Organ involvement in newly diagnosed sarcoidosis patients in the Netherlands: The first large European multicentre prospective study.

BACKGROUND: Clinical presentation and prevalence of organ involvement is highly variable in sarcoidosis and depends on ethnic, genetic and geographical factors. These data are not extensively studied in a Dutch population. AIM: To determine the prevalence of organ involvement and the indication for systemic immunosuppressive therapy in newly diagnosed sarcoidosis patients in the Netherlands. METHODS: Two large Dutch teaching hospitals participated in this prospective cohort study. All adult patients with newly diagnosed sarcoidosis were prospectively included and a standardized work-up was performed. Organ involvement was defined using the WASOG instrument. RESULTS: Between 2015 and 2020, a total of 330 patients were included, 55% were male, mean age was 46 (SD 14) years. Most of them were white (76%). Pulmonary involvement including thoracic lymph node enlargement was present in 316 patients (96%). Pulmonary parenchymal disease was present in 156 patients (47%). Ten patients (3%) had radiological signs of pulmonary fibrosis. Cutaneous sarcoidosis was present in 74 patients (23%). Routine ophthalmological screening revealed uveitis in 29 patients (12%, n = 256)). Cardiac and neurosarcoidosis were diagnosed in respectively five (2%) and six patients (2%). Renal involvement was observed in 11 (3%) patients. Hypercalcaemia and hypercalciuria were observed in 29 (10%) and 48 (26%, n = 182) patients, respectively. Hepatic involvement was found in 6 patients (2%). In 30% of the patients, systemic immunosuppressive treatment was started at diagnosis. CONCLUSIONS: High-risk organ involvement in sarcoidosis is uncommon at diagnosis. Indication for systemic immunosuppressive therapy was present in a minority of patients.

Numerical study of osteophyte effects on preoperative knee functionality in patients undergoing total knee arthroplasty.

Osteophytes are routinely removed during total knee arthroplasty, yet the preoperative planning currently relies on preoperative computed tomography (CT) scans of the patient's osteoarthritic knee, typically including osteophytic features. This complicates the surgeon's ability to anticipate the exact biomechanical effects of osteophytes and the consequences of their removal before the operation. The aim of this study was to investigate the effect of osteophytes on ligament strains and kinematics, and ascertain whether the osteophyte volume and location determine the extent of this effect. We segmented preoperative CT scans of 21 patients, featuring different osteophyte severity, using image-based active appearance models trained to identify the osteophytic and preosteophytic bone geometries and estimate the cartilage thickness in the segmented surfaces. The patients' morphologies were used to scale a template musculoskeletal knee model. Osteophytes induced clinically relevant changes to the knee's functional behavior, but these were variable and patient-specific. Generally, severe osteophytic knees significantly strained the oblique popliteal ligament (OPL) and posterior capsule (PC) relative to the preosteophytic state. Furthermore, there was a marked effect on the lateral collateral ligament and anterolateral ligament (ALL) strains compared to mild and moderate osteophytic knees, and concurrent alterations in the tibial lateral-medial translation and external-internal rotation. We found a strong correlation between the OPL, PC, and ALL strains and posterolateral condylar and tibial osteophytes, respectively. Our findings may have implications for the preoperative planning in total knee arthroplasty, toward reproducing the physiological knee biomechanics as close as feasibly possible.

The Simultaneous Model-Based Estimation of Joint, Muscle, and Tendon Stiffness is Highly Sensitive to the Tendon Force-Strain Relationship.

