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Background The primary objective was to quantify changes in vascular micro-environment in spinal metastases (SM) patients treated with stereotactic body radiotherapy (SBRT) with multi-parametric dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The secondary objective was to study plasma biomarkers related to endothelial apoptosis. Patients and methods Patients were imaged with DCE-MRI at baseline/1-week/12-weeks post-SBRT. Metrics including normalised time-dependent leakage (Ktrans), permeability surface product (PS), fractional plasma volume (Vp), extracellular volume (Ve) and perfusion (F) were estimated using distributed parameter model. Serum acid sphingomyelinase (ASM) and sphingosine-1-phosphate (S1P) were quantified using ELISA. Clinical outcomes including physician-scored and patient-reported toxicity were collected. Results Twelve patients (with varying primary histology) were recruited, of whom 10 underwent SBRT. Nine patients (with 10 lesions) completed all 3 imaging assessment timepoints. One patient died due to pneumonia (unrelated) before follow-up scans were performed. Median SBRT dose was 27 Gy (range: 24–27) over 3 fractions (range: 2–3). Median follow-up for alive patients was 42-months (range: 22.3–54.3), with local control rate of 90% and one grade 2 or higher toxicity (vertebral compression fracture). In general, we found an overall trend of reduction at 12-weeks in all parameters (Ktrans/PS/Vp/Ve/F). Ktrans and PS showed a reduction as early as 1-week. Ve/Vp/F exhibited a slight rise 1-week post-SBRT before reducing below the baseline value. There were no significant changes, post-SBRT, in plasma biomarkers (ASM/S1P). Conclusions Tumour vascular micro-environment (measured by various metrics) showed a general trend towards downregulation post-SBRT. It is likely that vascular-mediated cell killing contributes to excellent local control rates seen with SBRT. Future studies should evaluate the effect of SBRT on primary-specific spinal metastases (e.g., renal cell carcinoma).

Surveillance pouchoscopy is recommended for patients with restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis or familial adenomatous polyposis, with the surveillance interval depending on the risk of neoplasia. Neoplasia in patients with ileal pouches mainly have a glandular source and less often are of squamous cell origin. Various grades of neoplasia can occur in the prepouch ileum, pouch body, rectal cuff, anal transition zone, anus, or perianal skin. The main treatment modalities are endoscopic polypectomy, endoscopic ablation, endoscopic mucosal resection, endoscopic submucosal dissection, surgical local excision, surgical circumferential resection and re-anastomosis, and pouch excision. The choice of the treatment modality is determined by the grade, location, size, and features of neoplastic lesions, along with patients' risk of neoplasia and comorbidities, and local endoscopic and surgical expertise.

