Knowledge of head and neck cancer among medical students in the UK.

Head and neck cancer (HNC) refers to malignancies found in mucosal surfaces anywhere from the paranasal sinuses to the larynx, including the various glands and cavities. Between the years 2016 and 2018, there were about 3900 new cases every year in women and 8600 in men, making it the thirteenth most common cancer in women and fourth most common in men. The aim of our study was to evaluate the amount and type of teaching United Kingdom (UK) medical students receive on HNC, and to assess their current knowledge of these cancers. An online survey distributed via university representatives was responded to by 311 final year medical students from 25 medical schools across the UK. Regarding HNC teaching, 72 students (23.2%) reported receiving no teaching at their medical school. Of the 239 who reported receiving teaching, 169 (54.3%) received it in the format of a non-interactive, large group lecture. A total of 271 respondents (87.1%) believed that medical students at their university would benefit from more teaching on HNC. Based on our sample, there appears to be an overall dissatisfaction and lack of confidence surrounding HNC in the undergraduate curriculum. With its increasing prevalence in the UK, it is vital that red-flag symptoms and referral criteria are understood by the future medical workforce.

Ketamine Use in the Intubation of Critically Ill Children with Neurological Indications: A Multicenter Retrospective Analysis.

BACKGROUND: Ketamine has traditionally been avoided for tracheal intubations (TIs) in patients with acute neurological conditions. We evaluate its current usage pattern in these patients and any associated adverse events. METHODS: We conducted a retrospective observational cohort study of critically ill children undergoing TI for neurological indications in 53 international pediatric intensive care units and emergency departments. We screened all intubations from 2014 to 2020 entered into the multicenter National Emergency Airway Registry for Children (NEAR4KIDS) registry database. Patients were included if they were under the age of 18 years and underwent TI for a primary neurological indication. Usage patterns and reported periprocedural composite adverse outcomes (hypoxemia < 80%, hypotension/hypertension, cardiac arrest, and dysrhythmia) were noted. RESULTS: Of 21,562 TIs, 2,073 (9.6%) were performed for a primary neurological indication, including 190 for traumatic brain injury/trauma. Patients received ketamine in 495 TIs (23.9%), which increased from 10% in 2014 to 41% in 2020 (p < 0.001). Ketamine use was associated with a coindication of respiratory failure, difficult airway history, and use of vagolytic agents, apneic oxygenation, and video laryngoscopy. Composite adverse outcomes were reported in 289 (13.9%) Tis and were more common in the ketamine group (17.0% vs. 13.0%, p = 0.026). After adjusting for location, patient age and codiagnoses, the presence of respiratory failure and shock, difficult airway history, provider demographics, intubating device, and the use of apneic oxygenation, vagolytic agents, and neuromuscular blockade, ketamine use was not significantly associated with increased composite adverse outcomes (adjusted odds ratio 1.34, 95% confidence interval CI 0.99-1.81, p = 0.057). This paucity of association remained even when only neurotrauma intubations were considered (10.6% vs. 7.7%, p = 0.528). CONCLUSIONS: This retrospective cohort study did not demonstrate an association between procedural ketamine use and increased risk of peri-intubation hypoxemia and hemodynamic instability in patients intubated for neurological indications.

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib.

A physiologically-based pharmacokinetic (PBPK) model was developed to simulate plasma concentrations of tucatinib (TUKYSA®) after single-dose or multiple-dose administration of 300 mg b.i.d. orally. This PBPK model was subsequently applied to support evaluation of drug-drug interaction (DDI) risk as a perpetrator resulting from tucatinib inhibition of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was also applied to support evaluation of DDI risk as a victim resulting from co-administration with CYP3A4 or CYP2C8 inhibitors, or a CYP3A4 inducer. After refinement with clinical DDI data, the final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations for tucatinib when tucatinib was administered as a single agent in healthy subjects. In addition, the final model was able to recover clinically observed plasma concentrations of tucatinib when administered in combination with itraconazole, rifampin, or gemfibrozil as well as clinically observed plasma concentrations of probe substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was then applied to prospectively predict the potential perpetrator or victim DDIs with other substrates, inducers, or inhibitors. To simulate a potential interaction with a moderate CYP2C8 inhibitor, two novel PBPK models representing a moderate CYP2C8 inhibitor and a sensitive CYP2C8 substrate were developed based on the existing PBPK models for gemfibrozil and rosiglitazone, respectively. The simulated population geometric mean area under the curve ratio of tucatinib with a moderate CYP2C8 inhibitor ranged from 1.98- to 3.08-fold, and based on these results, no dose modifications were proposed for moderate CYP2C8 inhibitors for the tucatinib label.

