Genetic and neural bases of the neuroticism general factor.

We applied structural equation modeling to conduct a genome-wide association study (GWAS) of the general factor measured by a neuroticism questionnaire administered to ∼380,000 participants in the UK Biobank. We categorized significant genetic variants as acting either through the neuroticism general factor, through other factors measured by the questionnaire, or through paths independent of any factor. Regardless of this categorization, however, significant variants tended to show concordant associations with all items. Bioinformatic analysis showed that the variants associated with the neuroticism general factor disproportionately lie near or within genes expressed in the brain. Enriched gene sets pointed to an underlying biological basis associated with brain development, synaptic function, and behaviors in mice indicative of fear and anxiety. Psychologists have long asked whether psychometric common factors are merely a convenient summary of correlated variables or reflect coherent causal entities with a partial biological basis, and our results provide some support for the latter interpretation. Further research is needed to determine the extent to which causes resembling common factors operate alongside other mechanisms to generate the correlational structure of personality.

Using Health Forum Data to Assess User Needs for mHealth App Development: A Feasibility Study on Alzheimer's Disease.

Online health forums are used by patients and caregivers as community and information resources, especially for chronic disease management, and could help determine user needs for digital health app design. This study aims to assess the feasibility of using online forum posts on Alzheimer's disease to inform user needs in mobile health application design and whether this process can be automated through text clustering methods. A total of 413 posts were analyzed manually through thematic coding and yielded three themes and nine subthemes for patient and caregiver needs. The external evaluation showed fair to substantial similarity between the automatically and manually derived labels. Four personas were developed to assess the validity of forum-generated needs. These results establish that health forum data can provide sufficient information to understand user needs. However, further refinement of the analysis process and algorithm is necessary to generalize this method to other disease conditions and types of forum data.

The association between saving disposition and financial distress: A genetically informed approach.

Saving disposition, the tendency to save rather than consume, has been found to be associated with economic outcomes. People lacking the disposition to save are more likely to experience financial distress. This association could be driven by other economic factors, behavioral traits, or even genetic effects. Using a sample of 3,920 American twins, we develop scales to measure saving disposition and financial distress. We find genetic influences on both traits, but also a large effect of the rearing family environment on saving disposition. We estimate that 44% of the covariance between the two traits is due to genetic effects. Saving disposition remains strongly associated with lower financial distress, even after controlling for family income, cognitive ability, and personality traits. The association persists within families and monozygotic twin pairs; the twin who saves more tends to be the twin who experiences less financial distress. This result suggest that there is a direct association between saving disposition and financial distress, although the direction of causation remains unclear.

Defining the Cervical Line in Face-Lift Surgery: A Three-Dimensional Study of the Cervical and Marginal Mandibular Branches of the Facial Nerve.

BACKGROUND: Continuous sub-superficial musculoaponeurotic system (SMAS) dissection in the cheek with subplatysmal dissection in the neck is an important feature of many face-lift techniques, yet the neural anatomy in this area remains unclear, and recommendations regarding continuous dissection of these adjacent areas vary widely. The purpose of this study was to define the vulnerability of the facial nerve branches in this transitional area from the face-lift surgeon's perspective and to specifically identify the location of the cervical branch penetration through the deep cervical fascia. METHODS: Ten fresh and five preserved cadaveric facial halves were dissected under 4× loupe magnification. The skin was reflected, followed by elevation of a SMAS-platysma flap, with identification of the location of cervical branch penetration through the deep cervical fascia. The cervical and marginal mandibular branches were then dissected retrograde through the deep cervical fascia to the cervicofacial trunk to confirm identifications. RESULTS: Cervical and marginal mandibular branch anatomy was found to be similar to that of the other facial nerve branches, all of which initially course deep to the deep fascia in their postparotid course. The emergence of the terminal branch or branches of the cervical branch through the deep cervical fascia was consistently at or distal to a line from a point 5 cm below the mandibular angle on the anterior border of the sternocleidomastoid muscle to the point where the facial vessels course over the mandibular border (cervical line). CONCLUSIONS: Continuous dissection of the SMAS in the cheek, with subplatysmal dissection in the neck crossing over the mandibular border, is possible without jeopardizing the marginal mandibular or cervical branches if done proximal to the cervical line. This study serves as the anatomical justification for continuous SMAS-platysma dissection, and has implications for all types of SMAS flap manipulations.

Developing a machine learning model to detect diagnostic uncertainty in clinical documentation.