Background: PDAC is an aggressive and treatment-refractory cancer due to its desmoplastic and immunosuppressive tumor microenvironment (TME). Overexpression of pFAK, a master regulator of the TME, and CXCR4, a receptor involved immunosuppression and tumor progression, are associated with poorer outcomes in PDAC. Exceptional responders, broadly defined by extended survival and durable treatment responses, represent a rare subset in PDAC. We hypothesize that the immune and stromal signatures of exceptional responders vary significantly from non-exceptional responders, specifically exhibiting decreased p-FAK and CXCR4 expression and decreased immunosuppressive myeloid phenotypes in the TME. Methods: We performed correlative quantitative analysis of multiplex immunohistochemistry (mIHC) employing 40 biomarkers on stage I/II PDAC, surgically resected formalin-fixed paraffin-embedded tissues from 9 non-exceptional responders and 11 exceptional responders. Exceptional responders were selected based on degree and duration of disease-free survival or overall survival more than double the historical matched medians. mIHC and image cytometry were used to distinguish and quantify total immune cell populations and colocalize biomarker expression across each distinct cell type. Cell populations and expression levels were compared using unpaired T-tests. Results: Exceptional responders showed significantly decreased overall pFAK expression (p=0.02) and overall CXCR4 expression (p=0.04). In exceptional responders, pFAK expression and CXCR4 expression were significantly decreased in immunosuppressive CD66b+ granulocytes (p=0.01, p=0.03, respectively) and in tumor associated macrophages (p=0.01, p=0.006, respectively). While not significant, exceptional responders demonstrated a marked decrease in immunosuppressive pFAK+ fibroblasts (p=0.12) when compared to non-exceptional responders. No change was seen in the CD8+ T cell infiltration between groups; however, a trend was observed towards an increased proportion of granzyme B+ CD3+ CD8+ cytotoxic lymphocytes (p=0.57) in exceptional responders. Conclusion: Exceptional responders selected in this preliminary study have significantly lower FAK and CXCR4 expression and markedly reduced populations of immunosuppressive FAK+ and CXCR4+ myeloid cells. Suppression of pFAK and CXCR4 in fibroblasts and granulocytes, respectively are associated with exceptional clinical outcomes. Future expanded research comparing the distinct TME and genetic signatures of exceptional responders to non-exceptional is warranted. Citation Format: John Davelaar, Anser A. Abbas, Angela Minasyan, Omer H. Elmadbouh, Natalie Moshayedi, Brent Larson, Nicholas Nissen, Simon Lo, Srinivas Gaddam, Kambiz Kosari, Jun Gong, Andrew Hendifar, Stephen Pandol, Arsen Osipov. Suppression of phosphorylated focal adhesion kinase+ (pFAK+) fibroblasts and C-X-C chemokine receptor type 4 (CXCR4) expressing granulocytes is associated with exceptional clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5854.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a five-year survival rate of around 7% due to its late diagnosis, rapid metastasis, and chemotherapy resistance. For a small proportion (10-20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival (5-year rate of 20%). Given the clinical challenges and the need for personalized care strategies to maximize patient survival, we propose the utility of the minimally invasive liquid biopsy to identify circulating biomarkers in patient blood to guide prognosis and monitor treatment. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate the clinical significance of a heterogeneous circulating rare cell population in both the peripheral and portal vein blood of early-stage PDAC patients (n = 20) at four different time points—pre-, during, and post- surgical resection, as well as at one-week follow-up. Compared to normal donor samples (n = 50), PDAC patients had a significantly greater incidence of circulating tumor cells (CTCs: cytokeratin-positive (CK+) and CD35/45-negative). There was no significant difference in rare cell incidence between peripheral and portal vein samples. However, specific phenotypes of rare cells were observed at different frequencies based on time of sample collection. Patient samples collected pre-surgery had a significantly higher incidence of CTCs than samples collected during surgery, while post-surgery samples had a significantly higher incidence of total CK+ rare cells and mesenchymal CTCs (Vimentin-positive, CK+) than during-surgery samples. While post-surgical samples also had a higher total CK+ rare cell and CTC incidence than pre-surgical samples, the difference was not statistically significant. Additionally, patients who received neoadjuvant therapy with surgical resection had lower average incidence of rare cells. Overall, the data presented here reveal that 1) liquid biopsy analytes are detected at a higher incidence in localized PDAC than normal donors; 2) the time point of sample collection in relation to surgery leads to a statistically significant different in frequency of detectable analytes; and 3) anatomical location of blood draw is not associated with difference in rare cell incidence. This study demonstrates the liquid biopsy’s utility in early-stage PDAC detection at the time of surgical resection. Citation Format: Emmeline Y. Lin, George Courcoubetis, Divya Suresh, Jeremy Mason, Stephen J. Pandol, Simon Lo, Nicholas Nissen, Srinivas Gaddam, Peter Kuhn, Stephanie N. Shishido. Liquid biopsy to detect biomarkers in early-stage surgically-resected pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3320.

Directed flows of cellsin vivoare essential in morphogenesis. They shape living matter in phenomena involving cell mechanics and regulations of the acto-myosin cytoskeleton. However the onset of coherent motion is still poorly understood. Here we show that coherence is associated with spontaneous alignments of cell polarity by designing cellular rings of controlled dimensions. A tug-of-war between polarities dictates the onset of coherence, as assessed by tracking live cellular shapes and motions in various experimental conditions. In addition, we identify an internally driven constraint set by cellular acto-myosin cables at boundaries as essential to ensure coherence, and active force is generated as evaluated by the high RhoA activity. The cables are required to trigger coherence as shown by our numerical simulations based on a novel Vicsek-type model including free active boundaries. We quantitatively reproducein silicocoherence onsets and we predict criteria leading to coherence. Altogether, spontaneous coherent motion results from basic competitions between cell orientations and active cables at boundaries.