Tracheal Intubation by Advanced Practice Registered Nurses in Pediatric Critical Care: Retrospective Study From the National Emergency Airway for Children Registry (2015-2019).

OBJECTIVES: To describe tracheal intubation (TI) practice by Advanced Practice Registered Nurses (APRNs) in North American PICUs, including rates of TI-associated events (TIAEs) from 2015 to 2019. DESIGN/SETTING: Retrospective study using the National Emergency Airway Registry for Children with all TIs performed in PICU and pediatric cardiac ICU between January 2015 and December 2019. The primary outcome was first attempt TI success rate. Secondary outcomes were TIAEs, severe TIAEs, and hypoxemia. SUBJECTS: Critically ill children requiring TI in a PICU or pediatric cardiac ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 11,012 TIs, APRNs performed 1,626 (14.7%). Overall, TI by APRNs, compared with other clinicians, occurred less frequently in patients with known difficult airway (11.1% vs. 14.3%; p < 0.001), but more frequently in infants younger than 1 year old (55.9% vs. 44.4%; p < 0.0001), and in patients with cardiac disease (26.3% vs. 15.9%; p < 0.0001).There was lower odds of success in first attempt TI for APRNs vs. other clinicians (adjusted odds ratio, 0.70; 95% CI, 0.62-0.79). We failed to identify a difference in rates of TIAE, severe TIAE, and oxygen desaturation events for TIs by APRNs compared with other clinicians. The TI first attempt success rate improved with APRN experience (< 1 yr: 54.2%, 1-5 yr: 59.4%, 6-10 yr: 67.6%, > 10 yr: 63.1%; p = 0.021). CONCLUSIONS: TI performed by APRNs was associated with lower odds of first attempt success when compared with other ICU clinicians although there was no appreciable difference in procedural adverse events. There appears to be a positive relationship between experience and success rates. These data suggest there is an ongoing need for opportunities to build on TI competency with APRNs.

Women's Preferences for Masculinity in Male Faces Are Predicted by Material Scarcity, But Not Time or Psychological Scarcity.

Facial femininity in men is purportedly used as a cue by women as a signal of parental quality and willingness to provide resources. Accordingly, in contexts where choosing a partner that will provide resources is more beneficial (e.g., when resources are scarce), women have shown an increase preference for facial femininity in male faces. However, domains of scarcity often covary, and it is, therefore, unclear whether these contextual shifts in facial masculinity/femininity preferences are specific to material scarcity (as implied by previous theory), or due to an unrelated domain of scarcity (e.g., time or psychological scarcity). Here, a sample of 823 women completed the Perceived Scarcity Scale, which measures three separate domains of scarcity: material scarcity, time scarcity, and psychological scarcity. Participants also rated the attractiveness of 42 male faces, which were measured on objective sexual dimorphism and perceived masculinity. Consistent with theory, material scarcity, and not time or psychological scarcity, was associated with a decreased preference for objective sexual dimorphism (i.e., an increased preference for facial femininity). This study provides evidence that women use sexual dimorphism as a cue to material resource provisioning potential when assessing men as a mate.

The importance of face-shape masculinity for perceptions of male dominance depends on study design.

