Current treatment goals are achieved by the majority of patients with atopic dermatitis treated with tralokinumab: results from a multicentric, multinational, retrospective, cohort study.

BACKGROUND: Tralokinumab is a human monoclonal antibody targeting interleukin-13 that is approved for the treatment of moderate-severe atopic dermatitis. Studies analyzing the efficacy and safety of tralokinumab in a real-world setting are scarce. RESEARCH DESIGN AND METHODS: A European, multicentric, real-world, retrospective cohort study was defined to assess the effectiveness and safeness profile of tralokinumab, investigating the achievement of pre-specified treatment goals; and to detect potential differences in terms of effectiveness and safeness across some selected patient subcohorts. RESULTS: A total of 194 adult patients were included in this study. A significant improvement in physician-assessed disease severity was detected at each follow-up visit as compared with baseline and similar trend was observed for patient-reported outcomes and quality of life. No meaningful difference in effectiveness was found when considering patient age (<65 versus ≥65 years), neither dissecting patient cohort in dupilumab-naive vs dupilumab-treated subjects. Among tralokinumab-treated patients, 88% achieved at least one currently identified real-world therapeutic goal at week 16. CONCLUSIONS: This retrospective multicenter study confirmed the effectiveness and safeness of tralokinumab throughout 32 weeks of observation, showing the achievement of therapeutic goals identified in both trial and real-world settings in a large proportion of tralokinumab-treated patients.

High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Dupilumab-associated ocular adverse events are predicted by low tear break-up time and correlate with high IL-33 tear concentrations in patients with atopic dermatitis.

Dupilumab, blocking IL-4 and IL-13 signals, improves atopic dermatitis and Quality of Life but might be also associated with the occurrence of ocular adverse events (OAEs). The main objective of our prospective study was to characterize the cytokine and chemokine profile in the tear fluid of dupilumab-treated patients with moderate-to- severe atopic dermatitis and to identify biomarkers predicting the occurrence of ocular adverse events. Patients with moderate-to-severe AD underwent dermatological and ophthalmological evaluation at the baseline (T0) and week 16 or at the time of an eventual ocular adverse events (T1). A multiplex immunoassay measuring multiple cytokines and chemokines in the tear fluid extracted during ocular examination at both T0 and T1 was performed. Thirty-nine patients with moderate-to-severe AD and treated with dupilumab were included in the study. Baseline tear fluid levels revealed a significantly higher concentration of type 2 cytokines and chemokines in AD patients than healthy controls. The occurrence of ocular adverse events during dupilumab therapy was associated with a significant increase of IL-33 tear fluid levels and a significantly lower tear break-up time, this latter also identified as predictive factor. Our findings suggest that the ophthalmological examination should be considered a valid support to identify patients at risk of developing OAEs and to provide their appropriate management.

Melanoma in children and adolescents: analysis of susceptibility genes in 123 Italian patients.

BACKGROUND: A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients. OBJECTIVE: We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents. METHODS: One-hundred-twenty-three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated. RESULTS: Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi. CONCLUSION: Our results confirm the scarce involvement of the major high-risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.

Preliminary dosimetric analysis of DOTA-folate radiopharmaceutical radiolabelled with 47Sc produced through natV(p,x)47Sc cyclotron irradiation.

47Sc is one of the most promising theranostic radionuclides, thanks to its low energy γ-ray emission (159 keV), suitable for single photon emission computed tomography imaging and its intense ß - emission, useful for tumour treatment. Despite promising preclinical results, the translation of 47Sc-therapeutic agents to the clinic is hampered by its limited availability. Among different 47Sc-production routes currently being investigated, the natV(p,x)47Sc reaction has proved to be of particular interest, thanks to the low-cost and easy availability on the market of natV material and the diffusion of medium energy proton cyclotrons. However, the cross section of this specific nuclear reaction is quite low and small amounts of Sc-contaminants are co-produced at energies E P ≤ 45 MeV, namely 48Sc and 46Sc. The main concern with these Sc-contaminants is their contribution to the patient absorbed dose. For such a reason, the absorbed dose contributions to healthy organs and the effective dose contributions by the three radioisotopes, 48Sc, 47Sc and 46Sc, were evaluated using DOTA-folate conjugate (cm10) as an example of radiopharmaceutical product. Considering as acceptable the limits of 99% for the radionuclidic purity and 10% for the contribution of radioactive Sc-contaminants to the total effective dose after 47Sc-cm10 injection, it was obtained that proton beam energies below 35 MeV must be used to produce 47Sc through irradiation of a natV target.

Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies.

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all skin cancers. Although primary cSCCs can be successfully treated with surgery, a subset of highly aggressive lesions may progress to advanced disease, representing a public healthcare problem with significant cancer-related morbidity and mortality. A complex network of genes (TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) have been shown to play an important role in the pathogenesis of cSCC. The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH-activating agents capable to restore its tumour-suppressor function. EGFR inhibitors including both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors (erlotinib, gefitinib and dasatinib) have been used in clinical trials for the treatment of advanced cSCC, achieving only partial clinical benefit. Recently, an immune-modulatory drug (cemiplimab) has been introduced for the treatment of advanced cSCC with good clinical results and a favourable safety profile, while other PD1/PD-L1 inhibitors, either as monotherapy or in combination with targeted therapies, are currently under investigation. This review focuses on molecular findings involved in the pathogenesis of cSCC and their implications for the future development of new treatment strategies. In addition, current and ongoing treatments on targeted therapies and/or immunotherapy are illustrated.

Bactericidal activity of gallium-doped chitosan coatings against staphylococcal infection.

AIMS: The aim of this study was to develop a new class of gallium (Ga)-doped chitosan (CS) coatings fabricated by electrophoretic deposition (EPD) in staphylococcal infection therapy. METHODS AND RESULTS: Biofilm formation on EPD CS/Ga coatings by Staphylococcus epidermidis and Staphylococcus aureus, which are the main strains involved in postarthroplasty infections, was assessed. The codeposition of an antibacterial agent was effective; Ga loaded into CS matrix reduces biofilm viability by up to 86% and 80% for S. epidermidis and S. aureus strains respectively. Lastly, the influence of pulsed electromagnetic field (PEMF) on the bactericidal activity of CS/Ga coatings was investigated in vitro. To this end, the coatings were incubated with S. epidermidis and S. aureus and exposed to the PEMF using two different frequencies and times. Biofilm viability for S. epidermidis was decreased by 35-40% in the presence of low-frequency (LF) and high-frequency (HF) PEMF respectively. Biofilm viability by S. aureus was not further reduced in the presence of LF PEMF, but decreased by 38% at HF PEMF. CONCLUSIONS: This study has established that a combination of PEMFs with the antibacterial agent improves bactericidal activity of Ga against S. epidermidis strain 14990 and S. aureus strain 12600. SIGNIFICANCE AND IMPACT OF THE STUDY: This new integrated approach could reduce the incidence of infection in orthopaedic implant applications. It also clearly demonstrates that the combination of Ga treatment with PEMF could aid biofilm-associated infection therapy due to improved Ga efficiency.

Radioisotopic purity and imaging properties of cyclotron-produced 99mTc using direct 100Mo(p,2n) reaction.

Evaluation of the radioisotopic purity of technetium-99m (99mTc) produced in GBq amounts by proton bombardment of enriched molibdenum-100 (100Mo) metallic targets at low proton energies (i.e. within 15-20 MeV) is conducted. This energy range was chosen since it is easily achievable by many conventional medical cyclotrons already available in the nuclear medicine departments of hospitals. The main motivation for such a study is in the framework of the research activities at the international level that have been conducted over the last few years to develop alternative production routes for the most widespread radioisotope used in medical imaging. The analysis of technetium isotopes and isomeric states (9xTc) present in the pertechnetate saline Na99mTcO4 solutions, obtained after the extraction/purification procedure, reveals radionuclidic purity levels basically in compliance with the limits recently issued by European Pharmacopoeia 9.3 (2018 Sodium pertechnetate (99mTc) injection 4801-3). Moreover, the impact of 9xTc contaminant nuclides on the final image quality is thoroughly evaluated, analyzing the emitted high-energy gamma rays and their influence on the image quality. The spatial resolution of images from cyclotron-produced 99mTc acquired with a mini-gamma camera was determined and compared with that obtained using technetium-99m solutions eluted from standard 99Mo/99mTc generators. The effect of the increased image background contribution due to Compton-scattered higher-energy gamma rays (E γ > 200 keV), which could cause image-contrast deterioration, was also studied. It is concluded that, due to the high radionuclidic purity of cyclotron-produced 99mTc using 100Mo(p,2n)99mTc reaction at a proton beam energy in the range 15.7-19.4 MeV, the resulting image properties are well comparable with those from the generator-eluted 99mTc.