As new advances in the genomics and imaging of CNS tumors continues to evolve, a standardized system for classification is increasingly essential to diagnosis and management. The molecular markers introduced in the 2016 WHO classification of CNS tumors bring both practical and conceptual advances to the characterization of gliomas, strengthening the prognostic and predictive value of terminology while shedding light on the underlying mechanisms that drive biologic behavior. The purpose of this article is to provide a succinct overview of primary intracranial gliomas from a neuroradiologic prospective and according to the 5th edition WHO classification that was revised in 2016. An update of the molecular markers pertinent to defining the major lineages of brain gliomas will be provided, followed by discussion of the terminology, grading and imaging features associated with individual entities. Neuroradiologists should be aware of the key genomic and radiomic features of common brain gliomas, and familiar with an integrated approach to their diagnosis and grading.

TPS4192 Background: PDAC is an aggressive cancer. It remains refractory to checkpoint inhibition because of its significant desmoplastic and immunosuppressive tumor microenvironment (TME). Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is involved in tumor progression in many cancers and appears to be a targetable master regulator of the TME in PDAC. FAK inhibition combined with anti-PD1 antibody has been shown to modulate pancreatic stellate cells and decrease immunosuppressive myeloid and T-reg cells, leading to increased CD8 infiltration and improved survival in PDAC mouse models. A recent single arm phase I study of defactinib, a FAK inhibitor, combined with pembrolizumab, an anti-PD1 antibody, and chemotherapy was shown to be safe, and two confirmed partial responses were observed in patients with microsatellite-stable disease. Furthermore, increased CD8 T cell infiltration was observed in metastatic biopsies. Given the promising preclinical data and efficacy signals, as well as safety of the phase I clinical trial, our current study aims to assess the translational and clinical effects of sequentially combined defactinib and pembrolizumab following neoadjuvant and adjuvant chemotherapy in patients with high-risk resectable PDAC. Methods: This study is a multi-center, two-arm, randomized, open label, phase II clinical trial of neoadjuvant and adjuvant immunotherapy with defactinib and pembrolizumab, following neoadjuvant standard of care (SOC) gemcitabine and nab-paclitaxel in subjects with high-risk resectable PDAC. The primary objectives aim to assess changes in CD8 T cell intratumoral infiltration utilizing multiplex IHC and the pathologic complete response rate with defactinib and pembrolizumab or pembrolizumab alone, following neoadjuvant chemotherapy. Secondary objectives include assessment of disease-free survival, overall survival, and safety. Translational exploratory objectives include evaluating stromal and immune signatures among treatment groups via multiplex IHC and RNA/DNA sequencing. 36 subjects will be randomly assigned to receive 400 mg defactinib PO BID and 200 mg pembrolizumab IV every 3 weeks (Arm A) or 200 mg pembrolizumab IV alone every 3 weeks (Arm B). After enrollment, subjects will undergo 2 cycles (̃2 months) of standard neoadjuvant therapy of gemcitabine and nab-paclitaxel, followed by 2 cycles (6 weeks) of investigational treatment (Arm A or B) before surgical resection. Following surgery, subjects will receive SOC adjuvant chemotherapy followed by investigational treatment (Arm A or B) for 8 cycles (̃24 weeks). Key inclusion criteria include: resectable PDAC, CA 19-9>200, no prior systemic treatment for PDAC, and ECOG PS ≤1. As of February 2022, 14 patients have been enrolled. Clinical trial information: NCT03727880.