BACKGROUND AND OBJECTIVE: Diagnostic uncertainty, when unrecognized or poorly communicated, can result in diagnostic error. However, diagnostic uncertainty is challenging to study due to a lack of validated identification methods. This study aims to identify distinct linguistic patterns associated with diagnostic uncertainty in clinical documentation. DESIGN, SETTING AND PARTICIPANTS: This case-control study compares the clinical documentation of hospitalized children who received a novel uncertain diagnosis (UD) diagnosis label during their admission to a set of matched controls. Linguistic analyses identified potential linguistic indicators (i.e., words or phrases) of diagnostic uncertainty that were then manually reviewed by a linguist and clinical experts to identify those most relevant to diagnostic uncertainty. A natural language processing program categorized medical terminology into semantic types (i.e., sign or symptom), from which we identified a subset of these semantic types that both categorized reliably and were relevant to diagnostic uncertainty. Finally, a competitive machine learning modeling strategy utilizing the linguistic indicators and semantic types compared different predictive models for identifying diagnostic uncertainty. RESULTS: Our cohort included 242 UD-labeled patients and 932 matched controls with a combination of 3070 clinical notes. The best-performing model was a random forest, utilizing a combination of linguistic indicators and semantic types, yielding a sensitivity of 89.4% and a positive predictive value of 96.7%. CONCLUSION: Expert labeling, natural language processing, and machine learning methods combined with human validation resulted in highly predictive models to detect diagnostic uncertainty in clinical documentation and represent a promising approach to detecting, studying, and ultimately mitigating diagnostic uncertainty in clinical practice.

Multifaceted role for p53 in pancreatic cancer suppression.

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant-p5353,54-which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. Using both inflammation-induced and KRASG12D-driven PDAC models, we find that p5353,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p5353,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p5353,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53-null mice. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.

A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

BACKGROUND: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). METHODS: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. RESULTS: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. CONCLUSION: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

The Construct Validity of Intellect and Openness as Distinct Aspects of Personality through Differential Associations with Reaction Time.

The construct validity of group factor models of personality, which are typically derived from factor analysis of questionnaire items, relies on the ability of each factor to predict meaningful and differentiated real-world outcomes. In a sample of 481 participants, we used the Big Five Aspect Scales (BFAS) personality questionnaire, two laboratory-measured reaction time (RT) tasks, and a short-form test of cognitive ability (ICAR-16) to test the hypothesis that the Intellect and Openness aspects of Big Five Openness to Experience differentially correlate with reaction time moments. We found that higher scores on the Intellect aspect significantly correlate with faster and less variable response times, while no such association is observed for the Openness aspect. Further, we found that this advantage lies solely in the decisional, but not perceptual, stage of information processing; no other Big Five aspect showed a similar pattern of results. In sum, these findings represent the largest and most comprehensive study to date on personality factors and reaction time, and the first to demonstrate a mechanistic validation of BFAS Intellect through a differential pattern of associations with RT and Big Five personality aspects.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline.

PURPOSE: To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: For human epidermal growth factor receptor 2 (HER2)-negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Epacadostat Plus Pembrolizumab and Chemotherapy for Advanced Solid Tumors: Results from the Phase I/II ECHO-207/KEYNOTE-723 Study.

BACKGROUND: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy. METHODS: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab 200 mg was infused intravenously every 3 weeks. Epacadostat 100 mg was administered orally twice daily. The primary objectives of phase I were determining safety/tolerability and defining the maximum tolerated or pharmacologically active dose of epacadostat. Phase II of the study was designed to enroll efficacy-expansion cohorts and to assess changes in the tumor and tumor microenvironment via mandatory-biopsy cohorts. RESULTS: A total of 70 patients were enrolled. Twelve patients were enrolled in the phase II mandatory-biopsy cohorts. Due to early study closure, efficacy expansion did not enroll. Grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 78.6% of patients. Neutropenia and disease progression were the only grades 3 and 4 TEAEs reported in ≥10.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups. CONCLUSION: The combination of epacadostat 100 mg bid with pembrolizumab and chemotherapy had an acceptable safety profile. This regimen showed antitumor activity across multiple types of advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT03085914).

A User-Centered Evaluation of a COVID-19 Intelligent Query System (COVID-IQS).

As the fight against COVID-19 continues, it is critical to discover and accumulate knowledge in scientific literature to combat the pandemic. In this work, we shared the experience in developing an intelligent query system on COVID-19 literature. We conducted a user-centered evaluation with 12 researchers in our institution and identified usability issues in four categories: distinct user needs, functionality errors, suboptimal information display, and implementation errors. Furthermore, we shared two lessons for building such a COVID-19 literature search engine. We will deploy the system and continue refining it through multiple phases of evaluation to aid in redesigning the system to accommodate different user roles as well as enhancing repository features to support collaborative information seeking. The successful implementation of the COVID-IQS can support knowledge discovery and hypothesis generation in our institution and can be shared with other institutions to make a broader impact.

