Evaluation of non-stenotic carotid atherosclerotic plaques with combined FDG-PET imaging and CT angiography in patients with ischemic stroke of unknown origin.

OBJECTIVES: Non-stenotic plaques are an underestimated cause of ischemic stroke. Imaging aspects of high-risk carotid plaques can be identified on CT angiography (CTA) and 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) imaging. We evaluated in patients with cryptogenic ischemic stroke the usefulness of FDG-PET-CTA. METHODS: 44 patients imaged with CTA and FDG-PET were identified retrospectively. Morphological features were identified on CTA. Intensity of FDG uptake in carotid arteries was quantified on PET. RESULTS: Patients were imaged 7 ± 8 days after stroke. 44 non-stenotic plaques with increased 18F-FDG uptake were identified in the carotid artery ipsilateral to stroke and 7 contralateral. Most-diseased-segment TBR on FDG-PET was higher in artery ipsilateral vs. contralateral to stroke (2.24 ± 0.80 vs. 1.84 ± 0.50; p < .05). In the carotid region with high FDG uptake, prevalence of hypodense plaques and extent of hypodensity on CTA were higher in artery ipsilateral vs. contralateral to stroke (41% vs. 11%; 0.72 ± 1.2 mm2 vs. 0.13 ± 0.43 mm2; p < .05). CONCLUSIONS: In patients with ischemic stroke of unknown origin and non-stenotic plaques, we found an increased prevalence of high-risk plaques features ipsilateral vs. contralateral to stroke on FDG-PET-CTA imaging suggesting a causal role for these plaques.

Oral microbiota and atherothrombotic carotid plaque vulnerability in periodontitis patients. A cross-sectional study.

BACKGROUND: An increased risk of atherothrombotic vascular events has been reported in periodontitis patients. Periodontitis is associated with dysbiotic subgingival biofilms and bacteremia. OBJECTIVE: We hypothesized (a) that the oral microbiome is associated with the carotid microbiome and (b) that periodontitis could contribute to plaque vulnerability. The aim of this study was to determine the associations between periodontitis, the carotid microbiome, and the local innate immune response in carotid atherothrombotic plaques vulnerable to rupture. METHODS: In this cross-sectional study, 45 patients admitted for carotid endarterectomy underwent a preoperative periodontal examination. The volume of intraplaque hemorrhage reflected by the hemoglobin level released in carotid-conditioned media was considered as a criterion of carotid plaque vulnerability. Levels of antibodies against periodontal bacteria were determined in sera. The signature of the oral microbiota was assessed by microbial whole-genome sequencing, nested PCR, and immunostaining in carotid plaque samples. Markers of neutrophil recruitment (leukotriene B4), neutrophil activation (myeloperoxidase, defensins), and cytokines were measured in carotid-conditioned media and/or plasma. RESULTS: All patients exhibited periodontitis. One hundred and forty-four bacterial genera were detected in the carotid microbiome. While Streptococcus was found in 84% of the carotid samples, periodontitis-associated genera were detected in 21%. P. gingivalis DNA and gingipains were also identified in carotid samples. There were significant inverse correlations between periodontal attachment loss/serum anti-P. gingivalis Immunoglobulin A and cytokine inhibiting neutrophils (all P < .01). There were also significant positive correlations between lipopolysaccharides, myeloperoxidase/human neutrophil peptides1-3, and hemoglobin levels (all P < .01). CONCLUSIONS: In patients at risk of stroke, the carotid plaque microbiome was highly diverse and compatible with an oral origin. Periodontitis was significantly associated with neutrophil activation markers and plaque vulnerability to rupture.

Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study.

