Numerical investigation of heterogeneous soft particle pairs in inertial microfluidics.

The formation of pairs of particles or cells of different types in microfluidic channels can be desired or detrimental in healthcare applications. It is still unclear what role softness heterogeneity plays in the formation of these particle pairs. We use an in-house lattice-Boltzmann-immersed-boundary-finite-element solver to simulate a pair of particles with different softness flowing through a straight channel with a rectangular cross-section under initial conditions representative of a dilute suspension. We find that softness heterogeneity significantly affects the pair dynamics, determining whether a pair will form or not, and determining the lateral and inter-particle equilibrium behaviour in the pair. We also observe close matches between the transient deformation of particles in a linear pair and single particles in isolation. These results further our understanding of pair behaviour, providing a foundation for understanding particle train formation, and open up the potential to develop reduced-order models for particle pair formation based upon the behaviour of single particles.

Assessment of Contact Allergens in "Hypoallergenic" Athletic Shoes by Mass Spectrometry.

Background: Identification of athletic shoes for patients with contact allergy is difficult. Company reports of allergen content are often incorrect. Objectives: To determine whether chemical analysis of 4 athletic shoes, previously reported to be free of the most common contact allergens, contain quantifiable allergen levels. Methods: Samples from the uppers and insoles of 4 shoes believed to be free of common allergens were assessed by mass spectrometry. A total of 4 rubber accelerators and 2 adhesives were directly quantified and additional 7 rubber accelerators were assessed using semiquantitative measures. Results: Aside from carbamates (assayed as 59 ppm zinc in insoles) in SeaVee's Sixty-Six sneakers, para-tertiarybutylphenol formaldehyde resin (PTBFR) (assayed as 7.6 ppm paratertiary butylphenol or 4-tertiary butylphenol [4TBP] in uppers) in Allbirds Tree Runners and rosin (assayed as 628 ppm sodium abietate in uppers) and carbamates (24 ppm zinc in uppers) in Saucony Jazz sneakers, these shoes had low levels of all allergens assayed in this study. Tom's Carlo sneakers contained rosin (127 ppm sodium abietate in insoles), PTBFR (6.5 ppm 4TBP in uppers), and carbamates (112 ppm sodium abietate in insoles) but had low levels of all other assayed allergens. Conclusions: Although identifying allergen-free shoes is challenging, the results of this analysis will help patch testing physicians recommend athletic shoes to patients with specific allergies.

A general synthesis of aromatic and heteroaromatic lipoxin B4 analogues.

Lipoxins are an important class of pro-resolving mediators that play a crucial role in the resolution of inflammation. Thus, the synthesis of more chemically and metabolically stable synthetic lipoxin analogues is an area of significant interest. Whereas synthetic analogues of lipoxin A4 (LXA4) have been well studied, analogues of lipoxin B4 (LXB4) have been the focus of considerably less attention. Herein we report the asymmetric synthesis of a focused library of LXB4 mimetics in which the triene core of the molecule has been replaced with different aromatic and heteroaromatic rings. The synthesis of each of these analogues was achieved by a general strategy in which the key steps were a Suzuki cross coupling between a common upper chain fragment and an aromatic lower chain, followed by a stereoselective ketone reduction.

Numerical investigation of the dynamics of a rigid spherical particle in a vortical cross-slot flow at moderate inertia.

The study of flow and particle dynamics in microfluidic cross-slot channels is of high relevance for lab-on-a-chip applications. In this work, we investigate the dynamics of a rigid spherical particle in a cross-slot junction for a channel height-to-width ratio of 0.6 and at a Reynolds number of 120 for which a steady vortex exists in the junction area. Using an in-house immersed-boundary-lattice-Boltzmann code, we analyse the effect of the entry position of the particle in the junction and the particle size on the dynamics and trajectory shape of the particle. We find that the dynamics of the particle depend strongly on its lateral entry position in the junction and weakly on its vertical entry position; particles that enter close to the centre show trajectory oscillations. Larger particles have longer residence times in the junction and tend to oscillate less due to their confinement. Our work contributes to the understanding of particle dynamics in intersecting flows and enables the design of optimised geometries for cytometry and particle manipulation.

Synthesis of Highly Functionalized Bismacycles via Post-Transmetallation Modification of Arylboronic Acids.

