Alessia Alunno

Indoleamine 2,3-Dioxygenase 1 (IDO1) Is Up-Regulated in Thyroid Carcinoma and Drives the Development of an Immunosuppressant Tumor Microenvironment

CONTEXT Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it appears to exert an immunosuppressive function as part of an acquired mechanism of immune escape mediated by the inhibition of lymphocyte proliferation and survival and by the induction of FoxP3+ T regulatory cells. OBJECTIVE The objective of the study was to evaluate IDO1 expression in thyroid carcinoma and demonstrate its immunosuppressive function in the context of thyroid tumors. SETTING IDO1 expression was evaluated by quantitative PCR in 105 papillary thyroid carcinomas (PTCs), 11 medullary thyroid carcinomas, six anaplastic thyroid carcinomas, and five thyroid carcinoma cell lines (TCCLs), by immunohistochemistry in 55 PTCs and by Western blotting in five TCCLs. FoxP3+ Treg lymphocyte density was evaluated by immunohistochemistry in 29 PTCs. IDO1 inhibitory effect on lymphocyte proliferation was tested in coculture experiments of TCCLs and activated lymphocytes. RESULTS IDO1 mRNA expression resulted significantly higher in all the analyzed thyroid carcinoma histotypes compared with normal thyroid. Interestingly, an increase of IDO1 mRNA expression magnitude could be observed with gain of aggressiveness (PTCs and medullary thyroid carcinomas ≪ anaplastic thyroid carcinomas). In PTCs, IDO1 mRNA expression magnitude correlated with IDO1 immunostaining intensity in cancer cells and with FoxP3+ Treg lymphocyte density in the tumor microenvironment. IDO1 was expressed in human thyroid cancer cell lines in vitro, and FTC-133 cells showed high kynurenine concentration in the conditioned medium and a strong suppressive action on the proliferation of activated lymphocytes in coculture experiments. CONCLUSIONS For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.

Aortic stiffness is increased in polymyalgia rheumatica and improves after steroid treatment

Background Inflammatory rheumatic diseases have been associated with increased cardiovascular risk and arterial stiffness. Polymyalgia rheumatica (PMR), a disease which affects primarily older people, is characterised by a systemic inflammatory response but little is known about aortic involvement in PMR. A study was undertaken to investigate whether aortic stiffness is increased in PMR and whether it improves after steroid treatment. Methods Thirty-nine patients with PMR (age 72±8 years, 44% men, blood pressure (BP) 134/75±16/9 mm Hg) and 39 age-, sex- and BP-matched control subjects underwent aortic pulse wave velocity (PWV) determination. Aortic augmentation as a measure of the impact of the reflection wave on central haemodynamics was also measured and corrected for heart rate. Twenty-nine of the patients were re-examined after 4 weeks of treatment with prednisone at a dose of 15 mg/day. Results Aortic PWV was higher in patients with PMR than in control subjects (12.4±4 vs 10.2±2 m/s, p<0.01). Treatment was followed by a reduction in heart rate (from 78±12 to 70±10 beats/min, p<0.001) and no significant change in BP. Aortic PWV decreased after prednisone treatment (from 11.8±3 to 10.5±3 m/s, p=0.015), and the difference was independent of BP and heart rate changes. The change in aortic PWV had a direct correlation with percentage change in plasma C reactive protein (r=0.40, p=0.037). Treatment was also associated with a significant reduction in aortic augmentation index (from 34±7% to 29±8%, p=0.012). Conclusions Polymyalgia rheumatica is associated with increased aortic stiffness which may improve upon reduction of systemic inflammation induced by treatment with glucocorticoids.

Cardiovascular disease in systemic sclerosis.

Cardiovascular (CV) system involvement is a frequent complication of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It still remains unclear if a premature atherosclerosis (ATS) occurs even in systemic sclerosis (SSc). Although microvascular disease is a hallmark of SSc, in the last few years a number of studies highlighted a higher prevalence of macrovascular disease in SSc patients in comparison to healthy individuals and these data have been correlated with a poorer prognosis. The mechanisms promoting ATS in SSc are not fully understood, but it is believed to be secondary to multi-system organ inflammation, endothelial wall damage and vasculopathy. Both traditional risk factors and endothelial dysfunction have been proposed to participate to the onset and progression of ATS in such patients. In particular, endothelial cell injury induced by anti-endothelial antibodies, ischemia/reperfusion damage, immune-mediated cytotoxicity represent the main causes of vascular injury together with an impaired vascular repair mechanism that determine a defective vasculogenesis. Aim of this review is to analyse both causes and clinical manifestations of macrovascular involvement and ATS in SSc.