BACKGROUND: Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage. METHODS: In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434. FINDINGS: Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116 (70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority point estimate -9·1%; 95% CI -∞ to -1·0; p=0·0038; and superiority test p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141 patients (95% CI 91·0-98·4) in the OCS group and 165 patients (100%; 97·8-100·0) in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients (83·1-93·9) for the OCS group compared with 146 (88·1%) of 165 patients (81·8-92·8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%) of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015). The primary safety endpoint was met (0·23 lung graft-related serious adverse events in the OCS group compared with 0·28 events in the control group [point estimate -0·045%; 95% CI -∞ to 0·047; non-inferiority test p=0·020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1). INTERPRETATION: The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation. FUNDING: TransMedics Inc.

Reverse Regulatory Pathway (H2S / PGE2 / MMP) in Human Aortic Aneurysm and Saphenous Vein Varicosity.

Hydrogen sulfide (H2S) is a mediator with demonstrated protective effects for the cardiovascular system. On the other hand, prostaglandin (PG)E2 is involved in vascular wall remodeling by regulating matrix metalloproteinase (MMP) activities. We tested the hypothesis that endogenous H2S may modulate PGE2, MMP-1 activity and endogenous tissue inhibitors of MMPs (TIMP-1/-2). This regulatory pathway could be involved in thinning of abdominal aortic aneurysm (AAA) and thickening of saphenous vein (SV) varicosities. The expression of the enzyme responsible for H2S synthesis, cystathionine-γ-lyase (CSE) and its activity, were significantly higher in varicose vein as compared to SV. On the contrary, the endogenous H2S level and CSE expression were lower in AAA as compared to healthy aorta (HA). Endogenous H2S was responsible for inhibition of PGE2 synthesis mostly in varicose veins and HA. A similar effect was observed with exogenous H2S and consequently decreasing active MMP-1/TIMP ratios in SV and varicose veins. In contrast, in AAA, higher levels of PGE2 and active MMP-1/TIMP ratios were found versus HA. These findings suggest that differences in H2S content in AAA and varicose veins modulate endogenous PGE2 production and consequently the MMP/TIMP ratio. This mechanism may be crucial in vascular wall remodeling observed in different vascular pathologies (aneurysm, varicosities, atherosclerosis and pulmonary hypertension).

Intraplaque hemorrhage, a potential consequence of periodontal bacteria gathering in human carotid atherothrombosis.

Periodontal diseases are multifactorial inflammatory diseases, caused by a bacterial biofilm involving both innate and adaptative immunity, characterized by the destruction of tooth-supporting tissues. In the context of periodontitis, the spread of weak pathogenic bacteria into the bloodstream has been described. These bacteria will preferentially localize to existing clot within the circulation. Atherothrombosis of the carotid arteries is a local pathology and a common cause of cerebral infarction. Intraplaque hemorrhages render the lesion more prone to clinical complications such as stroke. The main objective of this study is to explore the biological relationship between carotid intraplaque hemorrhage and periodontal diseases. This study included consecutive patients with symptomatic or asymptomatic carotid stenosis, admitted for endarterectomy surgical procedure (n=41). In conditioned media of the carotid samples collected, markers of neutrophil activation (myeloperoxidase or MPO, DNA-MPO complexes) and hemoglobin were quantified. To investigate the presence of DNA from periodontal bacteria in atherosclerotic plaque, PCR analysis using specific primers was performed. Our preliminary results indicate an association between neutrophil activation and intraplaque hemorrhages, reflected by the release of MPO (p<0,01) and MPO-DNA complexes (p<0,05). Presence of DNA from periodontitis-associated bacteria was found in 32/41 (78%) atheromatous plaque samples. More specifically, DNA from Pg, Tf, Pi, Aa was found in 46%, 24%, 34% and 68% of the samples, respectively. Hemoglobin levels were higher in conditioned media in carotid samples where the bacteria were found, but this was not statistically significant. Our data confirm the relationship between intraplaque hemorrhage and neutrophil activation. In addition, the presence of periodontal bacteria DNA in carotid atheromatous plaque, may contribute to this activation. Further analysis is needed to fully explore the raw data and specimens.

