PET/CT assessment in follicular lymphoma using standardized criteria: central review in the PRIMA study

Purpose

We aimed to compare the standardized central review of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans performed after induction therapy for follicular lymphoma (FL) in the PRIMA study (Salles et al., Lancet 377:42–51, 2011; Trotman et al., J Clin Oncol 29:3194–3200, 2011) to scan review at local centres.

Methods

PET/CT scans were independently evaluated by two nuclear medicine physicians using the 2007 International Harmonization Project (IHP) criteria (Cheson et al., J Clin Oncol 25:579–586, 2007; Juweid et al., J Clin Oncol 25:571–578, 2007; Shankar et al., J Nucl Med 47:1059–1066, 2006) and Deauville 5-point scale (5PS) criteria (Meignan et al., Leuk Lymphoma 50:1257–1260, 2009; Meignan et al., Leuk Lymphoma 51:2171–2180, 2010; Barrington et al., Eur J Nucl Med Mol Imaging 37:1824–1833, 2010). PET/CT status was compared with prospectively recorded patient outcomes.

Results

Central evaluation was performed on 119 scans. At diagnosis, 58 of 59 were recorded as positive, with a mean maximum standardized uptake value (SUV_max) of 11.7 (range 4.6–35.6). There was no significant association between baseline SUV_max and progression-free survival (PFS). Sixty post-induction scans were interpreted using both the IHP criteria and 5PS. Post-induction PET-positive status failed to predict progression when applying the IHP criteria [p?=?0.14; hazard ratio (HR) 1.9; 95 % confidence interval (CI) 0.8–4.6] or 5PS with a cut-off ≥3 (p?=?0.12; HR 2.0; 95 % CI 0.8–4.7). However, when applying the 5PS with a cut-off ≥4, there was a significantly inferior 42-month PFS in PET-positive patients of 25.0 % (95 % CI 3.7–55.8 %) versus 61.4 % (95 % CI 45.4–74.1 %) in PET-negative patients (p?=?0.01; HR 3.1; 95 % CI 1.2–7.8). The positive predictive value (PPV) of post-induction PET with this liver cut-off was 75 %. The 42-month PFS for patients remaining PET-positive by local assessment was 31.1 % (95 % CI 10.2–55.0 %) vs 64.6 % (95 % CI 47.0–77.6 %) for PET-negative patients (p?=?0.002; HR 3.3; 95 % CI 1.5–7.4), with a PPV of 66.7 %.

Conclusion

We confirm that FDG PET/CT status when applying the 5PS with a cut-off ≥4 is strongly predictive of outcome after first-line immunochemotherapy for FL. Further efforts to refine the criteria for assessing minimal residual FDG uptake in FL should provide a reproducible platform for response assessment in future prospective studies of a PET-adapted approach.     

Contrast-enhanced MRI compared with the physical examination in the evaluation of disease activity in juvenile idiopathic arthritis

Objectives

To assess the value of magnetic resonance imaging (MRI) in discriminating between active and inactive juvenile idiopathic arthritis (JIA) patients and to compare physical examination outcomes with MRI outcomes in the assessment of disease status in JIA patients.

Methods

Consecutive JIA patients with knee involvement were prospectively studied using an open-bore MRI. Imaging findings from 146 JIA patients were analysed (59.6 % female; mean age, 12.9 years). Patients were classified as clinically active or inactive. MRI features were evaluated using the JAMRIS system, comprising validated scores for synovial hypertrophy, bone marrow oedema, cartilage lesions and bone erosions.

Results

Inter-reader reliability was good for all MRI features (intra-class correlation coefficient [ICC]?=?0.87–0.94). No differences were found between the two groups regarding MRI scores of bone marrow oedema, cartilage lesions or bone erosions. Synovial hypertrophy scores differed significantly between groups (P?=?0.016). Nonetheless, synovial hypertrophy was also present in 14 JIA patients (35.9 %) with clinically inactive disease. Of JIA patients considered clinically active, 48.6 % showed no signs of MRI-based synovitis.