Expansion of regulatory GITR

IntroductionCD4+CD25low/-GITR+ T lymphocytes expressing forkhead box protein P3 (FoxP3) and showing regulatory activity have been recently described in healthy donors. The objective of the study was to evaluate the proportion of CD4+CD25low/-GITR+ T lymphocytes within CD4+ T cells and compare their phenotypic and functional profile with that of CD4+CD25highGITR- T lymphocytes in systemic lupus erythematosus (SLE) patients.MethodsThe percentage of CD4+CD25low/-GITR+ cells circulating in the peripheral blood (PB) of 32 patients with SLE and 25 healthy controls was evaluated with flow cytometry. CD4+CD25low/-GITR+ cells were isolated with magnetic separation, and their phenotype was compared with that of CD4+CD25highGITR- cells. Regulatory activity of both cell subsets was tested in autologous and heterologous co-cultures after purification through a negative sorting strategy.ResultsResults indicated that CD4+CD25low/-GITR+ cells are expanded in the PB of 50% of SLE patients. Expansion was observed only in patients with inactive disease. Phenotypic analysis demonstrated that CD4+CD25low/-GITR+ cells display regulatory T-cell (Treg) markers, including FoxP3, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), transforming growth factor-beta (TGF-β), and interleukin (IL)-10. In contrast, CD4+CD25highGITR- cells appear to be activated and express low levels of Treg markers. Functional experiments demonstrated that CD4+CD25low/-GITR+ cells exert a higher inhibitory activity against both autologous and heterologous cells as compared with CD4+CD25highGITR- cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-β.ConclusionsPhenotypic and functional data demonstrate that in SLE patients, CD4+CD25low/-GITR+ cells are fully active Treg cells, possibly representing peripheral Treg (pTreg) that are expanded in patients with inactive disease. These data may suggest a key role of this T-cell subset in the modulation of the abnormal immune response in SLE. Strategies aimed at expanding this Treg subset for therapeutic purpose deserve to be investigated.

Persistent Type II Endoleak: Two Cases of Successful Sacotomy

Endovascular treatment of persistent type II endoleak may not resolve the complication. We report two cases of sacotomy performed to treat this problem: the first case was in an emergency setting for aneurismal sac rupture, and the second occurred in an elective surgery setting after several unsuccessful endovascular procedures. In both cases, sacotomy allowed us identify the bleeding sources without aortic cross-clamping and endograft explantation. By minimizing hemodynamic modifications and reducing operative time, this procedure can be carried out even in patients considered unfit for surgery. Sacotomy could be considered as an alternative in selected cases of persistent type II endoleak with aneurysm sac enlargement.

Central Hemodynamics and Arterial Stiffness in Systemic Sclerosis

Although microvascular disease is a hallmark of systemic sclerosis (SSc), a higher prevalence of macrovascular disease and a poorer related prognosis have been reported in SSc than in the general population. The simultaneous assessment of prognostically relevant functional properties of larger and smaller arteries, and their effects on central hemodynamics, has never been performed in SSc using the state-of-the-art techniques. Thirty-four women with SSc (aged 61±15 years, disease duration 17±12 years, and blood pressure 123/70±18/11 mm Hg) and 34 healthy women individually matched by age and mean arterial pressure underwent the determination of carotid-femoral (aortic) and carotid-radial (upper limb) pulse wave velocity (a direct measure of arterial stiffness), aortic augmentation (a measure of the contribution of reflected wave to central pulse pressure), and aortobrachial pulse pressure amplification (brachial/aortic pulse pressure) through applanation tonometry (SphygmoCor). Patients and controls did not differ by carotid-femoral or carotid-radial pulse wave velocity. Aortic augmentation index corrected for a heart rate of 75 bpm (AIx@75) was higher in women with SSc (30.9±16% versus 22.2±12%; P=0.012). Patients also had a lower aortobrachial amplification of pulse pressure (1.22±0.18 versus 1.33±0.25; P=0.041). SSc was an independent predictor of AIx@75 (direct) and pulse pressure amplification (inverse). Among patients, age, mean arterial pressure, and C-reactive protein independently predicted carotid-femoral pulse wave velocity. Age and mean arterial pressure were the only predictors of AIx@75. Women with SSc have increased aortic augmentation and decreased pulse pressure amplification (both measures of the contribution of reflected wave to central waveform) but no changes in aortic or upper limb arterial stiffness. Microvascular involvement occurs earlier than large artery stiffening in SSc.

Large Aortic Pseudoaneurysm and Subsequent Spondylodiscitis as a Complication of Endovascular Treatment of Iliac Arteries

Both aortic pseudoaneurysm following endovascular aortoiliac reconstruction and spondylodiscitis subsequent to endograft infections are rare complications. We present a case of aortic false aneurysm following iliac arteries treatment complicated by spondylodiscitis after its endovascular repair. In this patient, a huge aortic pseudoaneurysm was diagnosed and treated in an emergency setting a few days after the procedure. A left aortomonoiliac endograft was placed and a femoro-femoral crossover bypass was performed. Afterward, the patient developed a stent graft infection and a lumbar spondylodiscitis. The patient was managed with a conservative treatment and, after 4 years, he continues to live. Analyzing this case, we would like to point out the following aspects: any procedure, although well established and technically simple, can cause life-threatening complications; hematomas resulting from endovascular exclusion of large pseudoaneurysms could be drained, to prevent bacterial infections.

