CSF1R Inhibition in Patients With Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase 1 Study of Vimseltinib.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

Accumulation and depletion of E. coli in surfaces mediated by curvature.

Can topography be used to control bacteria accumulation? We address this question in the model system of smooth-swimming and run-and-tumble Escherichia coli swimming near a sinusoidal surface, and show that the accumulation of bacteria is determined by the characteristic curvature of the surface. For low curvatures, cells swim along the surface due to steric alignment and are ejected from the surface when they reach the peak of the sinusoid. Increasing curvature enhances this effect and reduces the density of bacteria in the curved surface. However, for curvatures larger than κ^{*}≈0.25µm^{-1}, bacteria become trapped in the valleys, where they can remain for long periods of time. Minimal simulations considering only steric interactions with the surface reproduce these results and give insights into the physical mechanisms defining the critical curvature, which is found to scale with the inverse of the bacterial length. We show that for curvatures larger than κ^{*}, the otherwise stable alignment with the wall becomes unstable while the stable orientation is now perpendicular to the wall, thus predicting accurately the onset of trapping at the valleys.

Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.

Kinetic Theory of Motility Induced Phase Separation for Active Brownian Particles.

When two active Brownian particles collide, they slide along each other until they can continue their free motion. For persistence lengths much larger than the particle diameter, the directors do not change, but the collision can be modeled as producing a net displacement on the particles compared to their free motion in the absence of the encounter. With these elements, a Boltzmann-Enskog-like kinetic theory is built. A linear stability analysis of the homogeneous state predicts a density instability resulting from the effective velocity reduction of tagged particles predicted by the theory.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).

Factores asociados a la ingesta dietética en universitarios peruanos en tiempos de post pandemia / Factors associated with dietary intake in Peruvian university students in post-pandemic times

Introducción: La ingesta dietética de los universitarios peruanos pueden verse afectados por diferentes factores que determinan una condición de salud física y mental lo cual frus trael desarrollo académico óptimo. Objetivo: Identificar los factores asociados a la ingesta dietética en universitarios del Perú, en tiempos de postpandemia. Material y métodos: El estudio fue de corte transversal, participaron 393 universitarios peruanos, mediante una encuesta de ingesta dietética con 8 grupos de alimentos (tubérculos y raíces, cereales y derivados, menestras, carnes y de-rivados, alimentos ultraprocesados, aceites vegetales, verduras, frutas), 7 factores (convive con la familia, lugar deconsumo de alimentos, consumo de alcohol, consumo de tabaco, cambios económicos en el hogar, horas de sueño, actividad física) y tres categorías (disminuyó, sin cambios, incre-mentó). El análisis bivariado se realizó entre los grupos de alimentos y los factores asociados a la ingesta dietética y seempleó la prueba de Chi-cuadrado. Resultados: Los alimentos tuvieron una asociación directacon ingesta de cereales y tubérculos con la convivencia fami-liar (p=0.037; p=0.01 respectivamente), las menestras conlugar de consumo de alimentos (p=0.002) y convivencia fa-miliar (p=0.001), la ingesta de carnes con lugar de consumode alimentos (p= 0.006), consumo de alcohol (p= 0.028) y cambios económicos en el hogar (p=0.033). La ingesta defrutas con la actividad física (p=0.021), la ingesta de verdu-ras con la convivencia familiar (p= 0.003), lugar de consumode alimentos (p= 0.001), consumo de alcohol (p=0.049) yhoras de sueño (p=0.036). La ingesta de aceites vegetalescon la convivencia familiar (p=0.02) y los alimentos ultrapro-cesados con el lugar de consumo (p=0.002) y consumo de al-cohol (p=0.044) (AU)