Bismacycles featuring a sulfone-bridged scaffold have recently been developed as versatile and convenient electrophilic arylating agents. Here, we report that the exocyclic aryl group, which is ultimately transferred to a nucleophilic coupling partner, can be functionalized through cross-coupling, heteroatom substitutions, oxidations and reductions, and protecting group manipulations. This "postsynthetic modification" approach provides concise and divergent access to complex aryl bismacycles. The utility of the functionalized bismacycles in electrophilic arylation of C-H and O-H bonds is demonstrated.

Effective Colonization by Nontoxigenic Clostridioides difficile REA Strain M3 (NTCD-M3) Spores following Treatment with Either Fidaxomicin or Vancomycin.

Colonization with nontoxigenic Clostridioides difficile strain M3 (NTCD-M3) has been demonstrated in susceptible hamsters and humans when administered after vancomycin treatment. NTCD-M3 has also been shown to decrease risk of recurrent C. difficile infection (CDI) in patients following vancomycin treatment for CDI. As there are no data for NTCD-M3 colonization after fidaxomicin treatment, we studied the efficacy of NTCD-M3 colonization and determined fecal antibiotic levels in a well-studied hamster model of CDI. Ten of 10 hamsters became colonized with NTCD-M3 after 5 days of treatment with fidaxomicin when NTCD-M3 was administered daily for 7 days after treatment discontinuation. The findings were nearly identical to 10 vancomycin-treated hamsters also given NTCD-M3. High fecal levels of OP-1118, the major fidaxomicin metabolite, and vancomycin were noted during treatment with the respective agents and modest levels noted 3 days after treatment discontinuation at the time when most of the hamsters became colonized. These findings support the ongoing development of NTCD-M3 for the prevention of recurrent CDI. IMPORTANCE NTCD-M3 is a novel live biotherapeutic, that has been shown in a Phase 2 clinical trial to prevent recurrence of C. difficile infection (CDI) when administered shortly after antibiotic treatment of the initial CDI episode. Fidaxomicin was not, however, in widespread use at the time this study was conducted. A large multi-center Phase 3 clinical trial is now currently in the planning stage, and it is anticipated that many patients eligible for this study will be treated with fidaxomicin. Since efficacy in the hamster model of CDI has predicted success in patients with CDI, we studied the ability of NTCD-M3 to colonize hamsters after treatment with either fidaxomicin or vancomycin.

Altered EEG, disrupted hippocampal long-term potentiation and neurobehavioral deficits implicate a delirium-like state in a mouse model of sepsis.

Sepsis and systemic inflammation are often accompanied by severe encephalopathy, sleep disruption and delirium that strongly correlate with poor clinical outcomes including long-term cognitive deficits. The cardinal manifestations of delirium are fluctuating altered mental status and inattention, identified in critically ill patients by interactive bedside assessment. The lack of analogous assessments in mouse models or clear biomarkers is a challenge to preclinical studies of delirium. In this study, we utilized concurrent measures of telemetric EEG recordings and neurobehavioral tasks in mice to characterize inattention and persistent cognitive deficits following polymicrobial sepsis. During the 24-hour critical illness period for the mice, slow-wave EEG dominance, sleep disruption, and hypersensitivity to auditory stimuli in neurobehavioral tasks resembled clinical observations in delirious patients in which alterations in similar outcome measurements, although measured differently in mice and humans, are reported. Mice were tested for nest building ability 7 days after sepsis induction, when sickness behaviors and spontaneous activity had returned to baseline. Animals that showed persistent deficits determined by poor nest building at 7 days also exhibited molecular changes in hippocampal long-term potentiation compared to mice that returned to baseline cognitive performance. Together, these behavioral and electrophysiological biomarkers offer a robust mouse model with which to further probe molecular pathways underlying brain and behavioral changes during and after acute illness such as sepsis.

Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis.

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through expression of its receptor, GLP-1R. RNA-seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 µg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP-1R pharmacotherapies already in clinical use.

Blockade of TGF-ß signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo.