Miniaturized microdosimeters as LET monitors: First comparison of calculated and experimental data performed at the 62 MeV/u 12C beam of INFN-LNS with four different detectors.

PURPOSE: The aim of this paper is to investigate the limits of LET monitoring of therapeutic carbon ion beams with miniaturized microdosimetric detectors. METHODS: Four different miniaturized microdosimeters have been used at the 62 MeV/u 12C beam of INFN Southern National Laboratory (LNS) of Catania for this purpose, i.e. a mini-TEPC and a GEM-microdosimeter, both filled with propane gas, and a silicon and a diamond microdosimeter. The y-D (dose-mean lineal energy) values, measured at different depths in a PMMA phantom, have been compared withLET¯D (dose-mean LET) values in water, calculated at the same water-equivalent depth with a Monte Carlo simulation setup based on the GEANT4 toolkit. RESULTS: In these first measurements, no detector was found to be significantly better than the others as a LET monitor. The y-D relative standard deviation has been assessed to be 13% for all the detectors. On average, the ratio between y-D and LET¯D values is 0.9 ±â€¯0.3, spanning from 0.73 ±â€¯0.08 (in the proximal edge and Bragg peak region) to 1.1 ±â€¯0.3 at the distal edge. CONCLUSIONS: All the four microdosimeters are able to monitor the dose-mean LET with the 11% precision up to the distal edge. In the distal edge region, the ratio of y-D to LET¯D changes. Such variability is possibly due to a dependence of the detector response on depth, since the particle mean-path length inside the detectors can vary, especially in the distal edge region.

Chitosan-Based Trilayer Scaffold for Multitissue Periodontal Regeneration.

Periodontal regeneration is still a challenge for periodontists and tissue engineers, as it requires the simultaneous restoration of different tissues-namely, cementum, gingiva, bone, and periodontal ligament (PDL). Here, we synthetized a chitosan (CH)-based trilayer porous scaffold to achieve periodontal regeneration driven by multitissue simultaneous healing. We produced 2 porous compartments for bone and gingiva regeneration by cross-linking with genipin either medium molecular weight (MMW) or low molecular weight (LMW) CH and freeze-drying the resulting scaffolds. We synthetized a third compartment for PDL regeneration by CH electrochemical deposition; this allowed us to produce highly oriented microchannels of about 450-µm diameter intended to drive PDL fiber growth toward the dental root. In vitro characterization showed rapid equilibrium water content for MMW-CH and LMW-CH compartments (equilibrium water content after 5 min >85%). The MMW-CH compartment degraded more slowly and provided significantly more resistance to compression (28% ± 1% of weight loss at 4 wk; compression modulus HA = 18 ± 6 kPa) than the LMW-CH compartment (34% ± 1%; 7.7 ± 0.8 kPa) as required to match the physiologic healing rates of bone and gingiva and their mechanical properties. More than 90% of all human primary periodontal cell populations tested on the corresponding compartment survived during cytocompatibility tests, showing active cell metabolism in the alkaline phosphatase and collagen deposition assays. In vivo tests showed high biocompatibility in wild-type mice, tissue ingrowth, and vascularization within the scaffold. Using the periodontal ectopic model in nude mice, we preseeded scaffold compartments with human gingival fibroblasts, osteoblasts, and PDL fibroblasts and found a dense mineralized matrix within the MMW-CH region, with weakly mineralized deposits at the dentin interface. Together, these results support this resorbable trilayer scaffold as a promising candidate for periodontal regeneration.

Microdosimetric Measurements in Gamma and neutron Fields with a Tissue Equivalent Proportional Counter Based on a Gas Electron Multiplier.

A multi-element tissue-equivalent proportional counter (TEPC), based on a single gas electron multiplier (GEM) foil of standard geometry, has been constructed with 16 cylindrical sensitives volumes. In this article, the design of this novel counter is described and first microdosimetric measurements are presented. To study the response of the GEM-TEPC to both low and high linear energy transfer radiation fields, the microdosimetric spectra due to a 137Cs gamma-ray source and to fast neutrons from 7Li(d,n)8Be reaction have been measured using pure propane gas at low pressure, in order to simulate a tissue site of about 1 µm equivalent size. The comparison with spectra measured with a spherical TEPC and with a mini-TEPC demonstrates promising properties for application of the GEM-TEPC for microdosimetric applications.