Introduction: The dietary intake of Peruvian universitys tudents may be affected by different factors that determine a physical and mental health condition which frustrates optimal academic development. Objective: To identify the factors associated with dietary intake in Peruvian university students in post-pandemic. Material and methods: The study was cross-sectional, 393 Peruvian university students participated in a dietary intake survey with 8 food groups (tubers and roots, cereals andderivatives, vegetables, menestras, meats and derivatives, ul-tra-processed foods, vegetable oils, vegetables, fruits), 7 fac-tors (living with the family, place of food consumption, alco-hol consumption, tobacco consumption, economic changes inthe home, hours of sleep, physical activity) and three categories (decreased, unchanged, increased). Bivariate analysiswas performed between food groups and factors associated with dietary intake and the Chi-square test was used. Results: Food had a direct association with cereal and tuber intake with family coexistence (p=0.037; p=0.01 respectively), menestras with place of food consumption (p=0.002)and family coexistence (p=0.001), meat intake with place offood consumption (p= 0.006), alcohol consumption (p=0.028) and economic changes in the household (p=0.033).Fruit intake with physical activity (p=0.021), vegetable intake with family coexistence (p= 0.003), place of food consump-tion (p= 0.001), alcohol consumption (p=0.049) and hours ofsleep (p=0.036). Vegetable oil intake with family cohabitation(p=0.02) and ultra-processed food with place of consumption(p=0.002) and alcohol consumption (p=0.044).Conclusions: The food intake of Peruvian university stu-dents was directly associated with family coexistence, place offood consumption, alcohol consumption, economic changes inthe home, physical activity and hours of sleep (AU)mes.

Mixtures of self-propelled particles interacting with asymmetric obstacles.

In the presence of an obstacle, active particles condensate into a surface "wetting" layer due to persistent motion. If the obstacle is asymmetric, a rectification current arises in addition to wetting. Asymmetric geometries are therefore commonly used to concentrate microorganisms like bacteria and sperms. However, most studies neglect the fact that biological active matter is diverse, composed of individuals with distinct self-propulsions. Using simulations, we study a mixture of "fast" and "slow" active Brownian disks in two dimensions interacting with large half-disk obstacles. With this prototypical obstacle geometry, we analyze how the stationary collective behavior depends on the degree of self-propulsion "diversity," defined as proportional to the difference between the self-propulsion speeds, while keeping the average self-propulsion speed fixed. A wetting layer rich in fast particles arises. The rectification current is amplified by speed diversity due to a superlinear dependence of rectification on self-propulsion speed, which arises from cooperative effects. Thus, the total rectification current cannot be obtained from an effective one-component active fluid with the same average self-propulsion speed, highlighting the importance of considering diversity in active matter.

Unraveling the Role of the Zinc-Dependent Metalloproteinase/HTH-Xre Toxin/Antitoxin (TA) System of Brucella abortus in the Oxidative Stress Response: Insights into the Stress Response and Virulence.

Toxin/antitoxin (TA) systems have been scarcely studied in Brucella abortus, the causative agent of brucellosis, which is one of the most prevalent zoonotic diseases worldwide. In this study, the roles of a putative type II TA system composed by a Zinc-dependent metalloproteinase (ZnMP) and a transcriptional regulator HTH-Xre were evaluated. The deletion of the open reading frame (ORF) BAB1_0270, coding for ZnMP, used to produce a mutant strain, allowed us to evaluate the survival and gene expression of B. abortus 2308 under oxidative conditions. Our results showed that the B. abortus mutant strain exhibited a significantly reduced capacity to survive under hydrogen peroxide-induced oxidative stress. Furthermore, this mutant strain showed a decreased expression of genes coding for catalase (katE), alkyl hydroperoxide reductase (ahpC) and transcriptional regulators (oxyR and oxyR-like), as well as genes involved in the general stress response, phyR and rpoE1, when compared to the wild-type strain. These findings suggest that this type II ZnMP/HTH-Xre TA system is required by B. abortus to resist oxidative stress. Additionally, previous evidence has demonstrated that this ZnMP also participates in the acidic stress resistance and virulence of B. abortus 2308. Therefore, we propose a hypothetical regulatory function for this ZnMP/HTH-Xre TA system, providing insight into the stress response and its potential roles in the pathogenesis of B. abortus.

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study.

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Continuum description of confluent tissues with spatial heterogeneous activity.