TGF-ß plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term antiretroviral therapy (ART). We hypothesized that releasing cells from TGF-ß-driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-ß and a TGF-ß type 1 receptor inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the 64Cu-DOTA-F(ab')2 p7D3 probe, along with plasma and tissue viral loads (VLs). Exogenous TGF-ß reduced HIV-1 reactivation in U1 and ACH-2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMCs from HIV-1-infected, ART-treated, aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values in PET/CT images in gut and lymph nodes of 5 out of 7 aviremic, long-term ART-treated, SIV-infected macaques. This increase correlated with an increase in SIV RNA in the gut. Two of the 7 animals also exhibited increases in plasma VLs. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-ß signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.

Synthesis and Biological Evaluation of Bicyclo[1.1.1]pentane-Containing Aromatic Lipoxin A4 Analogues.

Lipoxins are important drivers of inflammation resolution, suggesting a potential therapeutic benefit. Bicyclo[1.1.1]pentanes (BCPs) are potential isosteric replacements for arenes and/or alkyl groups within drug candidates. We carried out an asymmetric synthesis of four BCP-containing synthetic lipoxin A4 mimetics (BCP-sLXms) in which the key steps were a Suzuki coupling, an asymmetric ketone reduction, and a triethylborane-initiated radical bicyclopentylation. These mimetics were screened for their impact on inflammatory responses, and one imidazolo-BCP-sLXm (6a) was found to possess high anti-inflammatory activity.

Disruption of Synaptic Transmission in the Bed Nucleus of the Stria Terminalis Reduces Seizure-Induced Death in DBA/1 Mice and Alters Brainstem E/I Balance.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures (AGS) and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin (TeNT) significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic (HCVR) and hypoxic ventilatory response (HVR). This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory (E/I) synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of S-IRA, potentially through its outputs to brainstem respiratory regions.

Numerical investigation of the formation and stability of homogeneous pairs of soft particles in inertial microfluidics.

We investigate the formation and stability of a pair of identical soft capsules in channel flow under mild inertia. We employ a combination of the lattice Boltzmann, finite element and immersed boundary methods to simulate the elastic particles in flow. Validation tests show excellent agreement with numerical results obtained by other research groups. Our results reveal new trajectory types that have not been observed for pairs of rigid particles. While particle softness increases the likelihood of a stable pair forming, the pair stability is determined by the lateral position of the particles. A key finding is that stabilisation of the axial distance occurs after lateral migration of the particles. During the later phase of pair formation, particles undergo damped oscillations that are independent of initial conditions. These damped oscillations are driven by a strong hydrodynamic coupling of the particle dynamics, particle inertia and viscous dissipation. While the frequency and damping coefficient of the oscillations depend on particle softness, the pair formation time is largely determined by the initial particle positions: the time to form a stable pair grows exponentially with the initial axial distance. Our results demonstrate that particle softness has a strong impact on the behaviour of particle pairs. The findings could have significant ramifications for microfluidic applications where a constant and reliable axial distance between particles is required, such as flow cytometry.

Effects of divalent cations on Schaffer collateral axon function.

Previously, we reported that distal Schaffer collaterals undergo biphasic changes in excitability during high-frequency stimulation (HFS), with an early hyper-excitability period followed by an excitability depression period. The extracellular divalent cations calcium and magnesium can regulate membrane excitability in neuronal tissue. Therefore, we hypothesized that altering the concentrations of extracellular calcium and magnesium would alter the biphasic excitability changes. We tested this hypothesis by recording distal Schaffer collateral fiber volleys in stratum radiatum of hippocampal area CA1 during 100 Hz HFS in artificial cerebral spinal fluid (ACSF) containing normal and altered concentrations of extracellular divalent cations. Our normal ACSF contained 2.0 mM calcium and 2.0 mM magnesium. We examined four solutions with altered divalent cation concentrations: (1) high-calcium/low-magnesium (3.8 mM/0.2 mM), (2) low-calcium/high-magnesium (0.2 mM/3.8 mM), (3) high-calcium/normal-magnesium (3.8 mM/2.0 mM), or (4) normal-calcium/high-magnesium (2.0 mM/10.0 mM), and assessed the effects on Schaffer collateral responses. Increasing or decreasing extracellular calcium enhanced or reduced (respectively) the early hyper-excitable period whereas increasing extracellular magnesium reduced the later excitability depression. Because these results might be explained by altered calcium influx through voltage-gated calcium (CaV) channels, we tested CaV blockers (ω-agatoxin IVA, ω-conotoxin-GVIA, cadmium), but observed no effects on responses during HFS. Some of the effects of altered divalent cation concentration may be explained by altered membrane surface charge. Although this mechanism does not completely explain our findings, calcium influx through CaV channels is not required.

