Efficacy of a short sandwich protocol,methotrexate, gemcitabine,L-asparaginase and dexamethasone chemotherapy combined with radiotherapy,in localised newly diagnosed NK/T-cell lymphoma: A French retrospective study

Extranodal NK/T-cell lymphoma, nasal type is a rare and aggressive form of lymphoma, historically associated with poor prognosis. We report here the results of a retrospective multi-centre study evaluating the efficacy of MGAD (methotrexate, gemcitabine, L-asparaginase and dexamethasone) regimen (two cycles) combined with ‘sandwich’ radiotherapy in 35 patients with localised newly diagnosed extranodal NK/T-cell lymphoma. Thirty-two patients (91%) reached complete remission. With a long median follow-up of 59.6 months, progression-free and overall survival at 2 and 5 years were 71%, 80% and 53%, 73%, respectively. Around one third of the patients experienced relapse within a median time of 14.5 months. Side-effects were manageable with grades 3–4 cytopenias, mucositis and infection in 50%, 24% and 21% of the cases, respectively. Monitoring of asparaginase activity was performed in 13 patients and showed inactivation of the drug in seven (54%) patients. Our results indicate that a short therapy by sandwich MGAD chemoradiotherapy is a tolerable and effective treatment option in localised newly diagnosed extranodal NK/T-cell lymphoma patients.     

Forelimb dyskinesia mediated by high‐frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N‐methyl‐d‐aspartate receptors

Dyskinesia is a major side‐effect of chronic l ‐DOPA administration, the reference treatment for Parkinson’s disease. High‐frequency stimulation of the subthalamic nucleus (STN‐HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the l ‐DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN‐HFS‐evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for l ‐DOPA‐induced dyskinesias, focusing on the role of NR2B‐containing N‐methyl‐d ‐aspartate receptors (NR2B/NMDARs). We applied STN‐HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN‐HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr¹⁴⁷²) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN‐HFS‐induced forelimb dyskinesia was decreased in a dose‐dependent manner by systemic injections of CP‐101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non‐selective N‐methyl‐d ‐aspartate receptor antagonist, MK‐801.     

Phenotypic study of human gingival fibroblasts in a medium enriched with platelet lysate

Background: The modulation abilities of gingival fibroblasts open new therapeutic strategies for the treatment of vascular diseases (e.g., aneurism) and irradiation burns. Culture media are classically supplemented with animal sera to provide nutriments. Unfortunately, because of their potential for interspecies transmission of microorganisms, these media are not used for cells destined for human transplantation. This preliminary phenotypic study aims to test a serum‐free (SF) culture medium for human gingival fibroblasts (hGF) supplemented with human platelet lysates (PLs) for rapid cell expansion. Methods: An SF medium was first elaborated to compete with hGF proliferation in a reference medium containing 10% fetal bovine serum (BSmedium). Adhesion, proliferation, and doubling kinetics were run in the presence of PLs (SF+PL). Cytoskeletal proteins were analyzed and chromosomal abnormalities were evaluated by karyotype analyses. The SF+PL influence on secretion of molecules implied in tissue remodeling (i.e., matrix metalloproteinases [MMPs], their tissue inhibitors [TIMPs], and several growth factors) was studied. Results: SF+PL increased the proliferation rate 1.5‐fold in a week compared to BSmedium. Cytoskeleton protein expression was similar in BSmedium and in SF+PL. Chromosomal abnormalities were rare in SF+PL. MMP‐1, MMP‐2, MMP‐3, MMP‐7, MMP‐9, TIMP‐1, and the growth factors interleukin‐1β and ‐4 and transforming growth factor‐β1 secretions were stable during the experiment. TIMP‐2 and interleukin‐6 were slightly decreased in SF+PL compared to BSmedium. Conclusion: While waiting confirmation from a proteomic approach, this SF culture medium could allow a secured faster hGF proliferation adapted for human cell transplant therapy.     