A continuum description is built to characterize the stationary and transient deformations of confluent tissues subject to heterogeneous activities. By defining a coarse-grained texture matrix field to represent the shape and size of cells, we derive the coarse-grained stress tensor for the vertex model. Activity in the tissue takes the form of inhomogeneous apical contractions, which can be modeled as reductions of the vertex model reference areas or perimeters representing activity in the medial and perimeter regions of the cells, respectively. For medial activity, the extra stress is just an isotropic pressure, while for perimeter activity, it also has a deviatoric component, which is aligned with the texture matrix. The predictions of the continuum description are compared with the average spatiotemporal deformations obtained in simulations of the vertex model subject to localized apical contractions, showing an excellent agreement, even if the active patch is as small as one cell. The fluctuations around the average are more prominent when the activity is in the medial region due to the lack of negative active shape feedback, which, coupled with the confluent property, increases cellular shape and size variations.

Kinetic modeling of the chemotactic process in run-and-tumble bacteria.

The chemotactic process of run-and-tumble bacteria results from modulating the tumbling rate in response to changes in chemoattractant gradients felt by the bacteria. The response has a characteristic memory time and is subject to important fluctuations. These ingredients are considered in a kinetic description of chemotaxis, allowing the computation of the stationary mobility and the relaxation times needed to reach the steady state. For large memory times, these relaxation times become large, implying that finite-time measurements give rise to nonmonotonic currents as a function of the imposed chemoattractant gradient, contrary to the stationary regime where the response is monotonic. The case of an inhomogeneous signal is analyzed. Contrary to the usual Keller-Segel model, the response is nonlocal, and the bacterial profile is smoothed with a characteristic length that grows with the memory time. Finally, the case of traveling signals is considered, where appreciable differences appear compared to memoryless chemotactic descriptions.

Rootstocks Comparison in Grafted Watermelon under Water Deficit: Effects on the Fruit Quality and Yield.

Drought is widely recognized as one of the most significant agricultural constraints worldwide. A strategy to avoid the adverse effects of drought on crops is to cultivate high-yielding varieties by grafting them onto drought-tolerant rootstocks with a differentiated root system. Thus, the objective of this study was to evaluate fruit yield and quality, root system architecture, and water productivity of watermelon grafted onto Lagenaria siceraria rootstocks. To do so, a commercial watermelon cultivar "Santa Amelia" [Citrullus lanatus (Thunb.)] was grafted onto five L. siceraria rootstocks: 'Illapel', 'Osorno', 'BG-48', 'GC', and 'Philippines', which were grown under three irrigation treatments (100%, 75%, and 50% of evapotranspiration). The comparison of the L. siceraria rootstocks in the irrigation treatments demonstrated no significant effect on watermelon fruit quality parameters. The rootstocks 'Illapel', 'Osorno', and 'GC' significantly improved the fruit number and yield (total fruit weight) under water deficit. Similarly, 'Illapel', 'Osorno', and 'GC' consistently showed statistical differences for root system architecture traits compared to 'BG-48' and 'Philippines'. Based on these results, we concluded that the used L. siceraria rootstocks did not affect the fruit yield and quality of grafted watermelon under water deficit. This study may help adjust the amount of applied water for watermelon production where L. siceraria rootstocks are utilized.

Wetting dynamics by mixtures of fast and slow self-propelled particles.

We study active surface wetting using a minimal model of bacteria that takes into account the intrinsic motility diversity of living matter. A mixture of "fast" and "slow" self-propelled Brownian particles is considered in the presence of a wall. The evolution of the wetting layer thickness shows an overshoot before stationarity and its composition evolves in two stages, equilibrating after a slow elimination of excess particles. Nonmonotonic evolutions are shown to arise from delayed avalanches towards the dilute phase combined with the emergence of a transient particle front.

Removal of Heavy Metals from Mine Tailings in Central Chile Using Solidago chilensis Meyen, Haplopappus foliosus DC, and Lycium chilense Miers ex Bertero.

