François Brunotte

Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus

We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.

[18F]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy

PurposeTo evaluate, in breast cancer patients treated by neoadjuvant chemotherapy, the predictive value of reduction in FDG uptake with regard to complete pathological response (pCR).MethodsForty-seven women with non-metastatic, non-inflammatory, large or locally advanced breast cancer were included. Tumour uptake of FDG was evaluated before and after the first course of neoadjuvant chemotherapy. Four indices were used: maximal and average SUV without or with correction by body surface area and glycaemia (SUVmax, SUVavg, SUVmax-BSA-G and SUVavg-BSA-G, respectively). The predictive value of reduction in FDG uptake with respect to pCR was studied by logistic regression analysis. Relationships between baseline [18F]FDG uptake and prognostic parameters were assessed.ResultsThe relative decrease in FDG uptake (ΔSUV) after the first course of neoadjuvant chemotherapy was significantly greater in the pCR group than in the non-pCR group (p < 0.000066). The four FDG uptake indices were all strongly correlated with each other. A decrease in SUVmax-BSA-G of 85.4% ± 21.9% was found in pCR patients, versus 22.6% ± 36.6% in non-pCR patients. ΔSUVmax-BSA-G <−60% predicted the pCR with an accuracy of 87% and ΔSUVs were found to be only factors predictive of the pCR at multivariate analysis. An elevated baseline SUV was associated with high mitotic activity (p < 0.0016), tumour grading (p < 0.004), high nuclear pleomorphism score (p < 0.03) and negative hormonal receptor status (p < 0.005).ConclusionIn breast cancer patients, after only one course of neoadjuvant chemotherapy the reduction in FDG uptake is an early and powerful predictor of pCR.

Right ventricular overload and induced sustained ventricular tachycardia in operatively “repaired” tetralogy of Fallot

The aim of the study was to evaluate the main predictors of the inducibility of sustained ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot. Thirty-five patients (age 12 +/- 6 years) underwent right-sided cardiac catheterization, echocardiography, radionuclide angiography and ventricular stimulation; 10 had (group 1) and 25 had no (group 2) sustained VT. Group 1 patients were significantly older at the time of surgery and had longer follow-up periods (7 +/- 3 vs 4 +/- 4 years, p less than 0.02; and 12 +/- 4 vs 5 +/- 2 years, p less than 0.001, respectively). Right ventricular (RV) systolic pressure, end-systolic and end-diastolic normalized RV volumes were higher in group 1 (48 +/- 14 vs 38 +/- 11 mm Hg, p less than 0.05; 1.23 +/- 0.2 vs 0.86 +/- 0.17, p less than 0.001; and 2.35 +/- 0.37 vs 1.70 +/- 0.22, p less than 0.001, respectively). RV end-diastolic pressure, left ventricular and RV ejection fractions were similar in the 2 groups. A stepwise discriminant analysis was made to predict patients with inducible sustained VT (group 1): Time period from surgery to follow-up (p less than 0.001), normalized RV end-systolic volume (p less than 0.002) and RV systolic pressure (p = 0.01) were higher in group 1 and allowed classification of 90% of patients in group 1 and 96% in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

In Newly Diagnosed Diffuse Large B-Cell Lymphoma, Determination of Bone Marrow Involvement with 18F-FDG PET/CT Provides Better Diagnostic Performance and Prognostic Stratification Than Does Biopsy