Beneficial Cardiovascular Effects of Low-dose Glucocorticoid Therapy in Inflammatory Rheumatic Diseases

To the Editor: We read with great interest the report by Mazzantini, et al 1. That retrospective analysis of a large cohort of patients with polymyalgia rheumatica (PMR) demonstrated that duration or cumulative dose of longterm low-dose glucocorticoid (GC) therapy was significantly associated with higher risk of arterial hypertension and acute myocardial infarction. However, in a multivariate analysis adjusted for traditional cardiovascular (CV) risk factors, arterial hypertension was confirmed as the only adverse effect significantly associated with treatment duration. It is thought that longterm GC treatment, especially at high dose, may indirectly increase the risk of CV disease through its well-recognized effect on traditional CV risk factors, including arterial hypertension, dyslipidemia, hyperglycemia, and obesity2. As summarized in Table 1, GC have been associated with higher incidence of subclinical atherosclerosis, and their detrimental effects on the CV system seem to occur at a preclinical phase. Although results are not uniform, duration of treatment exposure and higher cumulative … Address correspondence to Dr. Gerli; E-mail: gerlir{at}unipg.it

Type IB and type III endoleak 8 years after endovascular aneurysm repair.

An 86-year-old man was admitted to our hospital for abdominal pain and underwent an AneurRx bifurcated endograft (Medtronic AVE, Sunnyvale, Calif) implantation 8 years earlier for a 7-cm-diameter abdominal aortic aneurysm (AAA). His comorbidities were chronic atrial fibrillation, diabetes, dyslipidemia, chronic renal failure, hypertension, severe chronic obstructive pulmonary disease, and coronary artery disease. This patient also underwent an appendicectomy, inguinal hernioplasty, and cholecystectomy. An expandible abdominal mass was found during a clinical examination. Doppler ultrasound imaging and a computed tomography scan showed a severe increase of AAA diameter to 11 cm, associated with a type IB endoleak from the right leg displaced into the aneurysmal sac itself and to a type III endoleak due to detachment of the contralateral leg (A-C). Similar patients reported in the literature underwent open or endovascular treatment. Our patient was assessed by the anesthesiologist and cardiologist as being in American Society of Anesthesiologist class IV and therefore unfit for surgical repair, so an endovascular approach was planned. Through a left transaxillary access, a hydrophilic guidewire was introduced first into the endograft main body and its right leg and, thereafter, was captured by means of an Amplatz GooseNeck (EV3, Plymouth, Minn) introduced through the right common femoral artery. This was exchanged with a stiff guidewire, and a right aorto-uni-iliac Zenith Cook endograft (Cook Inc, Bloomington, Ind) was deployed. After surgical exposure of the left common femoral artery, an endovascular plug (Iliac Plug Cook Zip-20) was inserted in the ipsilateral common iliac artery. A femoro-femoral crossover bypass was completed with a 7-mm external-supported polytetrafluoroethylene graft (Vascutek Ltd, Inchinnan, Scotland). The procedure was performed with spinal anesthesia, the operating time was 135 minutes, and the contrast medium amount was 250 mL. The patient’s postoperative period was uneventful and he was discharged after 8 days, with no worsening of renal condition. A computed tomography scan at 6 months showed a good result of the procedure, with no endoleak and reduction of the AAA diameter (D).

Cryoglobulinemia in Sjögren Syndrome: A Disease Subset that Links Higher Systemic Disease Activity, Autoimmunity, and Local B Cell Proliferation in Mucosa-associated Lymphoid Tissue

Objective. To compare systemic disease activity by validated tools, i.e., the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI) and the Clinical ESSDAI (ClinESSDAI) scores, between primary Sjögren syndrome (pSS) with positive serum cryoglobulins and pSS without serum cryoglobulins. Methods. There were 825 consecutive patients with pSS who were retrospectively evaluated. Results. The ESSDAI and the ClinESSDAI scores were significantly higher in cryoglobulin-positive patients (p < 0.0001, for both scores). Cryoglobulinemia was significantly associated with these domains: constitutional (p = 0.003), lymphadenopathy (p = 0.007), glandular (p = 0.0002), cutaneous (p < 0.0001), peripheral nervous system (p < 0.0001), hematological (p = 0.004), and biological (p < 0.0001). Conclusion. Cryoglobulin-positive patients show the highest systemic activity in pSS.