Canada. PATIENTS: Seventy-seven children recruited to the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial who had normal prearrest neurologic functioning and were alive 1 year post arrest. INTERVENTIONS: Family burden was assessed using the Infant Toddler Quality of Life Questionnaire for children less than 5 years old and the Child Health Questionnaire for children 5 years old or older at baseline (reflecting prearrest status), 3 months, and 12 months post arrest. Child functioning was assessed using the Vineland Adaptive Behavior Scale II, the Pediatric Overall Performance Category, and Pediatric Cerebral Performance Category scales and caregiver perception of global functioning. MEASUREMENTS AND MAIN RESULTS: Fifty-six children (72.7%) were boys, 48 (62.3%) were whites, and 50 (64.9%) were less than 5 years old prior to out-of-hospital cardiac arrest. Family burden at baseline was not significantly different from reference values. Family burden was increased at 3 and 12 months post arrest compared with reference values (p < 0.001). Worse Pediatric Overall Performance Category and Pediatric Cerebral Performance Category, lower adaptive behavior, lower global functioning, and higher family burden all measured 3 months post arrest were associated with higher family burden 12 months post arrest (p < 0.05). Sociodemographics and prearrest child functioning were not associated with family burden 12 months post arrest. CONCLUSIONS: Families of children who survive out-of-hospital cardiac arrest and have high risk for neurologic disability often experience substantial burden during the first year post arrest. The extent of child dysfunction 3 months post arrest is associated with family burden at 12 months.

Targeted Temperature Management After Pediatric Cardiac Arrest Due To Drowning: Outcomes and Complications.

OBJECTIVE: To describe outcomes and complications in the drowning subgroup from the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital trial. DESIGN: Exploratory post hoc cohort analysis. SETTING: Twenty-four PICUs. PATIENTS: Pediatric drowning cases. INTERVENTIONS: Therapeutic hypothermia versus therapeutic normothermia. MEASUREMENTS AND MAIN RESULTS: An exploratory study of pediatric drowning from the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital trial was conducted. Comatose patients aged more than 2 days and less than 18 years were randomized up to 6 hours following return-of-circulation to hypothermia (n = 46) or normothermia (n = 28). Outcomes assessed included 12-month survival with a Vineland Adaptive Behavior Scale score of greater than or equal to 70, 1-year survival rate, change in Vineland Adaptive Behavior Scale-II score from prearrest to 12 months, and select safety measures. Seventy-four drowning cases were randomized. In patients with prearrest Vineland Adaptive Behavior Scale-II greater than or equal to 70 (n = 65), there was no difference in 12-month survival with Vineland Adaptive Behavior Scale-II score of greater than or equal to 70 between hypothermia and normothermia groups (29% vs 17%; relative risk, 1.74; 95% CI, 0.61-4.95; p = 0.27). Among all evaluable patients (n = 68), the Vineland Adaptive Behavior Scale-II score change from baseline to 12 months did not differ (p = 0.46), and 1-year survival was similar (49% hypothermia vs 42%, normothermia; relative risk, 1.16; 95% CI, 0.68-1.99; p = 0.58). Hypothermia was associated with a higher prevalence of positive bacterial culture (any blood, urine, or respiratory sample; 67% vs 43%; p = 0.04); however, the rate per 100 days at risk did not differ (11.1 vs 8.4; p = 0.46). Cumulative incidence of blood product use, serious arrhythmias, and 28-day mortality were not different. Among patients with cardiopulmonary resuscitation durations more than 30 minutes or epinephrine doses greater than 4, none had favorable Pediatric Cerebral Performance Category outcomes (≤ 3). CONCLUSIONS: In comatose survivors of out-of-hospital pediatric cardiac arrest due to drowning, hypothermia did not result in a statistically significant benefit in survival with good functional outcome or mortality at 1 year, as compared with normothermia. High risk of culture-proven bacterial infection was observed in both groups.