In newly diagnosed diffuse large B-cell lymphoma (DLBCL), the sensitivity of bone marrow biopsy (BMB) for the detection of bone marrow involvement (BMI) can be low because of sampling error if the BMI is focal and not diffuse. Although 18F-FDG PET/CT is now recommended for initial staging of DLBCL, its role regarding BMI is not well defined. This study evaluated whether 18F-FDG PET/CT, in comparison with BMB, is useful for the detection of BMI and predictive of outcome. Methods: From the 142 patients who were referred to our institution for newly diagnosed DLBCL from June 2006 to October 2011, 133 were retrospectively enrolled in our study. All patients underwent whole-body 18F-FDG PET/CT and a BMB from the iliac crest before any treatment. 18F-FDG PET/CT was considered positive for BMI in cases of uni- or multifocal bone marrow 18F-FDG uptake that could not be explained by benign findings on the underlying CT image or history. A final diagnosis of BMI was considered if the BMB was positive or if the positive 18F-FDG PET/CT was confirmed by guided biopsy or targeted MR imaging or in cases of disappearance of focal bone marrow uptake concomitant with the disappearance of uptake in other lymphoma lesions on 18F-FDG PET/CT monitoring. Progression-free survival and overall survival were analyzed using the Cox proportional hazards regression model. Results: Thirty-three patients were considered to have BMI. Of these, 8 were positive according to the BMB and 32 were positive according to 18F-FDG PET/CT. 18F-FDG PET/CT was more sensitive (94% vs. 24%; P < 0.001), showed a higher negative predictive value (98% vs. 80%), and was more accurate (98% vs. 81%) than BMB. Median follow-up was 24 mo (range, 1–67 mo). Twenty-nine patients (22%) experienced recurrence or disease progression during follow-up, and 20 patients died (15%). In multivariate analysis, only the International Prognostic Index and the 18F-FDG PET/CT bone marrow status were independent predictors of progression-free survival (P = 0.005 and 0.02, respectively), whereas only the International Prognostic Index remained an independent predictor of overall survival (P = 0.004). Conclusion: Assessment of BMI with 18F-FDG PET/CT provides better diagnostic performance and prognostic stratification in newly diagnosed DLBCL than does BMB.

Effects of low-frequency electrical stimulation of quadriceps and calf muscles in patients with chronic heart failure.

PURPOSE The aim of this preliminary study was to evaluate the effects of low-frequency electrical stimulation of quadriceps and calf muscles on global exercise capacities, skeletal muscle metabolism, calf muscle volume, and cardiac output in patients with chronic heart failure. METHODS Fourteen patients with chronic heart failure (mean age of 56.4 years +/- 9.1 SD; mean radionuclide left ventricular ejection fraction of 22.3% +/- 8.8 SD) underwent 5 weeks (1 hour per day, 5 days per week) of low-frequency electrical stimulation of quadriceps and calf muscles. RESULTS Low-frequency electrical stimulation was well tolerated. Exercise capacity and the calf muscles volumes increased significantly after rehabilitation in comparison with prior rehabilitation (the peak oxygen consumption increased from 17.2 mL/(kgmin) +/- 5.3 SD to 19.6 mL/(kgmin) +/- 5.9 SD; the anaerobic threshold increased from 12.3 mL/(kgmin) +/- 3.2 SD to 15.2 mL/(kgmin) +/- 3.3 SD; the 6-minute walking test increased from 419 m +/- 122 SD to 459 m +/- 114.3 SD; the gastrocnemius volume increased from 259.4 cm3 +/- 58 SD to 273.4 cm3 +/- 74 SD, and the soleus volume increased from 319 cm3 +/- 42.9 SD to 338 cm3 +/- 52.5 SD). The New York Heart Association class was improved after rehabilitation. The P-31 nuclear magnetic resonance spectroscopy of gastrocnemius muscle data were not significantly modified after rehabilitation, thereby inferring that no significant improvement of the muscle metabolism occurred. These data reinforce the hypothesis of an increased muscle mass during stimulation. It is noteworthy that the electrical stimulation did not increase cardiac output at any stage; an enormous asset in favor of this mode of rehabilitation. CONCLUSION These results suggest that low-frequency muscular electrical stimulation is well tolerated, induces an increased exercise capacity in patients with chronic heart failure, without an undesirable increase in cardiac output.