Associations between patellofemoral joint cartilage T1ρ and T2 and knee flexion moment and impulse during gait in individuals with and without patellofemoral joint osteoarthritis.

OBJECTIVE: This study aimed to investigate the associations between patellofemoral cartilage T1ρ and T2 relaxation times and knee flexion moment (KFM) and KFM impulse during gait. METHOD: Knee magnetic resonance (MR) images were obtained from 99 subjects with and without patellofemoral joint (PFJ) osteoarthritis (OA), using fast spin-echo, T1ρ and T2 relaxation time sequences. Patellar and trochlear cartilage relaxation times were computed for the whole cartilage, and superficial and deep layers (laminar analysis). Subjects also underwent three-dimensional (3D) gait analysis. Peak KFM and KFM impulse were calculated during the stance phase. Linear regressions were used to examine whether cartilage relaxation times were associated with knee kinetics during walking while adjusting age, sex, body mass index (BMI) and walking speed. RESULTS: Higher peak KFM and KFM impulse were significantly related to higher T1ρ and T2 relaxation times of the trochlear and patellar cartilage, with standardized regression coefficients ranging from 0.21 to 0.28. Laminar analysis showed that overall the superficial layer of patellofemoral cartilage showed stronger associations with knee kinetics. Subgroup analysis revealed that in subjects with PFJ OA, every standard deviation change in knee kinetics was related to greater increases in PFJ cartilage T1ρ and T2 (standardized coefficients: 0.29 to 0.41). Conversely, in subjects without OA, weaker relationships were observed between knee kinetics and PFJ cartilage T1ρ and T2. CONCLUSIONS: Our findings suggest that increased peak KFM and KFM impulse were related to worse cartilage health at the PFJ. This association is more prominent in superficial layer cartilage and cartilage with morphological lesions.

Bioactivity and Mechanical Stability of 45S5 Bioactive Glass Scaffolds Based on Natural Marine Sponges.

Bioactive glass (BG) based scaffolds (45S5 BG composition) were developed by the replica technique using natural marine sponges as sacrificial templates. The resulting scaffolds were characterized by superior mechanical properties (compression strength up to 4 MPa) compared to conventional BG scaffolds prepared using polyurethane (PU) packaging foam as a template. This result was ascribed to a reduction of the total scaffold porosity without affecting the pore interconnectivity (>99%). It was demonstrated that the reduction of total porosity did not affect the bioactivity of the BG-based scaffolds, tested by immersion of scaffolds in simulated body fluid (SBF). After 1 day of immersion in SBF, a homogeneous CaP deposit on the surface of the scaffolds was formed, which evolved over time into carbonate hydroxyapatite (HCA). Moreover, the enhanced mechanical properties of these scaffolds were constant over time in SBF; after an initial reduction of the maximum compressive strength upon 7 days of immersion in SBF (to 1.2 ± 0.2 MPa), the strength values remained almost constant and higher than those of BG-based scaffolds prepared using PU foam (<0.05 MPa). Preliminary cell culture tests with Saos-2 osteoblast cell line, namely direct and indirect tests, demonstrated that no toxic residues remained from the natural marine sponge templates and that cells were able to proliferate on the scaffold surfaces.

T1ρ and T2 relaxation times are associated with progression of hip osteoarthritis.

OBJECTIVE: To evaluate whether baseline T1ρ and T2 relaxation times of hip cartilage are associated with magnetic resonance imaging (MRI) based progression of hip osteoarthritis (OA) at 18 months. METHODS: 3T MRI studies of the hip were obtained at baseline and 18-month follow-up for 54 subjects without evidence of severe OA at baseline [Kellgren-Lawrence (KL) score of 0-3]. 2D fast spin-echo sequences were used for semi-quantitative morphological scoring of cartilage lesions and a combined T1ρ/T2 sequence was used to quantitatively assess cartilage composition. Progression of hip OA was defined based on incident or progression of morphological semi-quantitative grade at 18 months. Baseline T1ρ and T2 relaxation times were compared between progressors and non-progressors using one-way analysis of variance and Mann-Whitney U tests and used to predict progression with binary logistic regression after adjusting for age, gender, body mass index, and KL score. Additionally, a novel voxel-based relaxometry technique was used to compare the spatial distribution of baseline T1ρ and T2 between progressors and non-progressors. RESULTS: Significantly higher baseline T1ρ and T2 values were observed in hip OA progressors compared to non-progressors, particularly in the posterosuperior and anterior aspects of the femoral cartilage. Logistic regression showed that higher baseline T1ρ or T2 values in the femoral cartilage were significantly associated with progression of femoral cartilage lesions at 18 months. CONCLUSION: T1ρ and T2 relaxation parameters are associated with morphological cartilage degeneration at 18 months and may serve as potential imaging biomarkers for progression of cartilage lesions in hip OA.