Dominance perceptions play an important role in social interactions. Although many researchers have proposed that shape masculinity is an important facial cue for dominance perceptions, evidence for this claim has come almost exclusively from studies that assessed perceptions of experimentally manipulated faces using forced-choice paradigms. Consequently, we investigated the role of masculine shape characteristics in perceptions of men's facial dominance (1) when shape-manipulated stimuli were presented in a forced-choice paradigm and (2) when unmanipulated face images were rated for dominance and shape masculinity was measured from face images. Although we observed large effects of masculinity on dominance perceptions when we used the forced-choice method (Cohen's ds = 2.51 and 3.28), the effect of masculinity on dominance perceptions was considerably smaller when unmanipulated face images were rated and shape masculinity measured from face images (Cohen's ds = 0.44 and 0.62). This pattern was observed when faces were rated separately for physical dominance, social dominance, and masculinity, and was seen for two different sets of stimuli. Collectively, these results suggest that shape masculinity may not be a particularly important cue for dominance perceptions when faces vary simultaneously on multiple dimensions, as is the case during everyday social interactions.

Facial Attractiveness, but not Facial Masculinity, is Used as a Cue to Paternal Involvement in Fathers.

Purpose: Facial femininity in men is purportedly used as a cue by women as a signal of paternal involvement. However, evidence for this claim is questionable. Previous findings have shown that paternal involvement is linked to testosterone, but have not investigated facial masculinity directly, while other studies have found that facial masculinity is negatively associated with perceptions of paternal involvement but do not assess the accuracy of this judgement. Here, we assess whether facial masculinity in men is used as a cue to paternal involvement, and whether this cue is accurate. Methods: We collected facial photographs of 259 men (156 of which were fathers) who also completed self-report measures of paternal involvement. Facial images were then rated by a separate group of raters on facial masculinity, attractiveness, and perceived paternal involvement. Shape sexual dimorphism was also calculated from the images using geometric morphometrics. Results: We found that facial masculinity was not associated with perceptions of paternal involvement, nor was it related with self-reported paternal involvement. Interestingly, facial attractiveness was negatively associated with perceptions of paternal involvement, and we found partial evidence that facial attractiveness was also negatively associated with self-reported paternal involvement. Conclusion: These findings challenge the hypothesis that sexual dimorphism is used as a cue to paternal involvement, and perhaps indicate that facial attractiveness is more important for this judgement instead. Supplementary Information: The online version contains supplementary material available at 10.1007/s40750-023-00217-y.

No evidence that sociosexual orientation moderates effects of conception probability on women's preferences for male facial masculinity.

Although many researchers have proposed that women will show stronger preferences for male facial masculinity when conception probability is high, empirical tests of this hypothesis have produced mixed results. One possible explanation for these inconsistent findings is that effects of conception probability on women's preferences for facial masculinity are moderated by additional factors not typically considered in these empirical tests. One such potential moderator is individual differences in women's openness to uncommitted sexual relationships (i.e., individual differences in women's sociosexual orientation); women who are more open to uncommitted sexual relationships might show stronger positive effects of conception probability on masculinity preferences, as their sexuality is more overt and sexual attitudes and behaviours are more diversified. Consequently, we analysed data from three independent samples (N = 2304, N = 483, and N = 339) to assess whether sociosexual orientation moderates the hypothesised positive effect of conception probability on women's facial masculinity preferences. Analyses showed no evidence that higher conception probability increased preferences for facial masculinity or that sociosexual orientation moderated the effect of conception probability on women's preferences for facial masculinity. While it remains possible that factors other than sociosexual orientation moderate effects of conception probability on masculinity preferences, our null results suggest that the mixed results for the effects of conception probability on facial masculinity preferences in previous studies are unlikely to be a consequence of failing to consider the moderating role of sociosexual orientation.

Glioblastoma remodelling of human neural circuits decreases survival.

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150.

PURPOSE: Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy. PATIENTS AND METHODS: Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non-small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumab+ bevacizumab+chemotherapy (ABCP) versus BCP, to mimic Phase Ib/II studies of 15 to 40 patients/arm with 6 to 24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics geometric mean ratio (GMR), objective response rate (ORR) difference (d), and progression-free survival (PFS), hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP versus BCP and BCP versus BCP, respectively, across 500 replicated subsamples for each design. RESULTS: For 40 patients/24 weeks follow-up, correct go decisions based on probability tumor growth rate (KG) GMR <0.90, dORR >0.10, and PFS HR <0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12%, and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently overperforming RECIST endpoints. The predicted overall survival (OS) HR was around 0.80 in most of the scenarios investigated. CONCLUSIONS: Model-based estimate of KG GMR is an exploratory endpoint that informs early clinical decisions for combination studies.

