Evaluation of laxity tests with a musculoskeletal model of total knee arthroplasty

Introduction Musculoskeletal models are emerging as potential tools for the use in many clinical applications. One important example is aid to the clinical decision in the orthopaedic field. Recently, a patient-specific model of Cruciate-Retaining Total Knee Arthroplasty (CR-TKA) was presented and validated with respect to knee joint forces and kinematics [1]. However, the ligament restraints were not calibrated and inaccuracies in knee kinematic predictions were present. The objective of this study was to evaluate the effect of ligament calibration on the performance of simulated laxity tests. Methods A musculoskeletal model of CR-TKA was previously described [1]. The model comprised the musculoskeletal architecture of a TKA patient and a force-dependent model of the prosthetic knee and patellofemoral joint. Ligament restraints were modelled using non-linear springs and contact was solved using a rigid formulation. To calibrate the ligament parameters we simulated anterior/posterior, valgus/varus and endo-/exorotation laxity tests. Each test was performed at four different knee flexion angles (0, 30, 60, 90 deg). The anterior (respectively posterior) laxity load consisted of a 35 N force applied on the tibia at a distance of approximately 15 cm from the surface of the tibial component, pointing anteriorly (respectively posteriorly). Valgus (respectively varus) test was simulated by applying a force on the tibia at a distance of approximately 15 cm from the ankle joint, pointing laterally (respectively medially) so that the resulting moment was equal to 10 Nm. For the endo- (respectively exo-) rotation a 1.5 Nm torque was applied to the longitudinal axis of the tibia. Laxity envelopes for each test were calculated as the difference between the values obtained in the two opposite directions of the test. Manual changes to ligament insertion site, stiffness, and reference strain were made iteratively in order to obtain laxity envelopes close to those reported in the literature for cadaveric tests on a CR-TKA [2]. All the laxity tests were eventually simulated with the same ligament configuration. Results The results for all simulated laxity tests and the reference values from the literature are summarized in Table 1. 0° 30° 60° 90° AP (M) 3.5mm 4.2mm 1.0mm 1.0mm AP (L) 1.5mm 5mm 4mm 4.5mm VV (M) 0.9° 4.3° 2.6° 1.5° VV (L) 3.0° 6.0° 7.0° 7.0° EE (M) 7.0° 16.5° 4.0° 5.5° EE (L) 6.5° 22.0° 21.0° 23.0° Table 1: AP: Anterior/Posterior, VV: Valgus/Varus, EE: Endo-/Exorotation, M: Model prediction, L: Literature value Discussion The laxity envelopes predicted by the model were in partial agreement with those reported in the literature. The largest differences were noted for 60-90 degrees of knee flexion for all laxity tests, where the model showed considerably less laxity. These deviations may be attributable to actual differences between the implant design and subject geometry currently simulated and those used in the cadaveric tests. In future studies we aim to simulate surgical variations such as implant size and positioning, joint line elevation and ligament restraint. This musculoskeletal model of TKA has potential as a pre-operative planning tool for orthopaedic interventions. References Marra et al, J Biomech Eng, 137, 2015 Saeki et al, Clin Orthop Relat Res, 392:184-189, 200

Using non-randomized trials to assess the clinical benefit of systemic anti-cancer treatments:Viable or not?

Background: The Dutch Committee for the Evaluation of Oncological Agents (cieBOM) assesses the clinical benefit of systemic anti-cancer treatments (SACTs). For SACTs tested in non-randomized trials (NRTs), cieBOM primarily utilizes response-related thresholds as assessment criteria. As sufficiency of NRT-based evidence for benefit assessments is questionable, this study investigated whether and how NRTs can be used to assess the clinical benefit of new SACTs initially appraised by cieBOM based on randomized controlled trials (RCTs). Methods: Using the RCTs underpinning cieBOM recommendations issued between 2015 and 2017, we searched for matching NRTs and applied the NRT-related assessment criteria by cieBOM to them. We then compared the assessment outcomes to the respective RCT-based cieBOM recommendations. Further, we investigated how the assessments would change when applying different response-related thresholds and adding a progression-free survival (PFS) threshold. Results: For 13 of the 37 eligible recommendations, a matching NRT was found. Two treatments were assessed positively and six negatively; five treatments were non-assessable. Two positive recommendations matched a positive NRT-based assessment; one matching negative assessment was found, and one treatment could not be assessed based on either trial results. Adding a &gt; 6 months PFS threshold decreased the number of non-assessable NRTs (five to two). Conclusions: Limited publications and inconsistent data reporting hampered the viability of NRTs for clinical benefit assessments of SACTs beyond the scope of rare indications. Further, response-related assessment criteria alone might not fully grasp the clinical benefit of novel SACTs. NRT-based assessments should be considered with caution due to uncertainty of the trial results.</p

A new in vitro assay for quantitation of chemotherapy-induced mucositis.