Major prognostic impact of persistent microvascular obstruction as assessed by contrast-enhanced cardiac magnetic resonance in reperfused acute myocardial infarction

The aim of this study was to compare the prognostic significance of microvascular obstruction (MO) and persistent microvascular obstruction (PMO) as assessed by cardiac magnetic resonance (CMR) in patients with acute myocardial infarction (AMI). CMR was performed in 184 patients within the week following successfully reperfused first AMI. First-pass images were performed to evaluate extent of MO and late gadolinium-enhanced images to assess PMO and infarct size (IS). Major adverse cardiac events (MACE) were collected at 1-year follow-up. MO and PMO were found in 127 (69%) and 87 (47%) patients, respectively. By using univariate logistic regression analysis, high Global Registry of Acute Coronary Events (GRACE) risk score (odds ratio [OR] 95% confidence interval [CI]: 3.6 [1.8–7.4], p < 0.001), IS greater than 10% (OR [95% CI]: 2.7 [1.1–6.9], p = 0.036), left ventricular ejection fraction less than 40% (OR [95% CI]: 2.4 [1.1–5.2], p = 0.027), presence of MO (OR [95% CI]: 3.1 [1.3–7.3], p = 0.004) and presence of PMO (OR [95% CI]:10 [4.1–23.9], p < 0.001) were shown to be significantly associated with the outcome. By using multivariate analysis, presence of MO (OR [95% CI]: 2.5 [1.0–6.2], p = 0.045) or of PMO (OR [95% CI]: 8.7 [3.6–21.1], p < 0.001), associated with GRACE score, were predictors of MACE. Presence of microvascular obstruction and persistent microvascular obstruction is very common in AMI patients even after successful reperfusion and is associated with a dramatically higher risk of subsequent cardiovascular events, beyond established prognostic markers. Moreover, our data suggest that the prognostic impact of PMO might be superior to MO.

Interim 18F-FDG PET SUVmax Reduction Is Superior to Visual Analysis in Predicting Outcome Early in Hodgkin Lymphoma Patients

PET performed after 2 cycles of chemotherapy (PET2) allows prediction of outcome in most patients with Hodgkin lymphoma (HL). Visual analysis using a 5-point scale was proposed to assess PET response, but a semiquantitative approach using maximum standardized uptake value (SUVmax) reduction between baseline and interim PET was shown to be superior to the 5-point scale in patients with diffuse large B-cell lymphoma and may also improve the accuracy of interim PET interpretation in HL. To compare the clinical usefulness of both methods in HL patients, we analyzed PET2 according to visual and ΔSUVmax criteria in a retrospective single-center study. Methods: From 2007 to 2010, 59 consecutive patients with a first diagnosis of HL were treated with 4–8 cycles of anthracycline-based chemotherapy. Radiotherapy was performed in 19 responding patients with localized disease. PET was done at baseline (PET0) and after 2 cycles of chemotherapy, and treatment was not modified according to the PET2 result. PET2 was interpreted using the 5-point scale (positivity for score 4 or 5). The SUVmax reduction between PET0 and PET2 (ΔSUVmax) was computed for all patients, and patients with a ΔSUVmax greater than 71% were considered good responders. Results: When the 5-point scale was used, 46 patients (78%) achieved a negative PET2 result, 7 of whom failed treatment (negative predictive value, 85%). Forty-nine patients (83%) had a ΔSUVmax greater than 71%, 6 of whom failed treatment (negative predictive value, 88%). The PET2 positive predictive value was significantly better for ΔSUVmax (70%) than for the 5-point scale (46%). When ΔSUVmax was used, 6 (46%) of the 13 PET2-positive patients could be reclassified as good responders. Although visual PET2 positivity was related to a lower 4-y progression-free survival (45%) compared with PET2 negativity (81%, P < 0.002), ΔSUVmax (>71 vs ≤71%) was more accurate for identifying patients with different 4-y progression-free survivals (82% vs. 30%; P < 0.0001). In multivariate analysis using the international prognosis score and ΔSUVmax as covariates, ΔSUVmax remained the unique independent predictor for progression-free survival (P = 0.0001; relative risk, 8.1). Conclusion: Semiquantitative analysis was more accurate than visual analysis based on the 5-point scale to interpret PET2 and predict the outcome of HL patients. These encouraging results warrant further confirmation in larger and prospective series.

