Lorenzo Nardo

Tumor immune profiling predicts response to anti–PD-1 therapy in human melanoma

BACKGROUND Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options. METHODS We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype. RESULTS Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs. CONCLUSIONS Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition. FUNDING This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.

Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus?†

To compare vertebral bone marrow fat content quantified with proton MR spectroscopy (1H‐MRS) with the volume of abdominal adipose tissue, lumbar spine volumetric bone mineral density (vBMD), and blood biomarkers in postmenopausal women with and without type 2 diabetes mellitus (T2DM).

Baseline mean and heterogeneity of MR cartilage T2 are associated with morphologic degeneration of cartilage, meniscus, and bone marrow over 3 years – data from the Osteoarthritis Initiative

OBJECTIVE The purpose of this study is to determine whether the mean and heterogeneity of magnetic resonance (MR) knee cartilage T(2) relaxation time measurements at baseline are associated with morphologic degeneration of cartilage, meniscus, and bone marrow tissues over 3 years in subjects with risk factors for osteoarthritis (OA). DESIGN Subjects with risk factors for OA (n=289) with an age range of 45-55 years were selected from the Osteoarthritis Initiative (OAI) database. 3.0 Tesla MR images were analyzed using morphological gradings of cartilage, bone marrow and menisci whole-organ magnetic resonance imaging scores (WORMS scoring). A T(2) mapping sequence was used to assess the mean and heterogeneity of cartilage T(2) (gray level co-occurrence matrix texture analysis). Regression models were used to assess the relationship between baseline T(2) parameters and changes in morphologic knee WORMS scores over 3 years. RESULTS The prevalence of knee abnormalities in the cartilage (P<0.0005), meniscus (P<0.00001), and bone marrow significantly (P<0.00001) increased from baseline to 3 years in all compartments combined. The baseline mean and heterogeneity of cartilage T(2) were significantly (P<0.05) associated with morphologic joint degeneration in the cartilage, meniscus and bone marrow over 3 years. CONCLUSIONS The prevalence of knee abnormalities significantly increased over 3 years; increased cartilage T(2) at baseline predicted longitudinal morphologic degeneration in the cartilage, meniscus, and bone marrow over 3 years in subjects with risk factors for OA.

Characterization of the regional distribution of skeletal muscle adipose tissue in type 2 diabetes using chemical shift‐based water/fat separation

To show the feasibility of assessing the spatial distribution of skeletal muscle adipose tissue using chemical shift‐based water/fat separation and to characterize differences in calf intermuscular adipose tissue (IMAT) compartmentalization in patients with type 2 diabetes mellitus (T2DM) compared to healthy age‐matched controls.

Texture analysis of cartilage T2 maps: individuals with risk factors for OA have higher and more heterogeneous knee cartilage MR T2 compared to normal controls - data from the osteoarthritis initiative

IntroductionThe goals of this study were (i) to compare the prevalence of focal knee abnormalities, the mean cartilage T2 relaxation time, and the spatial distribution of cartilage magnetic resonance (MR) T2 relaxation times between subjects with and without risk factors for Osteoarthritis (OA), (ii) to determine the relationship between MR cartilage T2 parameters, age and cartilage morphology as determined with whole-organ magnetic resonance imaging scores (WORMS) and (iii) to assess the reproducibility of WORMS scoring and T2 relaxation time measurements including the mean and grey level co-occurrence matrix (GLCM) texture parameters.MethodsSubjects with risk factors for OA (n = 92) and healthy controls (n = 53) were randomly selected from the Osteoarthritis Initiative (OAI) incidence and control cohorts, respectively. The specific inclusion criteria for this study were (1) age range 45-55 years, (2) body mass index (BMI) of 19-27 kg/m2, (3) Western Ontario and McMaster University (WOMAC) pain score of zero and (4) Kellgren Lawrence (KL) score of zero at baseline. 3.0 Tesla MR images of the right knee were analyzed using morphological gradings of cartilage, bone marrow and menisci (WORMS) as well as compartment specific cartilage T2 mean and heterogeneity. Regression models adjusted for age, gender, and BMI were used to determine the difference in cartilage parameters between groups.ResultsWhile there was no significant difference in the prevalence of knee abnormalities (cartilage lesions, bone marrow lesions, meniscus lesions) between controls and subjects at risk for OA, T2 parameters (mean T2, GLCM contrast, and GLCM variance) were significantly elevated in those at risk for OA. Additionally, a positive significant association between cartilage WORMS score and cartilage T2 parameters was evident.ConclusionsOverall, this study demonstrated that subjects at risk for OA have both higher and more heterogeneous cartilage T2 values than controls, and that T2 parameters are associated with morphologic degeneration.