OBJECTIVE: Accurate estimation of stiffness across anatomical levels (i.e., joint, muscle, and tendon) in vivo has long been a challenge in biomechanics. Recent advances in electromyography (EMG)-driven musculoskeletal modeling have allowed the non-invasive estimation of stiffness during dynamic joint rotations. Nevertheless, validation has been limited to the joint level due to a lack of simultaneous in vivo experimental measurements of muscle and tendon stiffness. METHODS: With a focus on the triceps surae, we employed a novel perturbation-based experimental technique informed by dynamometry and ultrasonography to derive reference stiffness at the joint, muscle, and tendon levels simultaneously. Here, we propose a new EMG-driven model-based approach that does not require external joint perturbation, nor ultrasonography, to estimate multi-level stiffness. We present a novel set of closed-form equations that enables the person-specific tuning of musculoskeletal parameters dictating biological stiffness, including passive force-length relationships in modeled muscles and tendons. RESULTS: Calibrated EMG-driven musculoskeletal models estimated the reference data with average normalized root-mean-square error ≈ 20%. Moreover, only when calibrated tendons were approximately four times more compliant than typically modeled, our approach could estimate multi-level reference stiffness. CONCLUSION: EMG-driven musculoskeletal models can be calibrated on a larger set of reference data to provide more realistic values for the biomechanical variables across multiple anatomical levels. Moreover, the tendon models that are typically used in musculoskeletal modeling are too stiff. SIGNIFICANCE: Calibrated musculoskeletal models informed by experimental measurements give access to an augmented range of biomechanical variables that might not be easily measured with sensors alone.

Automated spatial localization of ankle muscle sites and model-based estimation of joint torque post-stroke via a wearable sensorised leg garment.

Assessing a patient's musculoskeletal function during over-ground walking is a primary objective in post-stroke rehabilitation, due to the importance of walking recovery for everyday life. However, the quantitative assessment of musculoskeletal function currently requires lab-constrained equipment, and labor-intensive analyses, which hampers assessment in standard clinical settings. The development of fully wearable systems for the online estimation of muscle-tendon forces and resulting joint torque would aid clinical assessment of motor recovery, it would enhance the detection of neuro-muscular anomalies and it would consequently enable highly personalized treatments. Here, we present a wearable technology that combines (1) a soft garment for the human leg sensorized with 64 flexible and dry electromyography (EMG) electrodes, (2) a generalized and automated algorithm for the localization of leg muscle sites, and (3) an EMG-driven musculoskeletal modeling framework for the estimation of ankle dorsi-plantar flexion torques. Our results showed that the automated clustering algorithm could detect muscle locations in both healthy and post-stroke individuals. The estimated muscle-specific EMG envelopes could be used to drive forward person-specific musculoskeletal models and estimate resulting joint torques accurately across all healthy and post-stroke individuals and across different walking speeds (R2  > 0.82 and RMSD  < 0.16). The technology we proposed opens new avenues for automated muscle localization and quantitative musculoskeletal function assessment during gait in both healthy and neurologically impaired individuals.

Pre-Planning the Surgical Target for Optimal Implant Positioning in Robotic-Assisted Total Knee Arthroplasty.

Robotic-assisted total knee arthroplasty can attain highly accurate implantation. However, the target for optimal positioning of the components remains debatable. One of the proposed targets is to recreate the functional status of the pre-diseased knee. The aim of this study was to demonstrate the feasibility of reproducing the pre-diseased kinematics and strains of the ligaments and, subsequently, use that information to optimize the position of the femoral and tibial components. For this purpose, we segmented the pre-operative computed tomography of one patient with knee osteoarthritis using an image-based statistical shape model and built a patient-specific musculoskeletal model of the pre-diseased knee. This model was initially implanted with a cruciate-retaining total knee system according to mechanical alignment principles; and an optimization algorithm was then configured seeking the optimal position of the components that minimized the root-mean-square deviation between the pre-diseased and post-operative kinematics and/or ligament strains. With concurrent optimization for kinematics and ligament strains, we managed to reduce the deviations from 2.4 ± 1.4 mm (translations) and 2.7 ± 0.7° (rotations) with mechanical alignment to 1.1 ± 0.5 mm and 1.1 ± 0.6°, and the strains from 6.5% to lower than 3.2% over all the ligaments. These findings confirm that adjusting the implant position from the initial plan allows for a closer match with the pre-diseased biomechanical situation, which can be utilized to optimize the pre-planning of robotic-assisted surgery.