Conclusions

MRI can discriminate between clinically active and inactive JIA patients. However, physical examination is neither very sensitive nor specific in evaluating JIA disease activity compared with MRI. Subclinical synovitis was present in >35 % of presumed clinically inactive patients.

Key points

? MRI is sensitive for evaluating juvenile idiopathic arthritis (JIA) disease activity. ? Contrast-enhanced MRI can distinguish clinically active and inactive JIA patients. ? Subclinical synovitis is present in 35.9?% of presumed clinically inactive patients. ? Physical examination is neither sensitive nor specific in evaluating JIA disease activity.     

Analyses of the differentiation potential of satellite cells from <Emphasis Type="Italic">myoD</Emphasis><Superscript>-/-</Superscript>, <Emphasis Type="Italic">mdx</Emphasis>, and <Emphasis Type="Italic">PMP22</Emphasis> C22 mice

Background  

Sporadic and sometimes contradictory studies have indicated changes in satellite cell behaviour associated with the progressive nature of human Duchenne muscular dystrophy (DMD). Satellite cell proliferation and number are reportedly altered in DMD and the mdx mouse model. We recently found that satellite cells in MSVski transgenic mice, a muscle hypertrophy model showing progressive muscle degeneration, display a severe ageing-related differentiation defect in vitro. We tested the hypothesis that similar changes contribute to the gradual loss of muscle function with age in mdx and PMP22 mice, a model of human motor and sensory neuropathy type 1A (HMSN1A).     

Influence of weight and weight change on bone loss in perimenopausal and early postmenopausal Scottish women

Weight is recognized as an important factor in determining an individuals risk of osteoporosis. However, little is known about whether weight or weight change influences bone loss around the time of the menopause, and the relationship with energy intake and physical activity level remains largely undefined. Healthy premenopausal women (1,064 selected from a random population of 5,119 women aged 45–54 years at baseline) each had bone mineral density (BMD), weight and height measurements, and completed a food frequency and physical activity questionnaire. Of the original participants, 907 women (85.2%) returned 6.3 ± 0.6 years later for repeat BMD measurements, and 896 women completed the questionnaires. Bone loss at the hip (FN) and spine (LS) occurred before the menopause. Weight change rather than weight was associated with FN BMD loss (r=0.102, p=0.002), but weight at follow-up was associated with LS BMD change (r=0.105, p=0.002). Although an increase in physical activity level (PAL) appeared to be beneficial for FN BMD in women who were heavy weight gainers, PAL was associated with increased LS BMD loss in women who lost weight. For current HRT users, neither weight nor weight change was associated with change in BMD. Postmenopausal women not taking HRT should be made aware that low body weight or losing weight during this particularly vulnerable period may worsen bone loss.     

Reliability and responsiveness of the Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee

Objectives

To assess the reliability and responsiveness of a new Juvenile Arthritis MRI Scoring (JAMRIS) system for evaluating disease activity of the knee.

Methods

Twenty-five juvenile idiopathic arthritis (JIA) patients with clinical knee involvement were studied using open-bore 1-T MRI. MRI features of synovial hypertrophy, bone marrow changes, cartilage lesions and bone erosions were independently scored by five readers using the JAMRIS system. In addition, the JAMRIS system was determined to be a follow-up parameter by two readers to evaluate the response to therapy in 15 consecutive JIA patients.

Results

Inter-reader (ICCs 0.86–0.95) and intra-reader reliability (ICCs 0.92–1.00) for the scoring of JAMRIS features was good. Reliability of the actual scores and changes in scores over time was good for all items: ICCs 0.89–1.00, 0.87–1.00, respectively. Concerning therapy response, the mean synovial hypertrophy scores decreased significantly (mean 1.1 point; P?<?0.001, SRM?=??0.65). No change was observed with respect to bone marrow change, cartilage lesion and bone erosion scores.

Conclusions

The JAMRIS proved to be a simple and highly reliable assessment score in the evaluation of JIA disease activity of the knee. The JAMRIS system may serve as an objective and accurate outcome measure in future research and clinical trials.