T1ρ and T2 relaxation times predict progression of knee osteoarthritis

OBJECTIVE To evaluate whether T(2) and T(1ρ) relaxation times of knee cartilage determined with 3T magnetic resonance imaging (MRI) at baseline predict longitudinal progression of cartilage degenerative changes. METHODS Quantitative analysis of cartilage was performed using 3T MRI with both T(2) and T(1ρ) mapping techniques in 55 subjects without evidence of severe osteoarthritis (OA) [Kellgren-Lawrence (KL) score of 0-3] at baseline. Morphological abnormalities of cartilage, menisci, ligaments and bone marrow were analyzed on sagittal fat-saturated intermediate-weighted fast spin echo (FSE) sequences. Progression of degenerative changes was analyzed over a period of 2 years. Progression was detected in 27 subjects while in 28 subjects no changes were found. Differences between T(2) and T(1ρ) relaxation times in these two cohorts were compared using one-way analysis of variance (ANOVA) and t tests. RESULTS Baseline T(2) and T(1ρ) values were significantly higher in the progression cohort in all compartments (P < 0.05) except the lateral tibia (LT) for T(2) and the medial tibia (MT) for T(1ρ). Progression of cartilage degenerative disease was most pronounced at the medial femoral condyles and at the femoro-patellar joint; differences between the two cohorts for T(2) and T(1ρ) were also most significant in these compartments. CONCLUSIONS T(2) and T(1ρ) measurements were significantly higher at baseline in individuals that showed progression of cartilage abnormalities over a period of 2 years and may therefore serve as potential predictors for progression of degenerative cartilage abnormalities in knee OA.

Association of magnetic resonance imaging–based knee cartilage T2 measurements and focal knee lesions with knee pain: Data from the Osteoarthritis Initiative†

To evaluate the association of magnetic resonance imaging (MRI)–based knee cartilage T2 measurements and focal knee lesions with knee pain in knees without radiographic osteoarthritis (OA) among subjects with OA risk factors.

Quantitative assessment of fat infiltration in the rotator cuff muscles using water-fat MRI

To evaluate a chemical shift‐based fat quantification technique in the rotator cuff muscles in comparison with the semiquantitative Goutallier fat infiltration classification (GC) and to assess their relationship with clinical parameters.

Obesity increases the prevalence and severity of focal knee abnormalities diagnosed using 3T MRI in middle-aged subjects—data from the Osteoarthritis Initiative

ObjectiveTo study the effect of BMI on the prevalence, severity, and 36-month progression of early degenerative changes in the knee by using 3T MRI in middle-aged subjects without radiographic osteoarthritis (OA).Materials and methodsWe examined baseline and 36-month follow-up MR studies from 137 middle-aged individuals (45-55 years old) with risk factors for knee OA but no radiographic OA from the Osteoarthritis Initiative. Subjects were grouped into three categories: normal BMI (BMI < 25 kg/m2, n = 38), overweight (BMI 25–29.9 kg/m2, n = 37), and obese (BMI ≥ 30 kg/m2, n = 62). Using 3T MRI, cartilage, meniscus, and bone marrow abnormalities were graded using the OA Whole-organ MR Imaging Score (WORMS). The statistical analysis was corrected as necessary for differences in age, sex, and OA risk factors other than BMI.ResultsThe overall prevalence of lesions was 64% for meniscus and 79% for cartilage (including low grade lesions). At baseline, the prevalence and severity of knee lesions was positively associated with BMI, with a nearly fourfold increase in meniscal tears and more than twofold increase in high-grade cartilage defects in obese individuals relative to normal-weight subjects. Over the 36-month follow-up period, the number of new or worsening cartilage lesions of any grade was significantly higher in obese subjects (p = 0.039), while there was no significant difference in meniscal lesion progression.ConclusionObesity was associated with both higher prevalence and severity of early degenerative changes in the knee in middle-aged individuals without radiographic OA and with significantly increased cartilage lesion progression (of any grade) over 36 months.

Scoring Hip Osteoarthritis with MRI (SHOMRI): a Whole Joint Osteoarthritis Evaluation System

To develop a semi‐quantitative MR‐based hip osteoarthritis (OA) evaluation system (Scoring hip osteoarthritis with MRI, SHOMRI), and to test its reproducibility and face validity.