Modern intracranial electroencephalography for epilepsy localization with combined subdural grid and depth electrodes with low and improved hemorrhagic complication rates.

OBJECTIVE: Recent trends have moved from subdural grid electrocorticography (ECoG) recordings toward stereo-electroencephalography (SEEG) depth electrodes for intracranial localization of seizures, in part because of perceived morbidity from subdural grid and strip electrodes. For invasive epilepsy monitoring, the authors describe the outcomes of a hybrid approach, whereby patients receive a combination of subdural grids, strips, and frameless stereotactic depth electrode implantations through a craniotomy. Evolution of surgical techniques was employed to reduce complications. In this study, the authors review the surgical hemorrhage and functional outcomes of this hybrid approach. METHODS: A retrospective review was performed of consecutive patients who underwent hybrid implantation from July 2012 to May 2022 at an academic epilepsy center by a single surgeon. Outcomes included hemorrhagic and nonhemorrhagic complications, neurological deficits, length of monitoring, and number of electrodes. RESULTS: A total of 137 consecutive procedures were performed; 113 procedures included both subdural and depth electrodes. The number of depth electrodes and electrode contacts did not increase the risk of hemorrhage. A mean of 1.9 ± 0.8 grid, 4.9 ± 2.1 strip, and 3.0 ± 1.9 depth electrodes were implanted, for a mean of 125.1 ± 32 electrode contacts per patient. The overall incidence of hematomas over the study period was 5.1% (7 patients) and decreased significantly with experience and the introduction of new surgical techniques. The incidence of hematomas in the last 4 years of the study period was 0% (55 patients). Symptomatic hematomas were all delayed and extra-axial. These patients required surgical evacuation, and there were no cases of hematoma recurrence. All neurological deficits related to hematomas were temporary and were resolved at hospital discharge. There were 2 nonhemorrhagic complications. The mean duration of monitoring was 7.3 ± 3.2 days. Seizures were localized in 95% of patients, with 77% of patients eventually undergoing resection and 17% undergoing responsive neurostimulation device implantation. CONCLUSIONS: In the authors' institutional experience, craniotomy-based subdural and depth electrode implantation was associated with low hemorrhage rates and no permanent morbidity. The rate of hemorrhage can be nearly eliminated with surgical experience and specific techniques. The decision to use subdural electrodes or SEEG should be tailored to the patient's unique pathology and surgeon experience.

The role of valence, dominance, and pitch in perceptions of artificial intelligence (AI) conversational agents' voices.

There is growing concern that artificial intelligence conversational agents (e.g., Siri, Alexa) reinforce voice-based social stereotypes. Because little is known about social perceptions of conversational agents' voices, we investigated (1) the dimensions that underpin perceptions of these synthetic voices and (2) the role that acoustic parameters play in these perceptions. Study 1 (N = 504) found that perceptions of synthetic voices are underpinned by Valence and Dominance components similar to those previously reported for natural human stimuli and that the Dominance component was strongly and negatively related to voice pitch. Study 2 (N = 160) found that experimentally manipulating pitch in synthetic voices directly influenced dominance-related, but not valence-related, perceptions. Collectively, these results suggest that greater consideration of the role that voice pitch plays in dominance-related perceptions when designing conversational agents may be an effective method for controlling stereotypic perceptions of their voices and the downstream consequences of those perceptions.

The Role of Accurate Self-Assessments in Optimizing Mate Choice.