MICRODOSIMETRIC MEASUREMENTS OF A TISSUE-EQUIVALENT PROPORTIONAL COUNTER BASED ON A GAS ELECTRON MULTIPLIER DOWN TO 140 nm SIMULATED SITE SIZES.

A multi-element tissue-equivalent proportional counter (TEPC), based on a gas electron multiplier, has been constructed with several cavities of small dimensions (down to 0.5 mm of diameter), to be used for microdosimetric measurements in intense, pulsed, radiation fields. First micro- and nano-dosimetric spectra with low-energy X rays in various simulated tissue site sizes are presented. The specific advantages and the calibration methods of this type of TEPC are discussed.

Effects of cytosine methylation on DNA morphology: An atomic force microscopy study.

Methylation is one of the most important epigenetic mechanisms in eukaryotes. As a consequence of cytosine methylation, the binding of proteins that are implicated in transcription to gene promoters is severely hindered, which results in gene regulation and, eventually, gene silencing. To date, the mechanisms by which methylation biases the binding affinities of proteins to DNA are not fully understood; however, it has been proposed that changes in double-strand conformations, such as stretching, bending, and over-twisting, as well as local variations in DNA stiffness/flexibility may play a role. The present work investigates, at the single molecule level, the morphological consequences of DNA methylation in vitro. By tracking the atomic force microscopy images of single DNA molecules, we characterize DNA conformations pertaining to two different degrees of methylation. In particular, we observe that methylation induces no relevant variations in DNA contour lengths, but produces measurable incremental changes in persistence lengths. Furthermore, we observe that for the methylated chains, the statistical distribution of angles along the DNA coordinate length is characterized by a double exponential decay, in agreement with what is predicted for polyelectrolytes. The results reported herein support the claim that the biological consequences of the methylation process, specifically difficulties in protein-DNA binding, are at least partially due to DNA conformation modifications.

Relationship of unilateral total hip arthroplasty (THA) to contralateral and ipsilateral knee joint degeneration - a longitudinal 3T MRI study from the Osteoarthritis Initiative (OAI).

OBJECTIVE: To evaluate the association of prevalent unilateral total hip arthroplasty (THA) with worsening of degenerative knee abnormalities and clinical outcomes in the ipsilateral and contralateral knee. METHODS: Both knees of 30 individuals in the Osteoarthritis Initiative (OAI) with unilateral THA (n = 14 left, n = 16 right) at baseline were assessed at baseline and at 4-year follow-up for Whole-organ MR Imaging Scores (WORMS), cartilage T2 relaxation times (only available for right knees), Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores and upper leg isometric strength. Right knees of 30 individuals without THA were analyzed as controls. Contralateral knees were compared to ipsilateral knees with paired t-tests and to control knees with multivariate regression analysis adjusting for covariates. RESULTS: In paired analyses, compared to ipsilateral knees, contralateral knees had higher WORMS total (P = 0.008) and cartilage scores (P = 0.007) at baseline. Over 4 years contralateral knees worsened more on WORMS total score (P = 0.008). Cartilage T2 values were higher in knees contralateral to the THA (baseline, P = 0.02; follow-up, P < 0.001). Contralateral knees had greater declines in knee extension strength (P = 0.04) and had a trend for greater worsening in WOMAC pain, stiffness, function and total scores (P = 0.04-0.09). Similar results were found comparing contralateral knees with control knees in multivariate regression models. CONCLUSIONS: Prevalent unilateral THA is associated with an greater progression of degenerative findings for the knee contralateral to THA.

Association of Physical Activity Measured by Accelerometer, Knee Joint Abnormalities, and Cartilage T2 Measurements Obtained From 3T Magnetic Resonance Imaging: Data From the Osteoarthritis Initiative.

OBJECTIVE: To study the cross-sectional association between physical activity measured with an accelerometer, structural knee abnormalities, and cartilage T2 values assessed with 3T magnetic resonance imaging (MRI). METHODS: We included 274 subjects from the Osteoarthritis Initiative cohort without definite radiographic osteoarthritis (Kellgren/Lawrence grades 0 and 1) and with at most mild pain, stiffness, and functional limitation in the study knee (Western Ontario and McMaster Universities Osteoarthritis Index scale 0-1), which had not limited their activity due to knee pain. Physical activity was measured over 7 days with an ActiGraph GT1M accelerometer. Subjects were categorized by quartile of physical activity based on the average daily minutes of moderate to vigorous physical activity (mv-PA). MRI images of the right knee (at 48-month visit) were assessed for structural abnormalities using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) and for T2 relaxation times derived from segmented cartilage of 4 femorotibial regions and the patella. WORMS grades and T2 measurements were compared between activity quartiles using a linear regression model. Covariates included age, sex, body mass index, knee injury, family history of knee replacement, knee symptoms, hip and ankle pain, and daily wear time of the accelerometer. RESULTS: Higher mv-PA was associated with increased severity (P = 0.0087) and number of lesions of the medial meniscus (P = 0.0089) and with severity of bone marrow edema lesions (P = 0.0053). No association between cartilage lesions and mv-PA was found. T2 values of cartilage (loss, damage, and abnormalities) tended to be greater in the higher quartiles of mv-PA, but the differences were nonsignificant. CONCLUSION: In knees without radiographic osteoarthritis in subjects with no or mild knee pain, higher physical activity levels were associated with increases in meniscal and bone marrow edema pattern lesions.

A reference database of cartilage 3 T MRI T2 values in knees without diagnostic evidence of cartilage degeneration: data from the osteoarthritis initiative.

OBJECTIVE: 1) To establish a gender- and BMI-specific reference database of cartilage T2 values, and 2) to assess the associations between cartilage T2 values and gender, age, and BMI in knees without radiographic osteoarthritis or MRI-based (WORMS 0/1) evidence of cartilage degeneration. DESIGN: 481 subjects aged 45-65 years with Kellgren-Lawrence Scores 0/1 in the study knee were selected. Baseline morphologic cartilage 3T MRI readings (WORMS scoring) and T2 measurements (resolution = 0.313 mm × 0.446 mm) were performed in the medial and lateral femurs, medial and lateral tibias, and patella compartments. To create a reference database, a logarithmic transformation was applied to the data to obtain the 5th-95th percentile values for T2. RESULTS: Significant differences in mean cartilage T2 values were observed between joint compartments. Although females had slightly higher T2 values than males in a majority of compartments, the differences were only significant in the medial femur (P < 0.0001). A weak positive association was seen between age and T2 in all compartments, most pronounced in the patella (3.27% increase in median T2/10 years, P = 0.009). Significant associations between BMI and T2 were observed, most pronounced in the lateral tibia (5.33% increase in median T2/5 kg/m(2) increase in BMI, P < 0.0001), and medial tibia (4.81% increase in median T2 /5 kg/m(2) increase in BMI, P < 0.0001). CONCLUSIONS: This study established the first reference database of T2 values in a large sample of morphologically normal cartilage plates in knees without radiographic knee osteoarthritis (OA). While cartilage T2 values were weakly associated with age and gender, they had the highest correlations with BMI.

Association of cartilage degeneration with four year weight gain--3T MRI data from the Osteoarthritis Initiative.

OBJECTIVE: To determine the effect of weight gain on progression of early knee morphologic abnormalities using magnetic resonance imaging (MRI) in a longitudinal study over 48 months. DESIGN: We studied the right knee of 100 subjects from the Osteoarthritis Initiative (OAI), selecting subjects aged ≥ 45 with osteoarthritis (OA) risk factors who demonstrated weight gain (minimum 5% increase in body mass index, BMI, n = 50) or no change in weight (BMI change < 2%, n = 50), frequency matched for age, gender, and baseline BMI. Baseline and 48 month knee MRI studies were scored for lesions using a modified whole organ MRI score (WORMS). Logistic regression models were used to compare the differences between the two groups. RESULTS: The odds of worsening maximum cartilage (11.3, 95%, CI 3.5-51.4) and meniscal WORMS (4.5, 95% CI 1.4-17.3) were significantly greater in the weight gain group compared to the no change group, in addition to the odds of worsening cartilage defects at the patella and average meniscal WORMS (P < 0.05). Odds of worsening average bone marrow edema pattern (BMEP) were significantly greater for the weight gain group compared to the no change cohort (P < 0.05). CONCLUSION: Our study demonstrated that weight gain is strongly associated with increased progression of cartilage degeneration in middle-aged individuals with risk factors for OA.