e16270 Background: PDAC is the third most fatal cancer, where most patients present with metastases at diagnosis. Previous studies, including a retrospective analysis from our single-center experience, suggests survival rates are significantly higher for those with lung-only metastases (mets) when compared to liver metastasis or other sites of metastases (liver+other). The objective of this analysis is to explore this difference based on sites and metastasis and the impact of chemotherapy from a national cohort. Methods: We identified PDAC patients (>18years) from with metastases to either 1) lung-only; 2) liver+other sites in the National Cancer Database diagnosed between 2010 and 2015.We analyzed patient characteristics, demographics, type of chemotherapy, and survival outcomes. Kaplan Meir survival curves were generated, and Cox proportional hazard models adjusted for age and sex were fit to evaluate associations between met site and survival. Survival was calculated from time of diagnosis to death and compared across mets site, receipt of chemotherapy, and treatment and type (single versus multi-agent). Results: 15359 PDAC patients were included in the analysis [51.6% male 48.4% female, mean age 69 years] of which 4512 (29.4%) patients had lung only mets and 10847 (70.6%) had liver + other mets. Median survival was 5.72 and 2.37 months for lung only vs. liver+other mets, respectively (log rank p

Domain alignment is currently the most prevalent solution to unsupervised domain-adaptation tasks and are often being presented as minimizers of some theoretical upper-bounds on risk in the target domain. However, further works revealed severe inadequacies between theory and practice: we consolidate this analysis and confirm that imposing domain invariance on features is neither necessary nor sufficient to obtain low target risk. We instead argue that successful deep domain adaptation rely largely on hidden inductive biases found in the common practice, such as model pre-training or design of encoder architecture. We perform various ablation experiments on popular benchmarks and our own synthetic transfers to illustrate their role in prototypical situations. To conclude our analysis, we propose to meta-learn parametric inductive biases to solve specific transfers and show their superior performance over handcrafted heuristics., 10 pages, 8 Figures

Paru sous le titre publié :Collective Dynamics of Focal Adhesions Regulate Direction of Cell Motion; International audience; Directed cell motion is essential in physiological and pathological processes such as morphogenesis, wound healing, and cancer spreading. Chemotaxis has often been proposed as the driving mechanism, even though evidence of long-range gradients is often lacking in vivo. By patterning adhesive regions in space, we control cell shape and the potential to move along one direction in another migration mode coined ratchetaxis. We report that focal contact distributions collectively dictate cell directionality, and bias is non-linearly increased by gap distance between adhesive regions. Focal contact dynamics on micro-patterns allow to integrate these phenomena in a model where each focal contact is translated into a force with known amplitude and direction, leading to quantitative predictions for cell motion in new conditions with their successful experimental tests. Altogether, our study shows how local and minute timescale dynamics of focal adhesions and their distribution lead to long-term cellular motion with simple geometric rules.

Imaging dynamics of cellular morphogenesis with high spatial-temporal resolution in 3D is challenging, due to the low spatial resolution along the optical axis and photo-toxicity. However, some cellular structures are planar and hence 2D imaging should be sufficient, provided that the structure of interest can be oriented with respect to the optical axis of the microscope. Here, we report a 3D microfabrication method which positions and orients cell divisions very close to the microscope coverglass. We use this approach to study cytokinesis in fission yeasts and polarization to lumen formation in mammalian epithelial cells. We show that this method improves spatial resolution on range of common microscopies, including super-resolution STED. Altogether, this method could shed new lights on self-organization phenomena in single cells and 3D cell culture systems.

Cell motility is essential in a variety of biological phenomena ranging from early development to organ homeostasis and diseases. This phenomenon was so far mainly studied and characterized on flat surfaces in vitro whereas this situation is rarely seen in vivo. Recently, cell motion in 3D microfabricated channels was reported to be possible, and it was shown that confined cells push on walls. However, rules setting cell directions in this context were not characterized yet. Here, we show by using assays that ratchetaxis operates in 3D ratchets on fibroblasts and on epithelial cancerous cells. Open ratchets rectify cell motion, whereas closed ratchets impose a direct cell migration along channels set by the cell orientation at the channel entry point. We also show that nuclei are pressed at constrictions zones through mechanisms involving dynamic asymmetries of focal contacts, stress fibers, and intermediate filaments. Interestingly, cells do not pass these constricting zones when defective in the keratin fusion implicated in squamous cancer. By combining ratchetaxis with chemical gradients, we finally report that cells are sensitive to local asymmetries in confinement and that topological and chemical cues may be encoded differently by cells. Altogether our ratchet channels could mimic small blood vessels where cells are confined: cells would probe local asymmetries which would determine their entry into tissues and direction. Our results could shed light on invasions mechanisms in cancer.