Individuals are thought to seek the best possible romantic partner in exchange for their own desirability. We investigated whether individuals' self-evaluations were related to their partner choices and whether the accuracy of these self-evaluations was associated with mating outcomes. Participants (N = 1,354) took part in a speed-dating study where they rated themselves and others on mate value and indicated their willingness to date each potential partner. Individuals were somewhat accurate in their self-evaluations, and these self-evaluations were associated with individuals' revealed minimum and maximum standards for a potential partner, but not the number of partners they were interested in. Participants who overestimated their mate value were accepted by an equivalent number of partners compared with under-estimators, but the over-estimators were choosier and thus ended up with fewer (but similarly attractive) reciprocal matches. Results support social exchange theory and the matching hypothesis, and contrast findings that self-enhancement facilitates positive social outcomes.

The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment.

BACKGROUND AND OBJECTIVE: Tucatinib, a highly selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved for HER2-positive metastatic breast cancer, is cleared by hepatic metabolism and subsequent biliary excretion. Liver disease can alter drug disposition and pharmacokinetics (PK). The objective of this study is to characterize PK and safety of tucatinib in volunteers with hepatic impairment. METHODS: This Phase 1 study compared the PK and safety of a single 300-mg oral dose of tucatinib in volunteers with mild, moderate, and severe hepatic impairment (Child-Pugh A/B/C) to healthy volunteers matched for sex, age, and body mass index. Pharmacokinetic parameters were determined for tucatinib and its predominant metabolite ONT-993. RESULTS: Compared with healthy volunteers, tucatinib exposure was similar in volunteers with mild impairment and increased in those with moderate or severe impairment without reaching statistical significance. Respective fold increases in geometric mean ratios for AUC0-t and AUC0-∞ were 1.13 and 1.15 in moderate impairment, and 1.43 and 1.61 in severe impairment compared with healthy volunteers. Three treatment-emergent adverse events (nausea, dermatitis, and increased transaminases) were reported in three volunteers and showed no obvious association with hepatic impairment status. CONCLUSION: The 1.61-fold geometric mean ratio AUC0-∞ increase in volunteers with severe hepatic impairment supports the recommendation in the tucatinib prescribing information to reduce the dose from 300 mg twice daily to 200 mg twice daily in patients with severe impairment; no dose adjustment is recommended for patients with mild or moderate hepatic impairment. This trial (NCT03722823) was registered on October 29, 2018.

The development and potential implications of the US Fenestrated and Branched Aortic Research Consortium.

The endovascular repair of thoracoabdominal aortic aneurysms has evolved during the last 2 decades, making fenestrated and branched endovascular aortic repair the preferred method to repair thoracoabdominal aortic aneurysms in high-risk patients. Single-center publications have given vascular specialists a significant amount of data, but patient numbers and clinical event rates remain limited. Statistical power to answer important clinical questions is often limited in the single-center studies published to date. In 2018, the principal investigators at the 10 physician-sponsored Investigational Device Exemption centers in the United States decided to coordinate and collect their data in a similar fashion. This effort would allow for the development of the largest cohort of patients in the world treated with complex endovascular devices. By combining efforts and resources, a much larger dataset was compiled to help resolve some of the unanswered questions about patients with complex aortic pathology. To date, the US Aortic Research Consortium has collected data from 2,281 patients and 9,124 target vessel treatment with complex aortic aneurysms treated with custom-manufactured fenestrated and branched endovascular aortic repair devices. These data have resulted in the publication of seven peer-reviewed articles describing various aspects and outcomes of complex endovascular aortic treatment.

Targeting Accuracy and Clinical Outcomes of Awake versus Asleep Interventional Magnetic Resonance Imaging-Guided Deep Brain Stimulation for Parkinson's Disease: The University of California, San Francisco Experience.