Spontaneous and isolated dissection of the superior mesenteric artery: proposal of a management algorithm.

BACKGROUND: Spontaneous and isolated dissection of the superior mesenteric artery (SIDSMA) is a rare pathology, and the treatment of symptomatic forms is not consensual. The objective of this study was to analyze the management of a series of patients presenting a symptomatic SIDSMA within a structure taking care of intestinal vascular emergencies. METHODS: From January 2010 to January 2014, the patients presenting a symptomatic SIDSMA were included retrospectively. The clinical and radiologic data as well as the treatment and the follow-up were analyzed. RESULTS: Nine patients were included. Among them, 2 patients presenting with acute mesenteric ischemia were revascularized surgically in emergency, and 1 patient presenting a rupture of a superior mesenteric artery aneurysm had an arteriography followed by medical care. The 6 other patients received medical treatment. Among these, 2 patients developed mesenteric angina requiring surgical revascularization during the follow-up. CONCLUSIONS: The revascularization of spontaneous and isolated dissections of the superior mesenteric artery is indicated in the cases complicated with acute mesenteric ischemia, aneurysmal rupture, or in the event of appearance of mesenteric angina or aneurysmal evolution. It should also be discussed in the event of failure of the medical treatment.

Decreased PGE2 content reduces MMP-1 activity and consequently increases collagen density in human varicose vein.

UNLABELLED: Varicose veins are elongated and dilated saphenous veins. Despite the high prevalence of this disease, its pathogenesis remains unclear. AIMS: In this study, we investigated the control of matrix metalloproteinases (MMPs) expression by prostaglandin (PG)E2 during the vascular wall remodeling of human varicose veins. METHODS AND RESULTS: Varicose (small (SDv) and large diameter (LDv)) and healthy saphenous veins (SV) were obtained after surgery. Microsomal and cytosolic PGE-synthases (mPGES and cPGES) protein and mRNA responsible for PGE2 metabolism were analyzed in all veins. cPGES protein was absent while its mRNA was weakly expressed. mPGES-2 expression was similar in the different saphenous veins. mPGES-1 mRNA and protein were detected in healthy veins and a significant decrease was found in LDv. Additionally, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), responsible for PGE2 degradation, was over-expressed in varicose veins. These variations in mPGES-1 and 15-PGDH density account for the decreased PGE2 level observed in varicose veins. Furthermore, a significant decrease in PGE2 receptor (EP4) levels was also found in SDv and LDv. Active MMP-1 and total MMP-2 concentrations were significantly decreased in varicose veins while the tissue inhibitors of metalloproteinases (TIMP -1 and -2), were significantly increased, probably explaining the increased collagen content found in LDv. Finally, the MMP/TIMP ratio is restored by exogenous PGE2 in varicose veins and reduced in presence of an EP4 receptor antagonist in healthy veins. CONCLUSIONS: In conclusion, PGE2 could be responsible for the vascular wall thickening in human varicose veins. This mechanism could be protective, strengthening the vascular wall in order to counteract venous stasis.

Impaired high-density lipoprotein anti-oxidant capacity in human abdominal aortic aneurysm.

AIMS: Abdominal aortic aneurysm (AAA) is a particular form of atherothrombotic disease characterized by the dilation of the aortic wall and the presence of an intraluminal thrombus (ILT). The objective of the present study was to evaluate the pro-oxidant properties of the ILT and to characterize the anti-oxidant capacity of high-density lipoproteins (HDLs). METHODS AND RESULTS: Our results show that ILT, adventitia, and plasma from AAA patients contained high concentrations of lipid and protein oxidation products. Mediators produced within or released by the thrombus and the adventitia were shown to induce reactive oxygen species (ROS) production by cultured aortic smooth muscle cells (AoSMCs) and to trigger the onset of apoptosis (an increase in mitochondrial membrane potential). Iron chelation limited these effects. Both concentration and functionality of HDLs were altered in AAA patients. Plasma levels of Apo A-I were lower, and small HDL subclasses were decreased in AAA patients. Circulating HDLs in AAA patients displayed an impaired capacity to inhibit copper-induced low-density lipoprotein oxidation and AoSMC ROS production. Western blot analyses of HDLs demonstrated that myeloperoxidase is associated with HDL particles in AAA patients. CONCLUSION: ILT and adventitia are a source of pro-oxidant products, in particular haemoglobin, which may impact on the wall stability/rupture in AAA. In addition, HDLs from AAA patients exhibit an impaired anti-oxidant activity. In this context, restoring HDL functionality may represent a new therapeutic option in AAA.

A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor.

Prostacyclin (PGI2) and its mimetics (iloprost, treprostinil, beraprost and MRE-269) are potent vasodilators (via IP-receptor activation) and a major therapeutic intervention for pulmonary hypertension (PH). These PGI2 mimetics have anti-proliferative and potent vasodilator effects on pulmonary vessels. We compared the relaxant effects induced by these recognized IP-agonists in isolated human pulmonary arteries (HPA) and veins (HPV). In addition, using selective antagonists, the possible activation of other prostanoid relaxant receptors (DP, EP4) was investigated. Iloprost and treprostinil were the more potent relaxant agonists when both vessels were analyzed. HPA were significantly more sensitive to iloprost than to treprostinil, pEC50 values: 7.94±0.06 (n=23) and 6.73±0.08 (n=33), respectively. In contrast, in HPV these agonists were equipotent. The relaxations induced by treprostinil were completely or partially inhibited by IP-antagonists in HPA or HPV, respectively. The effects of the IP-agonists were not significantly modified by the EP4 antagonist. Finally, DP-antagonists inhibited the relaxations induced by treprostinil in HPV, suggesting that the DP-receptor plays a role in treprostinil-induced relaxation in the HPV. These data suggest that iloprost and treprostinil should be the most effective clinically available agonists to decrease pulmonary vascular resistance and to prevent oedema formation (by similar decrease in HPA and HPV resistance) in PH patients.

Long-term survival after hepatic and pulmonary resection of colorectal cancer metastases.

BACKGROUND: Recent changes in adjuvant therapies improved the prognosis of metastatic colorectal cancers. Curative resection may be considered, even for both pulmonary and hepatic metastases, but prognostic factors are not well identified. METHODS: From 1995 to 2010, 69 patients had curative resection of pulmonary metastases of colorectal cancer; 31 had also hepatic metastases. Pulmonary and hepatic resection occurred in 2 steps (87%). We studied overall and disease-free survival and prognostic factors. RESULTS: Primary tumor location was the rectum in 10 cases (32%). Pulmonary metastases were synchronous in 5 (16%) and bilateral in 6 (19%). One patient (3%) died after pulmonary surgery. One (3%) had positive surgical margins for pulmonary metastases. Median overall survival was 44 months (5-year rate = 36%); median disease-free survival was 22 months (5-year rate = 10%). Factors linked to impaired survival were rectal primary tumor (P = 0.04) and bilateral pulmonary metastases (P = 0.02) for overall survival, and pulmonary metastase ≥ 20 mm (P = 0.04) for disease-free survival. CONCLUSION: When associated to adjuvant therapy, complete resection of pulmonary and hepatic metastases of colorectal cancer allows long-term survival in one third of the patients.

Survival benefit of lung transplant for cystic fibrosis since lung allocation score implementation.

RATIONALE: The survival benefit of lung transplantation (LT) in adult patients with cystic fibrosis (CF) is debated. OBJECTIVES: We sought to assess the survival benefit of LT in adult patients with CF. METHODS: We used data from the United Network for Organ Sharing Registry to identify adult patients with CF on a wait list for LT in the United States between 2005 and 2009. Survival times while on the wait list and after LT were modeled by use of a Cox model that incorporated transplantation status as a time-dependent covariate. Evolution in lung allocation score (LAS) while on the wait list was used as a surrogate for disease severity. We fitted a model for the joint distribution of survival and longitudinal disease process (LAS over time). MEASUREMENTS AND MAIN RESULTS: A total of 704 adult patients with CF were registered on a wait list during the study period. The cumulative incidence of LT was 39.3% (95% confidence interval, 35.6-42.9%) at 3 months and 64.7% (61.0-68.4%) at 12 months, whereas the incidence of death while on the wait list at the same times was 8.5% (6.4-10.6%) and 12.9% (10.3-15.5%), respectively. Survival after LT was 96.5% (94.7-98.2%) at 3 months; 88.4% (85.1-91.8%) at 12 months; and 67.8% (59.9-76.8%) at 3 years. LT conferred a 69% reduction in the instantaneous risk of death (51-80%). The interaction between LAS and LT was significant: the higher the LAS, the greater the survival benefit of LT (P < 0.001). CONCLUSIONS: LT confers a survival benefit for adult patients with CF.

Absence of inflammatory conditions in human varicose saphenous veins.

INTRODUCTION: Varicose veins affect one-third of the adult population in western countries, but their pathogenesis is incompletely characterized. One of the most controversial issues is the role of inflammation. It is well known that inflammation involves an increased expression/activity of inflammatory mediators. OBJECTIVE: The aim of this study was to investigate the presence or absence of mediators of inflammation in varicose as compared to healthy veins. METHODS AND RESULTS: Using immunohistofluorescence on varicose and healthy veins, we investigated the presence of inflammatory cells. They were not detectable. Venous wall C-reactive protein (CRP), fibrinogen (EIA) and pentraxin-3 (Western blot) content were measured. CRP was significantly lower in varicose veins, but no difference was found for fibrinogen or pentraxin-3 between varicose and healthy veins. No difference was observed for enzymes involved in inflammation and responsible for arachidonic acid metabolism such as the acute phase reactant secreted phospholipase A2-IIA and cyclooxygenase-2, as determined in varicose and healthy veins by Western blot and real-time qRT-PCR. CONCLUSIONS: Our experiments demonstrate no increase in the presence of mediators of inflammation in varicose as compared to healthy veins, suggesting that inflammation may not be an important contributor to the pathogenesis of varicose veins.

Effects of a multimodal management strategy for acute mesenteric ischemia on survival and intestinal failure.

BACKGROUND & AIMS: Acute mesenteric ischemia (AMI) is an emergency with a high mortality rate; survivors have high rates of intestinal failure. We performed a prospective study to assess a multidisciplinary and multimodal management approach, focused on intestinal viability. METHODS: In an Intestinal Stroke Center, we developed a multimodal management strategy involving gastroenterologists, vascular and abdominal surgeons, radiologists, and intensive care specialists; it was tested in a pilot study on 18 consecutive patients with occlusive AMI, admitted to a tertiary center from July 2009 to November 2011. Patients with left ischemic colitis, nonocclusive AMI, chronic mesenteric ischemia, and other emergencies were excluded. Patients received specific medical management: revascularization of viable small bowel and/or resection of nonviable small bowel; 12 patients received arterial revascularization. We evaluated the percentages of patients who survived for 30 days or 2 years, the number with permanent intestinal failure, and morbidity. Lengths and rates of intestinal resection were compared with or without revascularization, and in patients with early or late-stage disease. RESULTS: Patients were followed up for a mean of 497 days (range, 7-2085 d); 95% survived for 30 days, 89% survived for 2 years, and 28% had morbidities within 30 days. Intestinal resection was necessary for 7 cases (39%), with mean lengths of intestinal resection of 30 cm and 207 cm, with or without revascularization, respectively (P = .03). Among patients with early or late-stage AMI, rates of resection were 18% and 71%, respectively (P = .049). Patients with early stage disease had shorter lengths of intestinal resection than those with late-stage disease (7 vs 94 cm; P = .02), and spent less time in intensive care (2.5 vs 49.8; P = .02). CONCLUSIONS: A multidisciplinary and multimodal management approach might increase survival of patients with AMI and prevent intestinal failure.

The hedgehog system machinery controls transforming growth factor-ß-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-ß1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-ß pathway in human lung fibroblasts. TGF-ß1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-ß1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-ß1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis.

From intraplaque haemorrhages to plaque vulnerability: biological consequences of intraplaque haemorrhages.

Intraplaque hemorrhages are mainly related to inward neoangiogenesis, initiated from the adventitia by lipid-dependent outwardly convected signals, and by the immaturity of these neovessels, allowing leaks and hemorrhages. Repeated intraplaque hemorrhages play a major role in the evolution of thrombotic occlusive disease, similar to the role of intraluminal thrombus in the progression of abdominal aortic aneurysm toward rupture. Red blood cells (RBCs) are an important source of unesterified cholesterol, because their membranes are particularly cholesterol rich. This unesterified cholesterol is rapidly organized in cholesterol crystals, highly toxic for cell and membranes. Oxidized cholesterol and LDL provoke the irreversible covalent aggregation of proteins, including hemoglobin, forming ceroids, which are also highly toxic. Hemoglobin play a major role of prooxydant molecules in this context, by its ability to release heme and iron, the main catalyser of oxidative reaction. In the context of type 2 diabetes, the oxidative potential of intraplaque-free hemoglobin play a predominant role in the progression of atherothrombotic disease toward clinical expression. Associated to RBC, intraplaque hemorrhages convey leukocyte, mainly neutrophils in human, and plasma zymogen that are the main source of proteases, including coagulation proteases, activation of the fibrinolytique system, release of leukocyte serine proteases and cathepsins and activation of MMPs. These proteases concentrate in the hemorrhagic/necrotic core rendered plaque highly vulnerable. An adaptive immune response takes place in the adventitia, in regard of hemorrhagic plaques, in relation to outwardly convected oxidized or proteolyzed neoantigens, and chemokinic signals. Finally, intraplaque hemorrhages and thrombi are the site of weak pathogen entrapment, which promote all these oxydative and proteolytic phenomenons.

Minimal residual disease in solid neoplasia: New frontier or red-herring?

Despite recent advances in prevention, screening, molecular characterization, and treatment, cancer evolution is still associated with late local, regional, or metastastic recurrence, even in early stages. Residual tumor cells can persist locally as cancer stem cells, in the blood flow as circulating tumor cells, and in distant organs as disseminated tumor cells or micrometastasis, defining three faces of minimal residual disease. Definition, preclinical models and clinical implications of these patterns will be detailed, with emphasis on overlaps and therapeutic implications, to determine whether minimal residual disease is only an old concept currently revisited, or a major shift in cancer paradigm.

Carotid endarterectomy in the acute phase of stroke-in-evolution is safe and effective in selected patients.