Twofold Radical-Based Synthesis of N,C-Difunctionalized Bicyclo[1.1.1]pentanes.

Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to [1.1.1]propellane to afford iodo-BCPAs; the newly formed C-I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.

Excitatory synaptic transmission in hippocampal area CA1 is enhanced then reduced as chronic epilepsy progresses.

This study examines changes in synaptic transmission with progression of the chronic epileptic state. Male Sprague-Dawley rats (P40-45) were injected with either saline or pilocarpine. In rats injected with pilocarpine, status epilepticus ensued. Hippocampal slices were cut 20-60 days or 80-110 days post-treatment. Evoked and miniature EPSCs (mEPSCs) were recorded from CA1 pyramidal neurons using whole-cell voltage-clamp. Fiber volleys were also recorded from stratum radiatum. Evoked EPSCs from the pilocarpine-treated cohort showed enhanced amplitudes 20-60 days post-treatment compared to the saline-treated cohort, whereas mEPSCs recorded from the same age group showed no change in event frequency and a slight but significant decrease in mEPSC amplitude distribution. In contrast, comparing evoked EPSCs and mEPSCs recorded 80-110 days after treatment indicated reduced amplitudes from pilocarpine-treated animals compared to controls. mEPSC inter-event interval decreased. This could be explained by a partial depletion of the ready releasable pool of neurotransmitter vesicles in Schaffer collateral presynaptic terminals of the pilocarpine-treated rats. In both saline- and pilocarpine-treated cohorts, concomitant decreases in mEPSC amplitudes as time after treatment progressed suggest that age-related changes in CA1 circuitry may be partially responsible for changes in synaptic transmission that may influence the chronic epileptic state.

Dental resins used in 3D printing technologies release ovo-toxic leachates.

We recently engineered the first female reproductive tract on a chip (EVATAR), to enable sex-based ex vivo research. To increase the scalability and accessibility of EVATAR, we turned to 3D printing (3DP) technologies, selecting two biocompatible 3DP resins, Dental SG (DSG) and Dental LT (DLT) to generate 3DP microphysiologic platforms. Due to the known sensitivity of reproductive cells to leachable compounds, we first screened for toxicity of these biomaterials using an in vitro mammalian oocyte maturation assay. Culture of mouse oocytes in 3DP plates using conventionally treated DSG resin resulted in rapid oocyte degeneration. Oxygen plasma treatment of the surface of printed DSG resin prevented this degeneration, and the majority of the resulting oocytes progressed through meiosis in vitro. However, 57.0% ± 37.2% of the cells cultured in the DSG resin plates exhibited abnormal chromosome morphology compared to 19.4% ± 17.3% of controls cultured in polystyrene. All tested DLT resin conditions, including plasma treatment, resulted in complete and rapid oocyte degeneration. To identify the ovo-toxic component of DLT, we analyzed DLT leachate using mass spectroscopy. We identified Tinuvin 292, a commercial light stabilizer, as a major component of the DLT leachate, which resulted in a dose-dependent disruption of meiotic progression and increase in chromosomal abnormalities with oocyte exposure, showing significant ovo-toxicity in mammals. Severe reproductive toxicity induced by in vitro exposure to these 3D-printed resins highlights potential risks of deploying insufficiently characterized materials for biomedical applications and underscores the need for more rigorous evaluation and designation of biocompatible materials.

Heritability of haemodynamics in the ascending aorta.

