Clinical decision-making strategies for rare somatic variants in cancer

For patients with cancer, new drugs are available that specifically target tumor cells with certain DNA alterations (also called somatic variants). These innovative drugs offer new promising treatment opportunities referred to as precision medicine. This requires advanced molecular diagnostic techniques to perform an in-depth profiling of DNA alterations of each patient’s tumor by clinical scientists in molecular pathology. Using this molecular information, pathologists can reach a more appropriate diagnosis and oncologists can treat patients with drugs that exploit the cancer’s vulnerabilities. However, molecular testing results are increasingly difficult to interpret, which can influence the diagnosis or treatment decision. Bart Koopman explored such complex results from routine molecular diagnostics and investigated strategies that can be used to improve decision-making.Koopman compared Dutch Molecular Tumor Boards (MTB) in the Netherlands, multidisciplinary collections of experts that provide (treatment) recommendations for cancer patients with challenging molecular testing results. This revealed that MTBs were similar in setup, and demonstrate high agreement in treatment recommendations for challenging cases, with favorable treatment outcomes. In addition, Koopman investigated how rare somatic variants affect decision-making using real-world data from the Dutch Pathology registry. This included current needs for optimization of diagnostic testing algorithms, diagnostic considerations that succeed detection of a rare variant, the utility of classifying actionability and the interpretation of resistance mechanisms. His research also revealed points of improvement for which consensus guidances were proposed for the optimization and harmonization of somatic variant interpretation and clinical decision-making to ensure that all patients receive appropriate treatment options

Dynamics of human movement

The part of (bio)mechanics that studies the interaction of forces on the human skeletal system and its effect on the resulting movement is called rigid body dynamics. Some basic concepts are presented: A mathematical formulation to describe human movement and how this relates on the mechanical loads acting on the skeletal system. These equations of motion depend on the mechanical properties of the skeletal system, such as dimensions and mass distribution. It is applied to describe and analyze human gait

An inverse dynamics model for the analysis, reconstruction and prediction of bipedal walking

Walking is a constrained movement which may best be observed during the double stance phase when both feet contact the floor. When analyzing a measured movement with an inverse dynamics model, a violation of these constrains will always occur due to measuring errors and deviations of the segments model from reality, leading to inconsistent results. Consistency is obtained by implementing the constraints into the model. This makes it possible to combine the inverse dynamics model with optimization techniques in order to predict walking patterns or to reconstruct non-measured rotations when only a part of the three-dimensional joint rotations is measured. In this paper the outlines of the extended inverse dynamics method are presented, the constraints which define walking are defined and the optimization procedure is described. The model is applied to analyze a normal walking pattern of which only the hip, knee and ankle flexions/extensions are measured. This input movement is reconstructed to a kinematically and dynamically consistent three-dimensional movement, and the joint forces (including the ground reaction forces) and joint moments of force, needed to bring about this movement are estimated

A model-based approach to stabilizing crutch supported paraplegic standing by artifical hip joint stiffness

The prerequisites for stable crutch supported standing were analyzed in this paper. For this purpose, a biomechanical model of crutch supported paraplegic stance was developed assuming the patient was standing with extended knees. When using crutches during stance, the crutches will put a position constraint on the shoulder, thus reducing the number of degrees of freedom. Additional hip-joint stiffness was applied to stabilize the hip joint and, therefore, to stabilize stance. The required hip-joint stiffness for changing crutch placement and hip-joint offset angle was studied under static and dynamic conditions. Modeling results indicate that, by using additional hip-joint stiffness, stable crutch supported paraplegic standing can be achieved, both under static as well as dynamic situations. The static equilibrium postures and the stability under perturbations were calculated to be dependent on crutch placement and stiffness applied. However, postures in which the hip joint was in extension (C postures) appeared to the most stable postures. Applying at least 60 N /spl middot/ m/rad hip-joint stiffness gave stable equilibrium postures in all cases. Choosing appropriate hip-joint offset angles, the static equilibrium postures changed to more erect postures, without causing instability or excessive arm forces to occur

A case report of an unusual non-mucinous papillary variant of CPAM type 1 with KRAS mutations