Patients receiving high-dose chemotherapy (HD-CT) are at risk of severe mucositis. Most prevention studies evaluate the degree of mucositis on clinical, and therefore subjective, measurements. The aim of this study was to develop an objective in vitro assay of chemotherapy-induced mucositis. Twelve patients with locally advanced breast carcinoma received HD-CT followed by peripheral stem cell reinfusion. Before and twice weekly after HD-CT, the mucosa was evaluated by an oral washing, a buccal smear and the World Health Organization (WHO) toxicity grading; furthermore, blood leucocyte levels were determined. For the oral washings, the percentage of viable epithelial cells was determined by trypan blue dye exclusion and leucocytes were counted by fluorescence microscopy after incubation with acridine orange. Maturity of buccal cells was assessed by staining buccal smears for morphology according to Papanicolaou (Whitacker D and Williams V, 1994). Eight healthy volunteers served as controls. The mean percentage (+/- s.e.m.) of viable oral epithelial cells was stable in controls (44 +/- 2%). In patients, they increased after HD-CT, which was significant after day 7 compared with pretreatment (P < or = 0.05). In addition, a shift from mature to immature epithelial cells in buccal smears was observed. Oral leucocyte levels were closely correlated with the blood leucocyte counts. The WHO score followed the results of these other evaluations with some delay. The viability of buccal cells obtained by oral washings increases after HD-CT. This is possibly because of desquamation of the upper oral mucosa layer, with a shift from mature to more immature cells. These data can be quantitated, and this assay may therefore be useful in studies aimed at prevention of mucositis

Computed Tomography-Based Body Composition Is Not Consistently Associated with Outcome in Older Patients with Colorectal Cancer

Background: Current literature is inconsistent in the associations between computed tomography (CT)-based body composition measures and adverse outcomes in older patients with colorectal cancer (CRC). Moreover, the associations with consecutive treatment modalities have not been studied. This study compared the associations of CT-based body composition measures with surgery- and chemotherapy-related complications and survival in older patients with CRC. Materials and Methods: A retrospective single-center cohort study was conducted in patients with CRC aged ≥65 years who underwent elective surgery between 2010 and 2014. Gender-specific standardized scores of preoperative CT-based skeletal muscle (SM), muscle density, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue, IMAT percentage, SM/VAT, and body mass index (BMI) were tested for their associations with severe postoperative complications, prolonged length of stay (LOS), readmission, and dose-limiting toxicity using logistic regression and 1-year and long-term survival (range 3.7–6.6 years) using Cox regression. Bonferroni correction was applied to account for multiple testing. Results: The study population consisted of 378 patients with CRC with a median age of 73.4 (interquartile range 69.5–78.4) years. Severe postoperative complications occurred in 13.0%, and 39.4% of patients died during follow-up. Dose-limiting toxicity occurred in 77.4% of patients receiving chemotherapy (n = 53). SM, muscle density, VAT, SM/VAT, and BMI were associated with surgery-related complications, and muscle density, IMAT, IMAT percentage, and SM/VAT were associated with long-term survival. After Bonferroni correction, no CT-based body composition measure was significantly associated with adverse outcomes. Higher BMI was associated with prolonged LOS. Conclusion: The associations between CT-based body composition measures and adverse outcomes of consecutive treatment modalities in older patients with CRC were not consistent or statistically significant. Implications for Practice: Computed tomography (CT)-based body composition, including muscle mass, muscle density, and intermuscular, visceral, and subcutaneous adipose tissue, showed inconsistent and nonsignificant associations with surgery-related complications, dose-limiting toxicity, and overall survival in older adults with colorectal cancer. This study underscores the need to verify whether CT-based body composition measures are worth implementing in clinical practice

Using non-randomized trials to assess the clinical benefit of systemic anti-cancer treatments: Viable or not?

Background: The Dutch Committee for the Evaluation of Oncological Agents (cieBOM) assesses the clinical benefit of systemic anti-cancer treatments (SACTs). For SACTs tested in non-randomized trials (NRTs), cieBOM primarily utilizes response-related thresholds as assessment criteria. As sufficiency of NRT-based evidence for benefit assessments is questionable, this study investigated whether and how NRTs can be used to assess the clinical benefit of new SACTs initially appraised by cieBOM based on randomized controlled trials (RCTs). Methods: Using the RCTs underpinning cieBOM recommendations issued between 2015 and 2017, we searched for matching NRTs and applied the NRT-related assessment criteria by cieBOM to them. We then compared the assessment outcomes to the respective RCT-based cieBOM recommendations. Further, we investigated how the assessments would change when applying different response-related thresholds and adding a progression-free survival (PFS) threshold. Results: For 13 of the 37 eligible recommendations, a matching NRT was found. Two treatments were assessed positively and six negatively; five treatments were non-assessable. Two positive recommendations matched a positive NRT-based assessment; one matching negative assessment was found, and one treatment could not be assessed based on either trial results. Adding a > 6 months PFS threshold decreased the number of non-assessable NRTs (five to two). Conclusions: Limited publications and inconsistent data reporting hampered the viability of NRTs for clinical benefit assessments of SACTs beyond the scope of rare indications. Further, response-related assessment criteria alone might not fully grasp the clinical benefit of novel SACTs. NRT-based assessments should be considered with caution due to uncertainty of the trial results

Abdominal complaints and neurological symptoms as an early sign of lung cancer:a manifestation of the anti-Hu syndrome

In two patients, women aged 73 and 46 years, gastrointestinal symptoms were initially not recognised as a paraneoplastic syndrome due to small-cell lung cancer. This led to redundant diagnostics as well as a delay in final diagnosis. The anti-Hu syndrome is characterised by the presence of anti-Hu antibodies and neurological symptoms. About a quarter of the patients with the anti-Hu syndrome will develop gastrointestinal motility disorders in the course of their illness. The primary tumour is usually a small-cell lung cancer. Whereas the presence of anti-Hu antibodies appears to be beneficial for the oncological prognosis, the neurological outcome is less favourable.</p