Key Points

? MRI is increasingly used to diagnose and assess juvenile idiopathic arthritis. ? A simple and reliable scoring method would help monitor progress and research. ? The Juvenile Arthritis MRI Scoring (JAMRIS) system provides reliable objective measures. ? JAMRIS evaluates synovial hypertrophy, bone marrow changes, cartilage lesions and bone erosions. ? The JAMRIS system can detect therapeutic response and should help future research.     

(R)-[11C]verapamil is selectively transported by murine and human P-glycoprotein at the blood–brain barrier,and not by MRP1 and BCRP

IntroductionPositron emission tomography (PET) with [¹¹C]verapamil, either in racemic form or in form of the (R)-enantiomer, has been used to measure the functional activity of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) at the blood–brain barrier (BBB). There is some evidence in literature that verapamil inhibits two other ABC transporters expressed at the BBB, i.e. multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). However, previous data were obtained with micromolar concentrations of verapamil and do not necessarily reflect the transporter selectivity of verapamil at nanomolar concentrations, which are relevant for PET experiments. The aim of this study was to assess the selectivity of verapamil, in nanomolar concentrations, for Pgp over MRP1 and BCRP.MethodsConcentration equilibrium transport assays were performed with [³H]verapamil (5 nM) in cell lines expressing murine or human Pgp, human MRP1, and murine Bcrp1 or human BCRP. Paired PET scans were performed with (R)-[¹¹C]verapamil in female FVB/N (wild-type), Mrp1^(?/?), Mdr1a/b^(?/?), Bcrp1^(?/?) and Mdr1a/b^(?/?)Bcrp1^(?/?) mice, before and after Pgp inhibition with 15 mg/kg tariquidar.ResultsIn vitro transport experiments exclusively showed directed transport of [³H]verapamil in Mdr1a- and MDR1-overexpressing cells which could be inhibited by tariquidar (0.5 μM). In PET scans acquired before tariquidar administration, brain-to-blood ratio (K_b,brain) of (R)-[¹¹C]verapamil was low in wild-type (1.3 ± 0.1), Mrp1^(?/?) (1.4 ± 0.1) and Bcrp1^(?/?) mice (1.8 ± 0.1) and high in Mdr1a/b^(?/?) (6.9 ± 0.8) and Mdr1a/b^(?/?)Bcrp1^(?/?) mice (7.9 ± 0.5). In PET scans after tariquidar administration, K_b,brain was significantly increased in Pgp-expressing mice (wild-type: 5.0 ± 0.3-fold, Mrp1^(?/?): 3.2 ± 0.6-fold, Bcrp1^(?/?): 4.3 ± 0.1-fold) but not in Pgp knockout mice (Mdr1a/b^(?/?) and Mdr1a/b^(?/?)Bcrp1^(?/?)).ConclusionOur combined in vitro and in vivo data demonstrate that verapamil, in nanomolar concentrations, is selectively transported by Pgp and not by MRP1 and BCRP at the BBB, which supports the use of (R)-[¹¹C]verapamil or racemic [¹¹C]verapamil as PET tracers of cerebral Pgp function.     

Saturation‐recovery metabolic‐exchange rate imaging with hyperpolarized [1‐13C] pyruvate using spectral‐spatial excitation

Within the last decade hyperpolarized [1‐¹³C] pyruvate chemical‐shift imaging has demonstrated impressive potential for metabolic MR imaging for a wide range of applications in oncology, cardiology, and neurology. In this work, a highly efficient pulse sequence is described for time‐resolved, multislice chemical shift imaging of the injected substrate and obtained downstream metabolites. Using spectral‐spatial excitation in combination with single‐shot spiral data acquisition, the overall encoding is evenly distributed between excitation and signal reception, allowing the encoding of one full two‐dimensional metabolite image per excitation. The signal‐to‐noise ratio can be flexibly adjusted and optimized using lower flip angles for the pyruvate substrate and larger ones for the downstream metabolites. Selectively adjusting the excitation of the down‐stream metabolites to 90° leads to a so‐called “saturation‐recovery” scheme with the detected signal content being determined by forward conversion of the available pyruvate. In case of repetitive excitations, the polarization is preserved using smaller flip angles for pyruvate. Metabolic exchange rates are determined spatially resolved from the metabolite images using a simplified two‐site exchange model. This novel contrast is an important step toward more quantitative metabolic imaging. Goal of this work was to derive, analyze, and implement this “saturation‐recovery metabolic exchange rate imaging” and demonstrate its capabilities in four rats bearing subcutaneous tumors. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