BACKGROUND: congenital pulmonary airway malformation (CPAM) is the most frequent congenital lung disorder. CPAM type 1 is the most common subtype, typically having a cystic radiological and histological appearance. Mucinous clusters in CPAM type 1 have been identified as premalignant precursors for mucinous adenocarcinoma. These mucinous adenocarcinomas and the mucinous clusters in CPAM commonly harbor a specific KRAS mutation. CASE PRESENTATION: we present a case of a 6-weeks-old girl with CPAM type 1 where evaluation after lobectomy revealed a highly unusual complex non-mucinous papillary architecture in all cystic parts, in which both mucinous clusters and non-mucinous papillary areas harbored the known KRAS mutation. CONCLUSIONS: we found that a KRAS mutation thought to be premalignant in mucinous clusters only, was also present in the other cyst lining epithelial cells of this unusual non-mucinous papillary variant of CPAM type 1, warranting clinical follow-up because of uncertain malignant potential

Twente spine model:A complete and coherent dataset for musculo-skeletal modeling of the lumbar region of the human spine

Item does not contain fulltextMusculo-skeletal modeling can greatly help in understanding normal and pathological functioning of the spine. For such models to produce reliable muscle and joint force estimations, an adequate set of musculo-skeletal data is necessary. In this study, we present a complete and coherent dataset for the lumbar spine, based on medical images and dissection measurements from one embalmed human cadaver. We divided muscles into muscle-tendon elements, digitized their attachments at the bones and measured morphological parameters. In total, we measured 11 muscles from one body side, using 96 elements. For every muscle element, we measured three-dimensional coordinates of its attachments, fiber length, tendon length, sarcomere length, optimal fiber length, pennation angle, mass, and physiological cross-sectional area together with the geometry of the lumbar spine. Results were consistent with other anatomical studies and included new data for the serratus posterior inferior muscle. The dataset presented in this paper enables a complete and coherent musculo-skeletal model for the lumbar spine and will improve the current state-of-the art in predicting spinal loading

Conceptual Design of a Fully Passive Transfemoral Prosthesis to Facilitate Energy-Efficient Gait

In this study, we present the working principle and conceptual design towards the realization of a fully-passive transfemoral prosthesis that mimics the energetics of the natural human gait. The fundamental property of the conceptual design consists of realizing an energetic coupling between the knee and ankle joints of the mechanism. Simulation results show that the power flow of the working principle is comparable to that in human gait and a considerable amount of energy is delivered to the ankle joint for the push-off generation. An initial prototype in half scale is realized to validate the working principle. The construction of the prototype is explained together with the test setup that has been built for the evaluation. Finally, experimental results of the prosthesis prototype during walking on a treadmill show the validity of the working principle

A Patient-Specific Musculoskeletal Model of Total Knee Arthroplasty to Predict In Vivo Knee Biomechanics

Musculoskeletal(MS) models are useful to gain information on in vivo biomechanics that would be otherwise very difficult to obtain.However, before entering the clinical routine MS models must be thoroughlyvalidated. This study presents a novel MS modelling framework capable ofintegrating the patient-specific MS architecture in a very detailed way, andsimultaneously simulating body level dynamics and secondary knee kinematics.The model predictions were further validated against publicly available in vivo experimental data. The bonegeometries were segmented from CT images of a patient with an instrumentedTotal Knee Arthroplasty (TKA) from the “Grand Challenge Competition to Predict In Vivo Knee Loads” dataset. These were inputtedinto an advanced morphing technique in order to scale the MS architecture of thenew TLEM 2.0 model1 to the specific patient. A detailed 11-DOF modelof the knee joint was constructed that included ligaments and rigid contact. Aninverse kinematic and a force-dependent kinematic technique2 wereutilized to simulate one gait cycle and one right-turn trial. Tibiofemoral (TF)joint contact force predictions were evaluated against experimental TF forcesrecorded by the TKA prosthesis, and secondary knee kinematics againstexperimental fluoroscopy data. The coefficientof determination and the root-mean-square error between predicted andexperimental tibiofemoral forces were larger than 0.9 and smaller than 0.3body-weights, respectively, for both gait and right-turn trials. Secondary kneekinematics were estimated with an average Sprague and Geers’ combined error assmall as 0.06. Themodelling strategy proposed permits a high level of patient-specificpersonalization and does not require any non-physiological parameter tuning.The very good agreement between predictions and experimental in vivo data is promising for the futureintroduction of the model into clinical applications