Real-time myoelectric control of wrist/hand motion in Duchenne muscular dystrophy: A case study.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic disorder that induces progressive muscular degeneration. Currently, the increase in DMD individuals' life expectancy is not being matched by an increase in quality of life. The functioning of the hand and wrist is central for performing daily activities and for providing a higher degree of independence. Active exoskeletons can assist this functioning but require the accurate decoding of the users' motor intention. These methods have, however, never been systematically analyzed in the context of DMD. Methods: This case study evaluated direct control (DC) and pattern recognition (PR), combined with an admittance model. This enabled customization of myoelectric controllers to one DMD individual and to a control population of ten healthy participants during a target-reaching task in 1- and 2- degrees of freedom (DOF). We quantified real-time myocontrol performance using target reaching times and compared the differences between the healthy individuals and the DMD individual. Results and Discussion: Our findings suggest that despite the muscle tissue degeneration, the myocontrol performance of the DMD individual was comparable to that of the healthy individuals in both DOFs and with both control approaches. It was also evident that PR control performed better for the 2-DOF tasks for both DMD and healthy participants, while DC performed better for the 1-DOF tasks. The insights gained from this study can lead to further developments for the intuitive multi-DOF myoelectric control of active hand exoskeletons for individuals with DMD.

Spatial control of self-organizing vascular networks with programmable aptamer-tethered growth factor photopatterning.

Given the dynamic nature of engineered vascular networks within biofabricated tissue analogues, it is instrumental to have control over the constantly evolving biochemical cues within synthetic matrices throughout tissue remodeling. Incorporation of pro-angiogenic vascular endothelial growth factor (VEGF165) specific aptamers into cell-instructive polymer networks is shown to be pivotal for spatiotemporally controlling the local bioactivity of VEGF that selectively elicit specific cell responses. To harness this effect and quantitatively unravel its spatial resolution, herein, bicomponent micropatterns consisting of VEGF165 specific aptamer-functionalized gelatin methacryloyl (GelMA) (aptamer regions) overlaid with pristine GelMA regions using visible-light photoinitiators (Ru/SPS) were fabricated via two-step photopatterning approach. For the 3D co-culture study, human umbilical vein-derived endothelial cells and mesenchymal stromal cells were used as model cell types. Bicomponent micropatterns with spatially defined spacings (300/500/800 â€‹µm) displayed high aptamer retention, aptamer-fluorescent complementary sequence (CSF) molecular recognition and VEGF sequestration localized within patterned aptamer regions. Stiffness gradient at the interface of aptamer and GelMA regions was observed with high modulus in aptamer region followed by low stiffness GelMA regions. Leveraging aptamer-tethered VEGF's dynamic affinity interactions with CS that upon hybridization facilitates triggered VEGF release, co-culture studies revealed unique characteristics of aptamer-tethered VEGF to form spatially defined luminal vascular networks covered with filopodia-like structures in vitro (spatial control) and highlights their ability to control network properties including orientation over time using CS as an external trigger (temporal control). Moreover, the comparison of single and double exposed regions within micropatterns revealed differences in cell behavior among both regions. Specifically, the localized aptamer-tethered VEGF within single exposed aptamer regions exhibited higher cellular alignment within the micropatterns till d5 of culture. Taken together, this study highlights the potential of photopatterned aptamer-tethered VEGF to spatiotemporally regulate vascular morphogenesis as a tool for controlling vascular remodeling in situ.

Head support in wheelchairs (scoping review): state-of-the-art and beyond.