Mining activities have been a part of the history of Chile since time immemorial, generating pollution and environmental liabilities. Due to the lack of regulation, many tailings are deposited close to rivers or/and on unstable ground, near which towns have been built, generally in locations with no budget for their treatment. This study tested three plant species from Northern and Central Chile to remove total chromium, nickel, and zinc from tailings: Solidago chilensis, Haplopappus foliosus, and Lycium chilense, which complements the few existing studies on heavy metals removal with native or endemic Chilean shrubs. The experiments were conducted ex situ, and the initial and final concentrations of metals were determined in tailings and plants to obtain the removal efficiency, translocation and bioconcentration factors. Among these species, the best performance was obtained using Solidago chilensis, achieving removal efficiencies of 24% for Cr, 19% for Ni, and 17% for Zn, showing the ability to phytostabilize chromium and the higher resistance concerning the toxicity threshold. Haplopappus foliosus and Lycium chilense presented a slight tendency to stabilize chromium. Only Solidago chilensis showed little ability to extract Zn.

Recurrent multi-cameral cardiac myxomas in a child with Carney complex.

Cardiac myxoma is a relatively rare tumour, usually solitary, that occurs primarily in the left atrium of adults, but comprises only 30% of cardiac tumours in children. We recently treated a 12-year-old girl with multiple recurrent myxomas in three cardiac chambers(following surgical resection 3 years earlier). Genomic analysis showed the PKAR1A mutation typical for Carney complex.

Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial.

BACKGROUND: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.

Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial.

PURPOSE: Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501). PATIENTS AND METHODS: Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS: Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION: Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.

Variation in Root-Related Traits Is Associated With Water Uptake in Lagenaria siceraria Genotypes Under Water-Deficit Conditions.

In many agricultural areas, crop production has decreased due to a lack of water availability, which is having a negative impact on sustainability and putting food security at risk. In plants, the plasticity of the root system architecture (RSA) is considered to be a key trait driving the modification of the growth and structure of roots in response to water deficits. The purpose of this study was to examine the plasticity of the RSA traits (mean root diameter, MRD; root volume, RV; root length, RL; and root surface area, SA) associated with drought tolerance in eight Lagenaria siceraria (Mol. Standl) genotypes, representing three different geographical origins: South Africa (BG-58, BG-78, and GC), Asia (Philippines and South Korea), and Chile (Illapel, Chepica, and Osorno). The RSA changes were evaluated at four substrate depths (from 0 to 40 cm). Bottle gourd genotypes were grown in 20 L capacity pots under two contrasting levels of irrigation (well-watered and water-deficit conditions). The results showed that the water productivity (WP) had a significant effect on plasticity values, with the Chilean accessions having the highest values. Furthermore, Illapel and Chepica genotypes presented the highest WP, MRD, and RV values under water-deficit conditions, in which MRD and RV were significant in the deeper layers (20-30 and 30-40 cm). Biplot analysis showed that the Illapel and Chepica genotypes presented a high WP, MRD, and RV, which confirmed that these may be promising drought-tolerant genotypes. Consequently, increased root diameter and volume in bottle gourd may constitute a response to a water deficit. The RSA traits studied here can be used as selection criteria in bottle gourd breeding programs under water-deficit conditions.

Effects of CYP3A Inhibition, CYP3A Induction, and Gastric Acid Reduction on the Pharmacokinetics of Ripretinib, a Switch Control KIT Tyrosine Kinase Inhibitor.

Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50 mg alone and with itraconazole 200 mg once daily, 24 participants received ripretinib 100 mg alone and with rifampin 600 mg once daily, and 25 participants received ripretinib 50 mg alone and with pantoprazole 40 mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to ∞ (AUC0-∞ ) and maximum observed concentration (Cmax ) of 199% and 136%. Ripretinib exposure decreased with concomitant rifampin: geometric LS mean ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%. Pantoprazole coadministration had no effect on ripretinib pharmacokinetics. No unexpected safety signals occurred. No dose adjustment is required for ripretinib coadministered with gastric acid reducers and strong CYP3A inhibitors; patients also receiving strong CYP3A inhibitors should be monitored more frequently for adverse reactions. Concomitant ripretinib use with strong CYP3A inducers should be avoided. Prescribers should refer to approved labeling for specific dose recommendations with concomitant use of strong and moderate CYP3A inducers.