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.

PURPOSE: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. PATIENTS AND METHODS: Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. RESULTS: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. CONCLUSIONS: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.

Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis.

BACKGROUND: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. METHODS: We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1-5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. RESULTS: Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. CONCLUSIONS: The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440 .

Development of a Clinical Decision Support System to Predict Unplanned Cancer Readmissions.

Unplanned 30-day cancer readmissions are an important outcome of cancer hospitalization and can significantly raise mortality rates and costs for both the patient and the hospital. This paper aimed to develop a predictive model using machine learning and electronic health records to predict unplanned 30-day cancer readmissions and further develop it as a clinical decision support system. The three-stage study design followed the 2022 AMIA Artificial Intelligence Evaluation Showcase. In the first stage, the technical performance of the model was determined (81% of AUROC) and contributing factors were identified. In the second stage, the technical feasibility and workflow considerations of using such a predictive model were explored through semi-structured interviews. In the third stage, a decision tree analysis and a cost estimation showed that the model can reduce unplanned readmissions significantly if timely action is taken and that preventing a single readmission may significantly reduce costs.

Parent Contributions to the Development of Political Attitudes in Adoptive and Biological Families.

Where do our political attitudes originate? Although early research attributed the formation of such beliefs to parent and peer socialization, genetically sensitive designs later clarified the substantial role of genes in the development of sociopolitical attitudes. However, it has remained unclear whether parental influence on offspring attitudes persists beyond adolescence. In a unique sample of 394 adoptive and biological families with offspring more than 30 years old, biometric modeling revealed significant evidence for genetic and nongenetic transmission from both parents for the majority of seven political-attitude phenotypes. We found the largest genetic effects for religiousness and social liberalism, whereas the largest influence of parental environment was seen for political orientation and egalitarianism. Together, these findings indicate that genes, environment, and the gene-environment correlation all contribute significantly to sociopolitical attitudes held in adulthood, and the etiology and development of those attitudes may be more important than ever in today's rapidly changing sociopolitical landscape.

Genetic and environmental contributions to IQ in adoptive and biological families with 30-year-old offspring.

While adoption studies have provided key insights into the influence of the familial environment on IQ scores of adolescents and children, few have followed adopted offspring long past the time spent living in the family home. To improve confidence about the extent to which shared environment exerts enduring effects on IQ, we estimated genetic and environmental effects on adulthood IQ in a unique sample of 486 biological and adoptive families. These families, tested previously on measures of IQ when offspring averaged age 15, were assessed a second time nearly two decades later ( M offspring age = 32 years). We estimated the proportions of the variance in IQ attributable to environmentally mediated effects of parental IQs, sibling-specific shared environment, and gene-environment covariance to be .01 [95% CI .00, .02], .04 [95% CI .00, .15], and .03 [95% CI .00, .07] respectively; these components jointly accounted for 8 percent of the IQ variance in adulthood. The heritability was estimated to be .42 [95% CI .21, .64]. Together, these findings provide further evidence for the predominance of genetic influences on adult intelligence over any other systematic source of variation.

Parsing information flow in speeded cognitive tasks: The role of g in perception and decision time.

Although the correlation between general cognitive ability (g) and performance on speeded cognitive tasks is well-established, there is need for a better understanding of how successive stages of processing contribute to this relationship. Previous research suggests that g is primarily associated with the rapidity of decision-making rather than perceptual processing of stimuli; the implication is that g should statistically interact with a manipulation affecting the difficulty of the decision process, while simultaneously failing to interact with a perceptual manipulation. We applied Sternberg's method of additive factors to test this hypothesis in two reaction time tasks, each of which systematically manipulated the demands on perceptual acuity and decision-making. With a total of 773 participants, we found evidence of an interaction between a short-form measure of g and the decisional-but not perceptual-manipulations. This pattern was found in both number-comparison (Experiment 1) and tone-comparison (Experiment 2) tasks. Additionally, diffusion modeling of the Experiment 1 results revealed that the diffusion rate (v) is associated with g and affected by an informational attribute of the stimulus (numerical magnitude) but not a perceptual attribute (contrast); the nondecision time (Ter) is not associated with g and shows the opposite pattern of selective influence. Taken together, these findings add to the evidence for a theoretical framework partitioning reaction time into several processing stages, of which only the decision-making stage is associated with g. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors.

PURPOSE: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody. METHODS: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120-360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin. RESULTS: Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin. CONCLUSIONS: The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression. TRIAL REGISTRATION: NCT01749384 (First posted 12/13/2012).