OBJECTIVE: This study documented with independent neurologic assessment the 30-day and 90-day outcomes in selected patients with severe internal carotid artery (ICA) stenosis who underwent carotid endarterectomy (CEA) in the acute phase of stroke-in-evolution (SIE). METHODS: From January 2003 to December 2010, data from patients who had surgery ≤2 weeks of an SIE with high-grade carotid stenosis were extracted from two prospectively collected databases. Clinical assessment was by the vascular neurologist using the National Institute of Health Stroke Scale (NIHSS) and the modified Rankin Scale score. All patients had computed tomography or magnetic resonance brain imaging ≤3 hours of stroke onset. Those eligible received thrombolysis. Duplex ultrasound imaging was initially used for the diagnosis of severe (≥60%) ICA stenosis, and further assessment was by magnetic resonance or computed tomography angiography, or both. Perioperative medical treatment and operative techniques were standardized. Stroke, death, major cardiac events, and functional outcome were analyzed. RESULTS: Twenty-seven patients underwent carotid revascularization in the acute phase of SIE. Fluctuating or progressive neurologic deficit was the presenting pattern in 20 patients and occurred after otherwise successful thrombolytic therapy in the remaining 7 (26%). Median NIHSS score at admission was 8. Median delay to surgery from the index event was 6 days. The mean degree of ICA stenosis was 87%. All patients received antiplatelet and statin therapy during the intervening period. Procedures were conventional CEA with patch angioplasty (polytetrafluoroethylene) in 26 patients (96.3%) and redo interposition bypass grafting in 1 patient. CEA was done under local anesthesia in 23 patients (85.2%), with selective shunting in 3 (13.0%), and under general anesthesia, with systematic shunting in 4. At discharge and at 1 and 3 months, no recurrent stroke or death, and one nonfatal myocardial infarction occurred in this series, with a 100% complete follow-up. At 3 months, all patients had a favorable functional outcome defined as a modified Rankin Scale score of ≤2. CONCLUSIONS: This short series demonstrates that CEA in the acute phase of SIE with strict selection criteria and close blood pressure monitoring is safe, even after recent thrombolytic therapy, and is effective in functional outcome at 3 months. Larger series of patients are required to confirm the safety and efficacy of this management.

Successful surgical treatment of a posttransplantation bronchovascular fistula involving the pulmonary vein.

Bronchovascular fistula is a rare complication after lung transplantation, which usually has a fatal outcome. We describe the case of successful surgical treatment of bronchovascular fistula of the left upper pulmonary vein and the left main bronchus.

Bioluminescent orthotopic mouse models of human localized non-small cell lung cancer: feasibility and identification of circulating tumour cells.

BACKGROUND: Preclinical models of non-small cell lung cancer (NSCLC) require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. METHODS: Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models. RESULTS: Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. CONCLUSIONS: Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model.

Early severe digestive complications after lung transplantation.

OBJECTIVE: This study aimed to describe and to analyze early severe digestive complications (ESDC) after lung transplantation (LT) in our center. METHODS: A retrospective study included 351 patients, who underwent LT without cardiopulmonary bypass (CPB) at our center between March 1988 and December 2009. There were 86 double LTs and 265 single LTs. ESDCs were defined as complications (1) occurring during the first 30 days after transplantation or during initial hospitalization if longer; (2) involving the gastrointestinal tract; and (3) jeopardizing survival or requiring invasive therapeutic procedure. Patients' characteristics, associated risk factors, and influence of ESDC on early outcome have been analyzed. RESULTS: During the first 30 days after LT or initial hospitalization if longer, 26 ESDCs occurred in 26 patients (rate 7.4%, sex ratio M/F 66%, mean age 56 ± 6 years). This included 10 acute cholecystitis (38%), four angiocholitis (15%), three perforated gastroduodenal ulcers (11%), three digestive perforations (11%), two intestinal occlusions (8%), two mesenteric ischemia (8%), and two acute pancreatitis (8%). ESDC occurred after a mean postoperative follow-up of 14 days (5-46), required emergency surgical treatment in 20 cases (77%), significantly prolonged the mean duration of hospitalization (96 days with ESDC vs 55 days without ESDC, p < 0.0001), and was responsible for death in five cases (19%). Surgical treatment included cholecystectomy (n = 11), bowel resection (n = 3), ulcer surgery (n = 2), subtotal colectomy (n = 2), Hartmann procedure (n = 1), and open coelioscopy (n = 1). Age and bilateral LT were found to be significant risk factors for ESDC in both uni- and multivariate analyses. CONCLUSION: ESDC occurred in 7.4% of patients after LT without CPB, and was responsible for longer in-hospital stay. Relevant risk factors included older age and bilateral LT, interfering with current debate regarding recipients' selection and procedure's choice.