BACKGROUND: Interventional MRI (iMRI)-guided implantation of deep brain stimulator (DBS) leads has been developed to treat patients with Parkinson's disease (PD) without the need for awake testing. OBJECTIVE: Direct comparisons of targeting accuracy and clinical outcomes for awake stereotactic with asleep iMRI-DBS for PD are limited. METHODS: We performed a retrospective review of patients with PD who underwent awake or iMRI-guided DBS surgery targeting the subthalamic nucleus or globus pallidus interna between 2013 and 2019 at our institution. Outcome measures included Unified Parkinson's Disease Rating Scale Part III scores, levodopa equivalent daily dose, radial error between intended and actual lead locations, stimulation parameters, and complications. RESULTS: Of the 218 patients included in the study, the iMRI cohort had smaller radial errors (iMRI: 1.27 ± 0.72 mm, awake: 1.59 ± 0.96 mm, P < .01) and fewer lead passes (iMRI: 1.0 ± 0.16, awake: 1.2 ± 0.41, P < .01). Changes in Unified Parkinson's Disease Rating Scale were similar between modalities, but awake cases had a greater reduction in levodopa equivalent daily dose than iMRI cases ( P < .01), which was attributed to the greater number of awake subthalamic nucleus cases on multivariate analysis. Effective clinical contacts used for stimulation, side effect thresholds, and complication rates were similar between modalities. CONCLUSION: Although iMRI-DBS may result in more accurate lead placement for intended target compared with awake-DBS, clinical outcomes were similar between surgical approaches. Ultimately, patient preference and surgeon experience with a given DBS technique should be the main factors when determining the "best" method for DBS implantation.

Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers. METHODS: Parts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate). RESULTS: Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs. CONCLUSION: The potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window. TRIAL REGISTRATION: This trial (NCT03723395) was registered on October 29, 2018.

Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases.

PURPOSE: This study evaluated the central nervous system (CNS) pharmacokinetics and target engagement of lapatinib, neratinib, and tucatinib in patients with cancer, using a physiologically based pharmacokinetic (PBPK) modeling approach. EXPERIMENTAL DESIGN: Drug-specific parameters for in vitro metabolism, binding to plasma proteins and brain tissues, transcellular passive permeability, and interactions with efflux transporters were determined. Whole-body PBPK models integrated with a 4-compartment permeability-limited brain model was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration (Css,ave,br) to in vitro IC50 for HER2 inhibition, was used as a predictor of intracranial efficacy. RESULTS: PBPK models predicted that following 1 cycle of standard dosing, tucatinib and lapatinib achieved similar Css,ave,br (14.5 vs. 16.8 nmol/L), while neratinib Css,ave,br (0.68 nmol/L) was 20-fold lower. Tucatinib and neratinib were equally potent for HER2 inhibition (IC50, 6.9 vs. 5.6 nmol/L), while lapatinib was less potent (IC50, 109 nmol/L). The model-predicted population mean TER in the human normal brain was 2.1 for tucatinib, but < 0.20 for lapatinib and neratinib. CONCLUSIONS: The PBPK modeling suggests that tucatinib induces sufficient HER2 inhibition (TER > 2.0) in not only brain metastases with a disrupted blood-brain barrier (BBB), but also micrometastases where the BBB largely remains intact. These findings, in line with available clinical pharmacokinetics and efficacy data, support the therapeutic value of tucatinib for treatment of brain metastases and warrant further clinical investigation for the prevention of brain metastases in patients with HER2-positive breast cancer.

The role of cholesterol binding in the control of cholesterol by the Scap-Insig system.

Scap and Insig, two proteins embedded in the membrane of the endoplasmic reticulum (ER), regulate the synthesis of cholesterol in animal cells by forming a dimer in the presence of high concentrations of cholesterol. Cryo-electron microscopic structures for the Scap-Insig dimer show a sterol-binding site at the dimer interface, but none of the structures include cholesterol itself. Here, a molecular docking approach developed to characterise cholesterol binding to the transmembrane (TM) regions of membrane proteins is used to characterise cholesterol binding to sites on the TM surface of the dimer and to the interfacial binding site. Binding of cholesterol is also observed at sites on the extra-membranous luminal domains of Scap, but the properties of these sites suggest that they will be unoccupied in vivo. Comparing the structure of Scap in the dimer with that predicted by AlphaFold for monomeric Scap suggests that dimer formation could result in relocation of TM helix 7 of Scap and of the loop between TM6 and 7, and that this could be the key change on Scap that signals that there is a high concentration of cholesterol in the ER.