BACKGROUND: Many wheelchair users experience disabilities in stabilising and positioning of the head. For these users, adequate head support is required. Although several types of head supports are available, further development of these systems is needed to improve functionality and quality of life, especially for the group of severely challenged users. For this group, user needs have not been clearly established. In this article, we provide an overview of the state-of-the-art in wheelchair mounted head supports and associated scientific evidence in order to identify requirements for the next generation of head support systems. MATERIALS AND METHODS: A scoping review was performed including scientific literature (PubMed/Scopus), patents (Espacenet/Google Scholar) and commercial information. Types of head support and important system characteristics for future head support systems were proposed from consultations with wheelchair users (n = 3), occupational therapists (n = 3) and an expert panel. RESULTS: Forty scientific papers, 90 patents and 80 descriptions of commercial devices were included in the scoping review. The identified head support systems were categorised per head support type. Only limited scientific clinical evidence with respect to the effectiveness of existing head support systems was found. From the user and expert consultations, a need was identified for personalised head support systems that intuitively combine changes in sitting and head position with continuous optimal support of the head to accommodate severely challenged users. CONCLUSIONS: This study presents the state-of-the-art in head support systems. Additionally, several important system characteristics are introduced that provide guidance for the development and improvement of head supports.Implications for rehabilitationEspecially for the group of severely challenged wheelchair users, current head support systems require further development to improve their users' quality of life.The desired system characteristics which are discussed in this review are an important step in the definition of requirements for the next generation of head supports.

Electromyography-driven model-based estimation of ankle torque and stiffness during dynamic joint rotations in perturbed and unperturbed conditions.

The simultaneous modulation of joint torque and stiffness enables humans to perform large repertoires of movements, while versatilely adapting to external mechanical demands. Multi-muscle force control is key for joint torque and stiffness modulation. However, the inability to directly measure muscle force in the intact moving human prevents understanding how muscle force causally links to joint torque and stiffness. Joint stiffness is predominantly estimated via joint perturbation-based experiments in combination with system identification techniques. However, these techniques provide joint-level stiffness estimations with no causal link to the underlying muscle forces. Moreover, the need for joint perturbations limits the generalizability and applicability to study natural movements. Here, we present an electromyography (EMG)-driven musculoskeletal modeling framework that can be calibrated to match reference joint torque and stiffness profiles simultaneously via a multi-term objective function. EMG-driven models calibrated on <2 s of reference torque and stiffness data could blindly estimate reference profiles across 100 s of data not used for calibration. Model calibrations using an objective function comprising torque and stiffness terms always provided less feasible solutions than an objective function comprising solely a torque term, thereby reducing the space of feasible muscle-tendon parameters. Results also showed the proposed framework's ability to estimate joint stiffness in unperturbed conditions, while capturing differences against stiffness profiles derived during perturbed conditions. The proposed framework may provide new ways for studying causal relationships between muscle force and joint torque and stiffness during movements in interaction with the environment, with broad implications across biomechanics, rehabilitation and robotics.

Embedded 3D printing of dilute particle suspensions into dense complex tissue fibers using shear thinning xanthan baths.

In order to fabricate functional organoids and microtissues, a high cell density is generally required. As such, the placement of cell suspensions in molds or microwells to allow for cell concentration by sedimentation is the current standard for the production of organoids and microtissues. Even though molds offer some level of control over the shape of the resulting microtissue, this control is limited as microtissues tend to compact towards a sphere after sedimentation of the cells. 3D bioprinting on the other hand offers complete control over the shape of the resulting structure. Even though the printing of dense cell suspensions in the ink has been reported, extruding dense cellular suspensions is challenging and generally results in high shear stresses on the cells and a poor shape fidelity of the print. As such, additional materials such as hydrogels are added in the bioink to limit shear stresses, and to improve shape fidelity and resolution. The maximum cell concentration that can be incorporated in a hydrogel-based ink before the ink's rheological properties are compromised, is significantly lower than the concentration in a tissue equivalent. Additionally, the hydrogel components often interfere with cellular self-assembly processes. To circumvent these limitations, we report a simple and inexpensive xanthan bath based embedded printing method to 3D print dense functional linear tissues using dilute particle suspensions consisting of cells, spheroids, hydrogel beads, or combinations thereof. Using this method, we demonstrated the self-organization of functional cardiac tissue fibers with a layer of epicardial cells surrounding a body of cardiomyocytes.

Automated estimation of ankle muscle EMG envelopes and resulting plantar-dorsi flexion torque from 64 garment-embedded electrodes uniformly distributed around the human leg.