Blood flow in the vasculature can be characterised by dimensionless numbers commonly used to define the level of instabilities in the flow, for example the Reynolds number, Re. Haemodynamics play a key role in cardiovascular disease (CVD) progression. Genetic studies have identified mechanosensitive genes with causal roles in CVD. Given that CVD is highly heritable and abnormal blood flow may increase risk, we investigated the heritability of fluid metrics in the ascending aorta calculated using patient-specific data from cardiac magnetic resonance (CMR) imaging. 341 participants from 108 British Caucasian families were phenotyped by CMR and genotyped for 557,124 SNPs. Flow metrics were derived from the CMR images to provide some local information about blood flow in the ascending aorta, based on maximum values at systole at a single location, denoted max, and a 'peak mean' value averaged over the area of the cross section, denoted pm. Heritability was estimated using pedigree-based (QTDT) and SNP-based (GCTA-GREML) methods. Estimates of Reynolds number based on spatially averaged local flow during systole showed substantial heritability ([Formula: see text], [Formula: see text]), while the estimated heritability for Reynolds number calculated using the absolute local maximum velocity was not statistically significant (12-13%; [Formula: see text]). Heritability estimates of the geometric quantities alone; e.g. aortic diameter ([Formula: see text], [Formula: see text]), were also substantially heritable, as described previously. These findings indicate the potential for the discovery of genetic factors influencing haemodynamic traits in large-scale genotyped and phenotyped cohorts where local spatial averaging is used, rather than instantaneous values. Future Mendelian randomisation studies of aortic haemodynamic estimates, which are swift to derive in a clinical setting, will allow for the investigation of causality of abnormal blood flow in CVD.

A Patient-Specific CFD Pipeline Using Doppler Echocardiography for Application in Coarctation of the Aorta in a Limited Resource Clinical Context.

Congenital heart disease (CHD) is the most common birth defect globally and coarctation of the aorta (CoA) is one of the commoner CHD conditions, affecting around 1/1800 live births. CoA is considered a CHD of critical severity. Unfortunately, the prognosis for a child born in a low and lower-middle income country (LLMICs) with CoA is far worse than in a high-income country. Reduced diagnostic and interventional capacities of specialists in these regions lead to delayed diagnosis and treatment, which in turn lead to more cases presenting at an advanced stage. Computational fluid dynamics (CFD) is an important tool in this context since it can provide additional diagnostic data in the form of hemodynamic parameters. It also provides an in silico framework, both to test potential procedures and to assess the risk of further complications arising post-repair. Although this concept is already in practice in high income countries, the clinical infrastructure in LLMICs can be sparse, and access to advanced imaging modalities such as phase contrast magnetic resonance imaging (PC-MRI) is limited, if not impossible. In this study, a pipeline was developed in conjunction with clinicians at the Red Cross War Memorial Children's Hospital, Cape Town and was applied to perform a patient-specific CFD study of CoA. The pipeline uses data acquired from CT angiography and Doppler transthoracic echocardiography (both much more clinically available than MRI in LLMICs), while segmentation is conducted via SimVascular and simulation is realized using OpenFOAM. The reduction in cost through use of open-source software and the use of broadly available imaging modalities makes the methodology clinically feasible and repeatable within resource-constrained environments. The project identifies the key role of Doppler echocardiography, despite its disadvantages, as an intrinsic component of the pipeline if it is to be used routinely in LLMICs.

CT Volumetry and Basic Texture Analysis as Surrogate Markers in Advanced Non-small-cell Lung Cancer.

INTRODUCTION: We evaluated volumetric tumor measurements and computed tomography texture analysis as prognostic indicators in patients with advanced non-small-cell lung cancer when compared with the unidimensional tumor size measurements used in Response Evaluation Criteria in Solid Tumors (RECIST). PATIENTS AND METHODS: In a retrospective review, computed tomography examinations in 77 patients with advanced non-small-cell lung cancer were evaluated before and after 2 cycles of chemotherapy. Baseline and changes in tumor diameter, volume, and texture were analyzed. Survival was analyzed with Cox regression analysis and Kaplan-Meier survival statistics. RESULTS: Cox regression analysis demonstrated that only change in tumor volume (exp(B) = 1.006; P = .02) and the initial sum of the largest target lesion diameters predicted survival (exp(B) = 1.013; P = .02). Kaplan-Meier statistics demonstrated that patients with an initial sum of the largest target lesion diameters less than 88 mm had median survival time of 587 days (95% confidence interval [CI], 269-905 days), compared with the survival of those with larger tumor burden of 407 days (95% CI, 235-579 days). Patients in whom tumor volume decreased by more than 29% had a median survival time of 622 days (95% CI, 448-796 days), compared with 305 days for those with less decrease (95% CI, 34-240 days). CONCLUSION: This study demonstrates that change in lung tumor volume is a better marker of patient survival than change of unidimensional diameter measurements in our cohort. If confirmed in larger studies, this suggests that volumetry might improve clinical decision-making for individual patients and allow for faster assessment of new treatments.