The continuous epidural infusion of ropivacaine 0.1% with 0.5 μg·mL−1 sufentanil provides effective postoperative analgesia after total hip replacement: a pilot study

PURPOSE: To assess the analgesic efficacy and functional outcome of postoperative epidural infusion of ropivacaine combined with sufentanil in a randomized, controlled trial. METHODS: Thirty-two ASA I-III patients undergoing elective total hip replacement (THR) were included. Lumbar epidural block using 0.75% ropivacaine was combined with either propofol sedation or general anesthesia for surgery. On arrival in the recovery room, the epidural infusion was commenced at a rate in mL calculated as follows: (height in cm - 100) x 0.1. Eleven patients received an epidural infusion of ropivacaine 0.1% with 0.5 microg x mL(-1) sufentanil (Group R+S0.5), ten patients ropivacaine 0.1% with 0.75 microg x mL(-1) sufentanil (Group R+S0.75), and 11 patients ropivacaine 0.1% with 1 microg x mL(-1) sufentanil (Group R+S1) over a postoperative study period of 44 hr. All patients had access to iv piritramide via a patient-controlled analgesia (PCA) device. Postel-Merle-d'Aubigné scoring system (PMA score) was assessed preoperatively, three weeks after surgery, and three months after surgery by an orthopedic surgeon blinded to study group. RESULTS: Motor block was negligible in all three groups. After eight hours of epidural infusion, sensory block had regressed completely in all patients. There was no significant difference with regard to visual analogue scale (VAS) scores (at rest: P = 0.55, on movement: P = 0.63), consumption of rescue medication (P = 0.99), patient satisfaction (P = 0.22), and the incidence of adverse events. All treatment regimens provided effective postoperative analgesia with only a minimal use of supplemental opioid PCA. There was no difference between groups regarding orthopedic PMA score (pain: P = 0.24, mobility: P = 0.65, and ability to walk: P = 0.44). CONCLUSION: Ropivacaine 0.1% with 0.5 microg x mL(-1) sufentanil for postoperative analgesia after THR provides efficient pain relief and, compared with 0.75 and 1 microg x mL(-1) sufentanil, reduces sufentanil consumption without compromise in patient satisfaction, VAS scores, and functional outcome.     

Time course of reversed cardiac remodeling after pulmonary endarterectomy in patients with chronic pulmonary thromboembolism

To evaluate the time course of reversed remodeling after pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension(CTPEH), we studied 22 patients (age: 60 ± 13 years) with MRI immediately before, 1 month, 3 months, and 6 months after PEA. MRI included assessment of biventricular function, aortic and pulmonary artery(PA) flow, and right ventricular (RV) overload using the ratio of RV-to-biventricular diameter. Except in one patient, who died 2 months post-surgery, clinical improvement occurred early after PEA (NYHA class: 3.3 ± 0.6 to 1.5 ± 0.8, p < 0.0001) with a decrease of systolic pulmonary artery pressures (79 ± 14 to 44 ± 14 mmHg, p < 0.0001). At 1 month post PEA, RV end-diastolic volumes decreased (198 ± 72 to 137 ± 59 ml, p < 0.0001), and the RV ejection fraction (EF) improved (31 ± 9 to 47 ± 10%, p < 0.0001). No further significant improvement in pulmonary pressures or RV function occurred at 3 months or 6 months. Although no significant change was found in LV volumes or function, aortic flow increased early after surgery. PEA had only a beneficial effect on right PA flow. RV overload decreased early after PEA (ratio RV-to-biventricular diameter: before: 0.67 ± 0.04, after: 0.54 ± 0.06, p < 0.0001), showing a good correlation with the improvement in RVEF (r = 0.7, P < 0.0001). In conclusion, reversed cardiac remodeling occurs early after PEA, to slow down after 1 month. At 6 months, cardiac remodeling is incomplete as witnessed by low-normal RV function and residually elevated PA pressures.