Relationships between radiographic parameters and spinopelvic muscles in adult spinal deformity patients

While the clinical impact of coronal and sagittal alignment in adult spinal deformity (ASD) patients (pts) is established, there is a paucity of data in terms of axial plane deformity and potential association between muscle degeneration and 3D deformity. The purpose of this study was to analyze spinopelvic muscles characteristics in association with the 3D deformity of ASD patients. This is a prospective cohort study; primary lumbar scoliosis patients (Cobb > 20°) were enrolled and sustained a low-dose X-rays with 3D spinal reconstructions and a fat/water separation MRI (from C7 to the knee).Volumetric 3D reconstructions and fat infiltration (FI) of 6 muscles groups were performed. Relationships between muscular data, radiographic parameters and health-related quality of life were investigated. Patients were stratified and compared based on the SRS classification, the odontoid-hip axis (ODHA) angle (> or < 6.1°) and occurrence of rotatory subluxation. Twenty-eight patients were enrolled with a mean age of 60 ± 16yo and mean body mass index of 26 ± 4 kg/m2 without differences between groups. There were a moderate sagittal malalignment and a Cobb angle of 45 ± 11° (table). Muscular volume was smaller in patients with more severe deformity (p > 0.05). Pts with ODHA > 6.1° or pelvic incidence minus lumbar lordosis  > 10° had significantly higher FI for the 6 muscular groups, patients with pelvic tilt  > 20° had significantly higher FI for erector spinae, hip flexors and extensors (p < 0.05). SF36-PCS significantly correlated with the muscular volume; SRS and Oswestry disability index correlated with the erectors spinae volume (p < 0.05). This study analyzed for the first time the relationship between 3D radiographic parameters and muscular characteristics in ASD. Sagittal malalignment is associated with increased FI and decreased muscle volumes with poor outcomes. These slides can be retrieved under Electronic Supplementary Material.     

(18)F-fluoride PET for monitoring therapeutic response in Paget's disease of bone.

A prospective study was undertaken to evaluate PET with (18)F-fluoride for monitoring the response to bisphosphonates in Paget's disease of bones. METHODS: Fourteen patients with a monostotic (n = 9) or a polyostotic form (n = 5) of Paget's disease were scanned at baseline and at 1 and 6 mo after the beginning of treatment. Dynamic acquisition and arterial blood sampling were used to calculate the influx constant Ki (by both the Patlak [Ki-PAT] method and the nonlinear regression [Ki-NLR] method). Kinetic modeling was compared with maximal standardized uptake values (SUV(max)) and biochemical markers of bone remodeling. RESULTS: Baseline uptake of (18)F-fluoride by pagetic bones was significantly higher than in normal bones (P < 0.05). One month after the start of treatment, SUV(max), Ki-PAT, Ki-NLR, and K(1) (the unidirectional clearance of fluoride from plasma to the whole of the bone tissue) decreased significantly by 27.8%, 27.9%, 27.5%, and 23.6%, respectively. Biochemical markers were already normalized in 6 of 9 patients with monostotic disease, although all had high (18)F-fluoride uptake values. Six months after the start of treatment, (18)F-fluoride uptake further diminished by 22.3%-25.6%. Biochemical markers were normal in all but 2 patients, although 10 of 14 patients still showed high (18)F-fluoride uptake. One patient did not respond to treatment and maintained high uptake of (18)F-fluoride throughout the study. SUV(max) correlated with both Ki-PAT and Ki-NLR at baseline, 1 mo, and 6 mo (P < 0.05). Moreover, the change of SUV(max) between baseline and 1 mo, as well as between baseline and 6 mo, also correlated with the change of Ki-PAT and Ki-NLR (P < 0.05). CONCLUSION: Our results show that (18)F-fluoride PET can be used to noninvasively and accurately monitor the efficacy of treatment with bisphosphonates in Paget's disease of bones. SUV(max) correlates with Ki-PAT and Ki-NLR and, interestingly, varies in the same manner as kinetic indices. Therefore, the use of SUV(max) could avoid the need for dynamic acquisition and arterial blood sampling and would facilitate the use of whole-body PET in a clinical setting.     

In Utero Exposure to Maternal Diabetes Impairs Vascular Expression of Prostacyclin Receptor in Rat Offspring

OBJECTIVE

To evaluate modifications of arterial structure, gene expression, and function in our model of rats exposed to maternal diabetes.

RESEARCH DESIGN AND METHODS

Morphometric analyses of elastic vessels structure and determination of thoracic aortic gene expression profile with oligonucleotide chips (Agilent, G4130, 22k) were performed before the onset of established hypertension (3 months).

RESULTS

Arterial parameters of in situ fixed thoracic aorta were not significantly different between control mother offspring and diabetic mother offspring (DMO). The aortic gene expression profile of DMO is characterized by modifications of several members of the arachidonic acid metabolism including a twofold underexpression of prostacyclin receptor, which could contribute to decreased vasodilatation. This was confirmed by ex vivo experiments on isolated aortic rings. Pharmacological studies on conscious rats showed that systolic blood pressure decline in response to a PGI₂ analog was impaired in DMO rats.

CONCLUSIONS

These results suggest an abnormal vascular fetal programming of prostacyclin receptor in rats exposed in utero to maternal hyperglycemia that is associated with impaired vasodilatation and may be involved in the pathophysiology of hypertension in this model.Cardiovascular disease is one of the greatest health burdens worldwide. Cardiovascular risk is determined not only by conventional risk factors in adult life but also by early life events resulting in resetting of key physiological functions. Modifications of the intrauterine environment during specific windows of fetal development are now recognized as important causes of fetal stress (1), leading to several responses such as loss of structure/function and preemptive adaptations to an adverse postnatal environment (2), and finally to adult diseases such as metabolic abnormalities and hypertension (1,3).Nutrition is one of the major intrauterine environmental factor that alters expression of the fetal genome and may have lifelong consequences leading to limited physiological function and disease (4,5). Particularly, the consequences of maternal diabetes in the adult offspring are gaining attention (6,7). Interestingly, both metabolic disorders and raised blood pressure have increasingly been associated with in utero exposure to maternal diabetes (8).Several animal models such as modification of maternal nutrition, reduction of uterine supply, or glucocorticoid treatment have contributed to the understanding of some of the mechanisms involved in fetal/perinatal programming by showing that kidney changes and alterations of hormones regulation are involved in the fetal programming of hypertension (3,9,10). More recently, alterations of vascular function in several models of fetal programming also have been implied (11,12). In previous works (13,14), we developed a rat streptozotocin-induced model of fetal exposure to maternal diabetes, characterized by moderate levels of maternal hyperglycemia, normal gestation, and delivery with healthy pups without intrauterine growth retardation. Diabetic mother offspring (DMO) presented an established hypertension at 6 months of age (9). The exact mechanism leading to late onset of hypertension in this model is unknown. The present work was designed to evaluate changes in vascular properties through genetic profile and pharmacological studies in DMO compared with control mother offspring (CMO) at prehypertensive stage.     

Performance of existing risk scores around heart transplantation: validation study in a 4‐year cohort

Several risk scores exist to help identify best candidate recipients for heart transplantation (HTx). This study describes the performance of five heart failure risk scores and two post‐HTx mortality risk scores in a French single‐centre cohort. All patients listed for HTx through a 4‐year period were included. Waiting‐list risk scores [Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC), Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE‐HF) and Get With The Guidelines‐Heart Failure (GWTG‐HF)] and post‐HTx scores Index for Mortality Prediction After Cardiac Transplantation (IMPACT and CARRS) were computed. Main outcomes were 1‐year mortality on waiting list and after HTx. Performance was assessed using receiver operator characteristic (ROC), calibration and goodness‐of‐fit analyses. The cohort included 414 patients. Waiting‐list mortality was 14.0%, and post‐HTx mortality was 16.3% at 1‐year follow‐up. Heart failure risk scores had adequate discrimination regarding waiting‐list mortality (ROC AUC for HFSS = 0.68, SHFM = 0.74, OPTIMIZE‐HF = 0.72, MAGGIC = 0.70 and GWTG = 0.77; all P‐values <0.05). On the contrary, post‐HTx risk scores did not discriminate post‐HTx mortality (AUC for IMPACT = 0.58, and CARRS = 0.48, both P‐values >0.50). Subgroup analysis on patients undergoing HTx after ventricular assistance device (VAD) implantation (i.e. bridge‐to‐transplantation) (n = 36) showed an IMPACT AUC = 0.72 (P < 0.001). In this single‐centre cohort, existing heart failure risk scores were adequate to predict waiting‐list mortality. Post‐HTx mortality risk scores were not, except in the VAD subgroup.     