Background Metabolic syndrome is identified as a risk factor for the development of several systemic cancers, but its frequency among patients with glioblastoma and its association with clinical outcomes have yet to be determined. The aim of this study was to investigate metabolic syndrome as a risk factor for and affecting survival in glioblastoma patients. Methods A retrospective cohort study, consisting of patients with diagnoses at a single institution between 2007 and 2013, was conducted. Clinical records were reviewed, and clinical and laboratory data pertaining to 5 metabolic criteria were extrapolated. Overall survival was determined by time from initial surgical diagnosis to date of death or last follow-up. Results The frequency of metabolic syndrome among patients diagnosed with glioblastoma was slightly greater than the frequency of metabolic syndrome among the general population. Within a subset of patients (n = 91) receiving the full schedule of concurrent radiation and temozolomide and adjuvant temozolomide, median overall survival was significantly shorter for patients with metabolic syndrome compared with those without. In addition, the presence of all 5 elements of the metabolic syndrome resulted in significantly decreased median survival in these patients. Conclusions We identified the metabolic syndrome at a slightly higher frequency in patients with diagnosed glioblastoma compared with the general population. In addition, metabolic syndrome with each of its individual components is associated with an overall worse prognosis in patients receiving the standard schedule of radiation and temozolomide after adjustment for age.

This review will focus on the late neurological complications from cranial irradiation and relevant mitigation strategies.Radiotherapy (RT) remains an important pillar in the management of brain metastases. Patients being treated in the modern era do experience longer survival, because of superior intra- and extra-cranial disease control. As a result, they can be more prone to developing and manifesting late complications post-brain radiotherapy.A search and narrative review of prospective clinical trials relating to neurological toxicity outcomes was conducted.Neurological toxicities can be challenging to diagnose and manage and should be considered during consideration of radiotherapy in brain metastasis, hence more emphasis should be placed on prevention and upfront mitigation of these complications, with novel strategies showing promising results in prospective trials being adopted into clinical practice.

We have adapted a well-known constitutive model formulated by Morris and Boulay (1999) that describes the stress tensor for a mixture of particles in a Newtonian liquid into a two-phase finite-volume solver. The two-phase model treats each phase with a separate continuity and momentum equation that splits the stress of the constitutive model between the two phases, with the particle pressure applied only to the particle phase in addition to source terms related to the drag of particles in the fluid. We compare the resulting model using a variety of NMR experiments, considering the flow of neutrally buoyant monodisperse particles at low Reynolds number in the following geometries: 2D simple shear flow in a Couette device, axisymmetric and 3D pressure driven flow down a pipe and in a 2D and 3D asymmetric channel bifurcation. We find excellent agreement with velocity and volume fraction profiles in all of the comparisons with experimental data without much further numerical fitting beyond the original suspension stress model.

The scope of the Eulerian Multiphase (EMP) model in STAR-CCM+ is extended to simulate multi-scale two-phase flows using Large Scale Interface (LSI) model. The LSI model provides a criteria based on local phase-distribution to distinguish between regimes characterized by small and large scale interfaces. An appropriate closure for conserved variable is specified for each regime, weighted sum of which forms the closure for the interaction between the phases. The LSI model also allows to model surface tension effects in the vicinity of large scale interfaces as well. The large scale interface is treated as a moving wall using a turbulence damping procedure near the interface. This extended multifluid methodology implemented in STAR-CCM+® Software is validated using several standard two-phase flow problems.