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

Thoracic aortic aneurysm and aortic dissection (TAA and AD) are an important cause of sudden death. Familial cases could account for 20% of all cases. A genetic heterogeneity with two identified genes (FBN1 and COL3A1) and three loci (3p24–25 or MFS2/TAAD2, 5q13–q14 and 11q23.2–24) has been shown previously. Study of a single family composed of 179 members with an abnormally high occurrence of TAA/AD disease. A total of 40 subjects from three generations were investigated. In addition to five cases of stroke and three cases of sudden death, there were four cases of AD and four cases of TAA in adults. In all, 11 cases of patent ductus arteriosus (PDA) were observed, two of which were associated with TAA and one with AD. Segregation analysis showed that the distribution of these vascular abnormalities was more likely compatible with a single genetic defect with an autosomal dominant pattern of inheritance. There were no clinical signs of Marfan, Elhers–Danlos vascular type or Char syndromes. Genetic linkage analysis was performed for seven genes or loci implicated in familial TAA/AD disease (COL3A1, FBN1, 3p24–25 or MFS2/TAAD2, 5q13–q14 and 11q23.2–q24), Char syndrome (TFAP2B) or autosomal recessive PDA (12q24). Using different genetic models, linkage with these seven loci was excluded. Familial TAA/AD with PDA is likely to be a particular heritable vascular disorder, with an as yet undiscovered Mendelian genetic basis.

DOTAGA-anhydride: a valuable building block for the preparation of DOTA-like chelating agents.

A DOTA derivative that contains an anhydride group was readily synthesized by reacting DOTAGA with acetic anhydride and its reactivity was investigated. Opening the anhydride with propylamine led to the selective formation of one of two possible regioisomers. The structure of the obtained isomer was unambiguously determined by 1D and 2D NMR experiments, including COSY, HMBC, and NOESY techniques. This bifunctional chelating agent offers a convenient and attractive approach for labeling biomolecules and, more generally, for the synthesis of a large range of DOTA derivatives. The scope of the reaction was extended to prepare DOTA-like compounds that contained various functional groups, such as isothiocyanate, thiol, ester, and amino acid moieties. This versatile building block was also used for the synthesis of a bimodal tag for SPECT or PET/optical imaging.

Time course of NAA T2 and ADCw in ischaemic stroke patients: 1H MRS imaging and diffusion-weighted MRI

BACKGROUND AND PURPOSE Proton spectroscopy and quantitative diffusion-weighted imaging (DWI) were used to investigate the pertinence of N-acetyl aspartate (NAA) as a reliable marker of neuronal density in human stroke. METHODS The time courses of tissue water apparent diffusion coefficient (ADC(w)) and metabolite T2 were investigated on a plane corresponding to the largest area of cerebral infarction, within and outside the site of infarction in 71 patients with a large cortical middle cerebral artery territory infarction. RESULTS Significant reductions are seen in NAA T2 deep within the infarction during the period comprised between 5 and 20 days postinfarction; the relaxation times appearing to normalise several months after stroke. After an acute reduction in ADC(w), the pseudonormalisation of ADC(w) occurs at 8-12 days after the ischaemic insult. The minimum in N-acetyl aspartate T2 relaxation times and the pseudonormalisation of ADC(w) appear to coincide. CONCLUSIONS The data suggest that modifications in the behaviour of the observed proton metabolites occur during the period when the vasogenic oedema is formed and cell membrane integrity is lost. For this reason, NAA may not be a reliable marker of neuronal density during this period.