The design of personalized movement training and rehabilitation pipelines relies on the ability of assessing the activation of individual muscles concurrently with the resulting joint torques exerted during functional movements. Despite advances in motion capturing, force sensing and bio-electrical recording technologies, the estimation of muscle activation and resulting force still relies on lengthy experimental and computational procedures that are not clinically viable. This work proposes a wearable technology for the rapid, yet quantitative, assessment of musculoskeletal function. It comprises of (1) a soft leg garment sensorized with 64 uniformly distributed electromyography (EMG) electrodes, (2) an algorithm that automatically groups electrodes into seven muscle-specific clusters, and (3) a EMG-driven musculoskeletal model that estimates the resulting force and torque produced about the ankle joint sagittal plane. Our results show the ability of the proposed technology to automatically select a sub-set of muscle-specific electrodes that enabled accurate estimation of muscle excitations and resulting joint torques across a large range of biomechanically diverse movements, underlying different excitation patterns, in a group of eight healthy individuals. This may substantially decrease time needed for localization of muscle sites and electrode placement procedures, thereby facilitating applicability of EMG-driven modelling pipelines in standard clinical protocols.

Detection of NTRK Fusions and TRK Expression and Performance of pan-TRK Immunohistochemistry in Routine Diagnostics: Results from a Nationwide Community-Based Cohort.

Gene fusions involving NTRK1, NTRK2, and NTRK3 are rare drivers of cancer that can be targeted with histology-agnostic inhibitors. This study aimed to determine the nationwide landscape of NTRK/TRK testing in the Netherlands and the usage of pan-TRK immunohistochemistry (IHC) as a preselection tool to detect NTRK fusions. All pathology reports in 2017-2020 containing the search term 'TRK' were retrieved from the Dutch Pathology Registry (PALGA). Patient characteristics, tumor histology, NTRK/TRK testing methods, and reported results were extracted. NTRK/TRK testing was reported for 7457 tumors. Absolute testing rates increased from 815 (2017) to 3380 (2020). Tumors were tested with DNA/RNA-based molecular assay(s) (48%), IHC (47%), or in combination (5%). A total of 69 fusions involving NTRK1 (n = 22), NTRK2 (n = 6) and NTRK3 (n = 41) were identified in tumors from adult (n = 51) and pediatric (n = 18) patients. In patients tested with both IHC and a molecular assay (n = 327, of which 29 NTRK fusion-positive), pan-TRK IHC had a sensitivity of 77% (95% confidence interval (CI), 56-91) and a specificity of 84% (95% CI, 78-88%). These results showed that pan-TRK IHC has a low sensitivity in current routine practice and warrants the introduction of quality guidelines regarding the implementation and interpretation of pan-TRK IHC.

Spatiotemporally controlled, aptamers-mediated growth factor release locally manipulates microvasculature formation within engineered tissues.

Spatiotemporally controlled growth factor (GF) delivery is crucial for achieving functional vasculature within engineered tissues. However, conventional GF delivery systems show inability to recapitulate the dynamic and heterogeneous nature of developing tissue's biochemical microenvironment. Herein, an aptamer-based programmable GF delivery platform is described that harnesses dynamic affinity interactions for facilitating spatiotemporal control over vascular endothelial GF (VEGF165) bioavailability within gelatin methacryloyl matrices. The platform showcases localized VEGF165 sequestration from the culture medium (offering spatial-control) and leverages aptamer-complementary sequence (CS) hybridization for triggering VEGF165 release (offering temporal-control), without non-specific leakage. Furthermore, extensive 3D co-culture studies (human umbilical vein-derived endothelial cells & mesenchymal stromal cells), in bi-phasic hydrogel systems revealed its fundamentally novel capability to selectively guide cell responses and manipulate lumen-like microvascular networks via spatiotemporally controlling VEGF165 bioavailability within 3D microenvironment. This platform utilizes CS as an external biochemical trigger for guiding vascular morphogenesis which is suitable for creating dynamically controlled engineered tissues.

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer: Local Experience and Review of the Literature.

INTRODUCTION: Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors. PATIENTS AND METHODS: Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression-free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors. RESULTS: Of the pooled population of 387 patients in this analysis, 239 (62%) received at least 1 additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of 6 published models and observed clinical benefit ranged from 69% to 89%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented. CONCLUSION: Molecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients.