Microstructured surfaces provide a unique framework to probe cell migration and cytoskeletal dynamics in a standardized manner. Here, we report on the steady-state occupancy probability of cells in asymmetric two-state microstructures that consist of two fibronectin-coated adhesion sites connected by a thin guidance cue. In these dumbbell-like structures, cells transition between the two sites in a repeated and stochastic manner, and average dwell times in the respective microenvironments are determined from the cell trajectories. We study the dynamics of human breast carcinoma cells (MDA-MB-231) in these microstructures as a function of area, shape, and orientation of the adhesion sites. On square adhesive sites with different areas, we find that the occupancy probability ratio is directly proportional to the ratio of corresponding adhesion site areas. These asymmetries are well captured by a simple model for the stochastic nonlinear dynamics of the cells, which reveals generic features of the motion. Sites of equal area but different shape lead to equal occupancy if shapes are isotropic (e.g., squared or circular). In contrast, an asymmetry in the occupancy is induced by anisotropic shapes like rhombi, triangles, or rectangles that enable motion in the direction perpendicular to the transition axis. Analysis of the two-dimensional motion of cells between two rectangles with orthogonal orientation suggests that cellular transition rates depend on the cell polarization induced by anisotropic micropatterns. Taken together, our results illustrate how two-state micropatterns provide a dynamic migration assay with distinct dwell times and relative cell occupancy as readouts, which may be useful to probe cell-microenvironment interactions.

Paru sous le titre publié :Collective Dynamics of Focal Adhesions Regulate Direction of Cell Motion; International audience; Directed cell motion is essential in physiological and pathological processes such as morphogenesis, wound healing, and cancer spreading. Chemotaxis has often been proposed as the driving mechanism, even though evidence of long-range gradients is often lacking in vivo. By patterning adhesive regions in space, we control cell shape and the potential to move along one direction in another migration mode coined ratchetaxis. We report that focal contact distributions collectively dictate cell directionality, and bias is non-linearly increased by gap distance between adhesive regions. Focal contact dynamics on micro-patterns allow to integrate these phenomena in a model where each focal contact is translated into a force with known amplitude and direction, leading to quantitative predictions for cell motion in new conditions with their successful experimental tests. Altogether, our study shows how local and minute timescale dynamics of focal adhesions and their distribution lead to long-term cellular motion with simple geometric rules.

Maintaining produced water quality is a critical environmental target, and legislative requirement, for the oil and gas industry. Design and operation of effective produced water separation systems requires understanding and management of a range of complex multiphase flow phenomena, especially where gas flotation processes are used. This paper presents a novel modelling approach, using Computational Fluid Dynamics (CFD), developed to simulate gas flotation processes. The approach aims to predict the gas-oil coalescence process using a simple and time-efficient method. In the flotation process, small gas bubbles, introduced to the produced water, coalesce with the oil droplets present in the water. The combined gas-oil particles have more buoyancy than the oil droplets alone and separate more effectively from the water. While CFD approaches have been applied to improve the design and operation of a wide range of separation and compact and induced-gas flotation systems, it has typically been too technically challenging and time-consuming to attempt to capture the coalescence process involved in flotation in such simulations at a system level. Often, designers and engineers have to make use of general flow characteristics, behaviours and indicators to imply the flotation efficiency of a given design, with many combining simulations and physical testing to provide greater confidence in design and operating decisions. The approach presented in this work aims to predict the gas flotation process and coalescence efficiency, using a simplified approach by combining multiphase flow simulations, using Simcenter STAR-CCM+, representing both the small oil droplets and the gas bubbles. In the approach, the local concentration of oil droplets in water and in gas is tracked throughout a given produced water system. Oil is transferred between the water and the gas phases representing the coalescence process. The rate of transfer is governed by a model which depends on local flow conditions such as bubble size, probability of adhering and detaching and surface area of gas bubbles available for coalescence. The approach is applicable to both compact flotation and induced-gas flotation systems and the results of the approach give direct comparisons of oil in water concentration both through a system and in the water exiting. The oil concentration leaving the vessel is reported, thus directly quantifying the effectiveness of the vessel; this is an improvement over other approaches using CFD where flow characteristics are used as proxies to infer the separation effectiveness. In using flow characterisctics alone there is potential for critical aspects or counter-intuitive mechanisms to mislead engineers. It is hoped that the method presented will enable engineers and designers involved in the development, design and operation of produced water systems to more-fully understand both the complex fluid mechanics and efficiency of the flotation processes.