Bankart repair versus Bankart repair plus remplissage: an in vitro biomechanical comparative study

Purpose

To biomechanically compare Bankart lesion repair alone and Bankart lesion repair associated with infraspinatus capsulotenodesis described as «remplissage», in the treatment of combined Bankart and Hill-Sachs lesions.

Methods

Seven pairs (right and left) of cadaveric shoulders have been tested, first without any lesion and then after performing a combined Bankart and Hill-Sachs lesions. For each pair, the specimens were then randomly assigned for Bankart lesion repair alone on one side or for Bankart lesion repair associated with remplissage on the other side. During tests, the shoulder was placed at 90° of abduction and at maximal external rotation, which value was recorded. A 50 N postero-anterior load was then applied to the proximal humerus, and the stiffness was calculated from the obtained load–displacement curve.

Results

Bankart and Hill-Sachs lesions significantly (p < 0.05) decreased joint stiffness compared with intact joint. Bankart lesion repair alone did not restore stiffness to the level of intact, while adding the remplissage to the Bankart lesion repair did. External rotation was significantly increased after creation of the Bankart and Hill-Sachs lesion; Bankart repair restored the external rotation to the level of intact, while Bankart lesion repair associated with remplissage significantly decreased external rotation compared with intact and to Bankart lesion repair alone.

Conclusion

In cadaveric shoulders with combined Bankart and Hill-Sachs lesions, Bankart lesion repair associated with remplissage restored intact joint stiffness contrary to Bankart lesion repair alone. This increase in stiffness was associated with a decrease in external rotation.

     

Diagnostic value of quantitative assessment of cardiac <Superscript>18</Superscript>F-fluoro-2-deoxyglucose uptake in suspected cardiac sarcoidosis

Objective

The identification of cardiac sarcoidosis is challenging as there is no gold standard consensually admitted for its diagnosis. The aim of this study was to evaluate the diagnostic value of the assessment of cardiac dynamic ¹⁸F-fluoro-2-deoxyglucose positron emission tomography (¹⁸F-FDG PET/CT) and net influx constant (Ki) in patients suspected of cardiac sarcoidosis.

Methods

Data obtained from 30 biopsy-proven sarcoidosis patients suspected of cardiac sarcoidosis who underwent a 50-min list-mode cardiac dynamic ¹⁸F-FDG PET/CT after a 24 h high-fat and low-carbohydrate diet were analyzed. A normalized coefficient of variation of quantitative glucose influx constant, calculated as the ratio: standard deviation of the segmental Ki (min^?1)/global Ki (min^?1) was determined using a validated software (Carimas^® 2.4, Turku PET Centre). Cardiac sarcoidosis was diagnosed according to the Japanese Ministry of Health and Welfare criteria. Receiving operating curve analysis was performed to determine sensitivity and specificity of cardiac dynamic ¹⁸F-FDG PET/CT analysis to diagnose cardiac sarcoidosis.

Results

Six out of 30 patients (20%) were diagnosed as having cardiac sarcoidosis. Myocardial glucose metabolism was significantly heterogeneous in patients with cardiac sarcoidosis who showed significantly higher normalized coefficient of variation values compared to patients without cardiac sarcoidosis (0.513?±?0.175 vs. 0.205?±?0.081; p?=?0.0007). Using ROC curve analysis, we found a cut-off value of 0.38 for the diagnosis of cardiac sarcoidosis with a sensitivity of 100% and a specificity of 91%.

Conclusions

Our results suggest that quantitative analysis of cardiac dynamic ¹⁸F-FDG PET/CT could be a useful tool for the diagnosis of cardiac sarcoidosis.