Assessment of flow within developing chicken vasculature and biofabricated vascularized tissues using multimodal imaging techniques.

Fluid flow shear stresses are strong regulators for directing the organization of vascular networks. Knowledge of structural and flow dynamics information within complex vasculature is essential for tuning the vascular organization within engineered tissues, by manipulating flows. However, reported investigations of vascular organization and their associated flow dynamics within complex vasculature over time are limited, due to limitations in the available physiological pre-clinical models, and the optical inaccessibility and aseptic nature of these models. Here, we developed laser speckle contrast imaging (LSCI) and side-stream dark field microscopy (SDF) systems to map the vascular organization, spatio-temporal blood flow fluctuations as well as erythrocytes movements within individual blood vessels of developing chick embryo, cultured within an artificial eggshell system. By combining imaging data and computational simulations, we estimated fluid flow shear stresses within multiscale vasculature of varying complexity. Furthermore, we demonstrated the LSCI compatibility with bioengineered perfusable muscle tissue constructs, fabricated via molding techniques. The presented application of LSCI and SDF on perfusable tissues enables us to study the flow perfusion effects in a non-invasive fashion. The gained knowledge can help to use fluid perfusion in order to tune and control multiscale vascular organization within engineered tissues.

The Added Value of Musculoskeletal Simulation for the Study of Physical Performance in Military Tasks.

The performance of military tasks is often exacerbated by additional load carriage, leading to increased physical demand. Previous studies showed that load carriage may lead to increased risk of developing musculoskeletal injuries, a reduction in task speed and mobility, and overall performance degradation. However, these studies were limited to a non-ambulatory setting, and the underlying causes of performance degradation remain unclear. To obtain insights into the underlying mechanisms of reduced physical performance during load-carrying military activities, this study proposes a combination of IMUs and musculoskeletal modeling. Motion data of military subjects was captured using an Xsens suit during the performance of an agility run under three different load-carrying conditions (no load, 16 kg, and 31 kg). The physical performance of one subject was assessed by means of inertial motion-capture driven musculoskeletal analysis. Our results showed that increased load carriage led to an increase in metabolic power and energy, changes in muscle parameters, a significant increase in completion time and heart rate, and changes in kinematic parameters. Despite the exploratory nature of this study, the proposed approach seems promising to obtain insight into the underlying mechanisms that result in performance degradation during load-carrying military activities.

A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses.

EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR-mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR mutations and determine the role and clinical relevance of uncommon and composite EGFR mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013-2017, the uptake of EGFR testing gradually increased from 72.7% to 80.9% (p < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% (p < 0.001), but did not affect the number of detected EGFR mutations (n = 925; 11.7%; 95% confidence interval (CI), 11.0-12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors (n = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30-1.92; p < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60-2.84; p < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98-1.75; p = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of 'common' EGFR mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations.

Initial presentation of lymphangioleiomyomatosis in third trimester of pregnancy.

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease which mostly affects premenopausal women and could be exacerbated by pregnancy. Therefore, it is thought that oestrogen plays an important role in LAM pathogenesis. Here, a case of LAM is described in which the first presentation of symptoms occurred during the third trimester of pregnancy. Symptoms included acute onset dyspnoea and chest pain at gestational age of 39 weeks and 2 days. A CT was performed which showed multiple thin-walled cysts and a small pneumothorax. Serum levels of vascular endothelial growth factor-D (VEGF-D) was 1200 pg/mL. The typical cystic lung changes on chest CT in combination with elevated VEGF-D is diagnostic for LAM. Given the risk of respiratory complications, the decision was made to deliver the baby at a gestational age of 39 weeks and 6 days by a planned caesarean section. Both mother and child were discharged home in good condition.

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations.

BACKGROUND: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. MATERIALS AND METHODS: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. RESULTS: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type-specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). CONCLUSION: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a "Dutch MTB model" for an optimal, collaborative, and nationally aligned MTB workflow. IMPLICATIONS FOR PRACTICE: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing.