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Penile metastasization is an uncommon condition, mostly derived from primitive advanced abdominal cancers, with disabling symptoms. Palliative treatment, in reason of poor prognosis patients, is frequently surgical with destructive management. We report two cases of penile metastasis, from primitive prostatic adenocarcinoma and primitive urothelial carcinoma, effectively managed with radiation treatment at our institution. A three-dimensional conformal radiation therapy with 42Gy to the planning target volume in 14 fractions was delivered. Radiation treatment was safely delivered, with low toxicity profile and achieved adequate symptoms control without compromising genitourinary functions. Radiation therapy should be considered in management of rare penile metastases.

Background: Patients who received a kidney transplant (KT) are described in literature as a group with a higher incidence of malignant neoplasms compared to the general population. Cancer development after KT has become a major issue, as a remarkable percentage of patients are diagnosed with cancer. Treatment of prostate cancer (PCa) in renal transplant recipients (RTRs) is a challenging issue that has been discussed by many authors over the years, but evidence is sparse and often includes conflicting reports. Among the therapeutic options for PCa in these patients, prostate irradiation represents a valuable alternative to surgery or other systemic therapies, as RTRs are often ineligible for these treatments. Objective: To report six cases treated at our institution between 1998 and 2017 and discuss the available literature. Methods: Patients’ characteristics were reported along with biochemical status at diagnosis, type of immunosuppressive treatment, radiation therapy technique, and dose to transplanted kidney. Results: Overall, prostate irradiation was delivered respecting the dose constraints and patients showed good tolerance with no reports of acute or late transplanted kidney injury. Conclusions: Our experience confirms that prostate radiotherapy for RTRs is feasible and effective and represents a valid option that should be considered by the multidisciplinary team.

Spores or pollen from a single species or even an individual plant or sporangium may vary in morphology and size to a point that equivalent forms found dispersed in the sediment have been described as different species or even genera. In addition, not all these organs were mature at the moment of burial, and therefore they do not always contain completely developed microspores. To understand these variations better, we studied the intraspecific and interspecific morphological variability of in situ spores of leptosporangiate ferns (belonging to the Osmundales, possible Osmundales, and Gleicheniales) from the Triassic of Europe. The material comes from the Anisian Kuhwiesenkopf/Monte Pra della Vacca flora of Italy and the Carnian Lunz flora of Austria. Our analysis is aimed at distinguishing the normal range of variability, differentiating developmental stages, and determining the frequency of abnormal spores. Results show significant variation in both size and surface ornamentation of spores from the same sporangia, as well as between sporangia and individuals, which may have various causes. Abortive spores are usually rare but occurwith higher frequency in different samples from some specimens, suggesting that they can serve to identify systemic defects in the plants. (C) 2021 Published by Elsevier B.V.

Background The presence of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) has diagnostic and prognostic value in patients with acute myocarditis (AM). Aim of our study was to quantify the changes in LGE extension (LGE%) early after AM and evaluate its relations with biventricular function and morphology. Methods We investigated 76 consecutive patients with AM (acute onset of chest pain/heart failure/ventricular arrhythmias not explained by other causes, and raised troponin) that met CMR criteria based on myocardial oedema at T2-weighted images and LGE on post-contrast images at median time of 6 days from onset of symptoms. We quantified LGE% at baseline and after 148 days in 49 patients. Results Median left ventricular (LV)-ejection fraction (EF) was 64% (interquartile range [Q1–Q3]: 56–67%), and LGE% 9.4% (Q1–Q3: 7.5–13.2%). LGE% was correlated with LV end-systolic volume index (LV-ESVi; r = + 0.34; p = 0.003). LGE% was inversely correlated with LV-EF (r = − 0.31; p = 0.009) and time to CMR scan (r = − 0.25; p = 0.028). In the 49 patients with a second CMR scan, despite no significant variations in LV-EF, a significant decrease of LGE% was observed (p < 0.0001) with a relative reduction of 42% compared with baseline. Patients showing increased LV-ESVi at follow up had a lower decrease of LGE% (p = 0.038). Conclusions In the acute phase of AM the LGE extension is a dynamic process that reflects impairment of LV function and is time dependent. LGE% appears one of the CMR parameters with the largest relative variations in the first months after AM

Patient: Female, 11-year-old Final Diagnosis: Pyogenic granuloma Symptoms: Not painful • bleeding tendency Medication: — Clinical Procedure: Diode Laser excision Specialty: Dentistry • Surgery Objective: Unknown ethiology Background: A pyogenic granuloma is an inflammatory exophytic lesion that can occur in the oral cavity. Numerous factors are involved in the etiology of the lesion and can lead to the tissue proliferation underlying the lesion’s characteristic appearance. The main treatment is surgical excision with careful curettage of the surrounding tissues. The use of a laser has been proposed because it enables performing deep and precise incisions with better hemostasis and less invasive procedures with less discomfort to patients. The aim of this study was to evaluate the possible advantages of using a diode laser in the surgical treatment of pyogenic granuloma, particularly in the management of a pediatric patient. Case Report: A swelling in the lower lip of an 11-year-old female patient was analyzed. After several evaluations, a 980-nm diode laser in continuous wave mode was chosen for excision of the lesion. The lesion was excised successfully with a diode laser as a conservative method that was nonstressful for the pediatric patient. Conclusions: Among the techniques for surgical excision of a lesion, the use of a diode laser has the following advantages: less invasiveness, absence of intra- and postoperative discomfort and pain, effective hemostasis with better control of bleeding, absence of scarring, better postoperative management, and greater patient compliance.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis characterized by hypereosinophilia. EGPA typically develops in three clinical phases, beginning with asthma, followed by tissue eosinophilia and finally systemic vasculitis. Cardiac involvement is the most important predictor of mortality; it occurs in approximately 15–60% of EGPA patients, a significant proportion of whom are asymptomatic and have normal electrocardiogram (ECG) and echocardiogram. Early detection and management of cardiac disease could positevely affect prognosis. Cardiovascular magnetic resonance (CMR) has emerged as the gold standard cardiac imaging technique in the evaluation of cardiomyopathies, due to its ability to reliably assess anatomy, function, and tissue characterization. Aim Purpose of this study was to assess the role of CMR in detecting cardiac disease in patients with EGPA in clinical remission. Methods A dedicated CMR protocol including functional analysis, and pre and post-contrast tissue characterization was performed in 11 patients with EGPA and the results were compared with 11 healthy subjects. Results EGPA patients had lower left ventricular ejection fraction compared to controls (56 ± 19 vs 68.7 ± 5.2, p value 0.02). Late gadolinium enhancement (LGE), representing replacement fibrosis, was positive in 9/11 (82%) patients, mainly with a non-ischemic pattern. In 3/11 (27%) patients a left ventricular thrombus was detected; in 3/11 (27%) patients myocardial edema was detected. CMR parameters of interstitial fibrosis were significantly more elevated in EGPA patients compared to controls. Conclusions Patients with EGPA in clinical remission showed a high cardiovascular burden as demonstrated by lower EF, signs of active inflammation, presence of interstitial and replacement fibrosis and intraventricular thrombosis. Further studies on wider populations are warranted to better understand how these findings could impact on prognosis and eventually guide therapy.

Cardiac Magnetic Resonance Imaging offers incremental value as diagnostic and prognostic tool in a wide range of cardiac diseases in front of the traditional non-invasive imaging techniques. Tissue characterization with and without non-nephrotoxic contrast-media offers the opportunity of precise assessment of myocardial fibrosis, edema and fatty infiltration. The quantitative assessment of myocardial mass, left and right ventricular volumes is considered a gold standard reference with important effects on clinical decision making and cost effectiveness ratio. The recent introduction of new sequences for mapping tissue resonance signal and myocardial strain will improve the diagnostic and prognostic accuracy for cardiovascular diseases.

Background: Previous reports have suggested that despite their dramatic presentation, patients with fulminant myocarditis (FM) might have better outcome than those with acute nonfulminant myocarditis (NFM). In this retrospective study, we report outcome and changes in left ventricular ejection fraction (LVEF) in a large cohort of patients with FM compared with patients with NFM. Methods: The study population consists of 187 consecutive patients admitted between May 2001 and November 2016 with a diagnosis of acute myocarditis (onset of symptoms Results: In the whole population (n=187), the rate of in-hospital death or heart transplantation was 25.5% versus 0% in FM versus NFM, respectively ( P P P P =0.003). Similar results for survival and changes in LVEF in FM versus NFM were observed in the subgroup (n=130) with viral myocarditis. None of the patients with NFM and LVEF ≥55% at discharge had a significant decrease in LVEF at follow-up. Conclusions: Patients with FM have an increased mortality and need for heart transplantation compared with those with NFM. From a functional viewpoint, patients with FM have a more severely impaired LVEF at admission that, despite steep improvement during hospitalization, remains lower than that in patients with NFM at long-term follow-up. These findings also hold true when only the viral forms are considered and are different from previous studies showing better prognosis in FM.

Type 1 Gaucher disease (GD1) is the most common lysosomal disorder, characterized by the accumulation of beta-glucocerebroside into the macrophages of several organs. Cardiac involvement is rare and referred to as restrictive cardiomyopathy, pulmonary hypertension, and calcifications of the valves and the aortic arch.To assess the cardiovascular status by cardiac magnetic resonance, including evaluation of tissue characterization, in GD1 patients.Nine GD1 patients were recruited at the Tertiary Care Centre for Rare Diseases at Ca' Granda Foundation IRCCS Hospital, Milan. The patients' records were available for a mean time of 6 ± 3 years. Medical history of cardiac disease and cardiovascular risk factors were surveyed by direct interview. Patients were scanned with a 1.5 Avanto Siemens using a comprehensive cardiovascular evaluation protocol, including morphologic and functional sequences with gadolinium contrast media, to assess early and late enhancement (late gadolinium enhancement). Echocardiography was performed to study the cardiac morphology and function, including the measurement of pulmonary pressure.Three patients showed left atrial enlargement, one patient showed moderate aortic stenosis in bicuspid valve with mild aortic dilatation, and one patient showed moderate mitral regurgitation. No evidence of myocardial late gadolinium enhancement was detected after gadolinium contrast media. Seven patients received enzyme replacement therapy for a median of 1 year, and two patients were evaluated at diagnosis.Although cardiac disease in Gaucher disease is considered rare and associated with particular genotypes, we have found two valvular diseases and mild left atrial enlargement in three out of nine patients. Further studies to evaluate the prognostic value of these findings are warranted.

A 47-year-old male was admitted to hospital for severe pericardial effusion; he had undergone surgical removal of cutaneous melanoma 10 years before. Echocardiography-guided pericardiocentesis revealed the presence of intramyocardial masses, which were better defined and characterized, together with pericardial involvement, by cardiac magnetic resonance. Pericardial fluid drained was negative for malignant cells, so video-assisted thoracoscopy was performed and pathologic tissue was biopsied, leading to the diagnosis of metastatic melanoma. Multidisciplinary approach and multimodality imaging played a key role in allowing the diagnostic workup in this complex case..

Background Cardiac magnetic resonance (CMR) has gained a central role in the diagnosis of cardiac amyloidosis (CA). While the diagnostic role of a typical late gadolinium enhancement (LGE) pattern (global subendocardial enhancement coupled with accelerated contrast washout) has been identified, evidence is still conflicting regarding the prognostic role of such examination. Methods and results We retrospectively analysed all patients referring for CMR at Niguarda Hospital (Milan, Italy) from January 2006 to January 2015 for suspected CA. Primary outcome was all-cause mortality. We identified 42 patients and divided them into 2 groups, according to the presence (Group A) or absence (Group B) of a typical amyloidosis LGE pattern. At the end of the followup (median 37 months, interquartile range 10–50 months), 31 patients (74%) had died. The hazard ratio for all-cause death was 3.2 (95% confidence interval [CI] 1.5–6.4, p < 0.01) for Group A versus Group B. Median survival time was 17 months (95% CI 7–42 months) for Group A and 70 months (95% CI 49–94 months) for Group B (p < 0.01). Multivariate analysis did not find any adjunctive predictive role for biventricular volumes and ejection fraction, indexed left ventricular mass, transmitral E/e’ at echocardiography, age at diagnosis or serum creatinine. Conclusion In our population, a typical LGE pattern was significantly associated with higher mortality. Moreover, patients with a typical LGE pattern showed a globally worse prognosis. Our data suggest that the LGE pattern may play a central role in prognostic stratification of patients with suspected CA, thus prompting further diagnostic and therapeutic measures

Background Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload. Methods In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A “moving window” approach was taken to understand the strength of the association at different levels of iron overload. Results The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, 30ms, weak relationship. All subjects with T2*20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1. Conclusions In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.

In patients with suspected or established hypertrophic cardiomyopathy (HCM), cardiovascular magnetic resonance (CMR) is widely employed for clinical management, given its multimodality approach capable of providing unique information on cardiac morphology, function, and tissue characterization. Guidance regarding all aspects of HCM diagnosis and management is provided by the comprehensive 2014 European Society of Cardiology (ESC) guidelines on HCM. CMR should be performed in centres with recognized expertise in heart muscle diseases, by physicians who are familiar with the whole HCM disease spectrum, differential diagnoses, and pitfalls. Because CMR is usually performed and interpreted by physicians not directly involved in patient care, detailed, bidirectional, and standardized communication becomes essential to obtain best results and avoid misinterpretation. In order to maximize the potential of CMR, it is of paramount importance that reporting physicians are provided with the essential clinical information and that, in turn, referring physicians are given a core set of CMR morphological, functional, and tissue characterization results following the test. This article aims to summarize the current knowledge on the role of CMR in managing HCM and, in addition, to review the importance of the clinical context in which the report is provided, in both adult and paediatric population, highlighting implications for clinical research.

BACKGROUND Cardiac magnetic resonance (CMR) is useful for the diagnosis of left ventricular noncompaction (LVNC). However, there are limited data regarding its prognostic value. OBJECTIVES The goal of this study was to evaluate the prognostic relevance of CMR findings in patients with LVNC. METHODS A total of 113 patients with an echocardiographic diagnosis of LVNC underwent CMR at 5 referral centers. CMR diagnostic criterion of LVNC (noncompacted/compacted ratio >2.3 in end-diastole) was confirmed in all patients. We performed left ventricular (LV) and right ventricular quantitative analysis and late gadolinium enhancement (LGE) assessments and analyzed the following LVNC diagnostic criteria: left ventricular noncompacted myocardial mass (LV-ncMM) >20% and >25%, total LV-ncMM index >15 g/m2, noncompacted/compacted ratio ≥3:1 ≥1 of segments 1 to 3 and 7 to 16 or ≥2:1 in at least 1 of segments 4 to 6 of the American Heart Association model. Outcome was a composite of thromboembolic events, heart failure hospitalizations, ventricular arrhythmias, and cardiac death. RESULTS At a mean follow-up of 48 ± 24 months, cardiac events (CEs) occurred in 36 patients (16 heart failure hospitalizations, 10 ventricular arrhythmias, 5 cardiac deaths, and 5 thromboembolic events). LV dilation, impaired LV ejection fraction, and LV-ncMM >20% was significantly more frequent in patients with CEs. LV fibrosis was detected by using LGE in 11 cases. CMR predictors of CEs were LV dilation and LGE. LGE was associated with improved prediction of CEs, compared with clinical data and CMR functional parameters in all 3 models. No CEs occurred in patients without dilated cardiomyopathy and/or LGE. CONCLUSIONS In patients with LVNC evaluated by using CMR, the degree of LV trabeculation seems to have no prognostic impact over and above LV dilation, LV systolic dysfunction, and presence of LGE.

Introduction Partial anomalous pulmonary venous return (PAPVR) is an uncommon cause of right ventricular dilation. It may be difficult to identify and often remains undiagnosed. Methods We reviewed the database of the Cardiac Magnetic Resonance (CMR) Laboratory of Niguarda Hospital, in order to identify the cases of PAPVR between 2008 and 2014. Results On a total number of 7832 CMR scans, we identified 24 patients with PAPVR (14 male, age 41 ± 18 y) corresponding to 0.31% of the total population. Only 30% of patients had been referred for known or suspected PAPVR, 33% of patients had been referred for suspected right ventricular arrhythmogenic dysplasia and 37% had been referred for other cardiac disease. PAPVR involved mainly the right pulmonary veins (18 patients, 75%) and in 62% of our cases was associated with an atrial septal defect. Eight patients underwent corrective surgery in our institution, which confirmed and successfully repaired the anomalies. Conclusions PAPVR is a rare congenital cardiac pathology which should be suspected in case of unexplained right chambers enlargement. CMR imaging allows an accurate anatomic and functional definition of this pathology and associated abnormalities. Early correction has an excellent prognosis and prevents long term complications like pulmonary hypertension, right ventricular failure and atrial fibrillation.

Necrotizing eosinophilic myocarditis (NEM) is a life-threatening condition that needs rapid diagnosis by endomyocardial biopsy and hemodynamic support usually by mechanical circulatory systems. We present the case of a 25-year-old Caucasian man who developed a refractory cardiogenic shock due to a NEM that was supported with a peripheral veno-arterial extracorporeal membrane oxygenation associated with intravenous steroids and recovered after 2 weeks. Further instrumental investigations lead to the final diagnosis of NEM as first presentation of eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), remarking the importance of identifying the systemic disorder that usually triggers the eosinophilic damage of the myocardium.

A 31-year-old man presenting with cardiogenic shock and left ventricular ejection fraction of 10% received the diagnosis of giant cell myocarditis by endomyocardial biopsy. The patient was successfully treated with high-dose inotropes, intra-aortic balloon pump and venoarterial extracorporeal membrane oxygenation for 21 days associated with combined immunosuppression (thymoglobulin, steroids, cyclosporine). Immunosuppression including thymoglobulin is the regimen associated with the highest probability of recovery in case of giant cell myocarditis. Immunosuppression needs time to be effective; thus, hemodynamic support must be guaranteed. In the present case, we observed that full recovery can be obtained up to 21 days of support with extracorporeal membrane oxygenation and adequate immunosuppression.

Cardiac Magnetic Resonance (CMR) has a relevant role in the comprehensive assessment of cardiac function...

Dispersed pollen grains of Lagenella martini from the Upper Triassic of Austria were studied by means of light, scanning and transmission electron microscopy. Pollen grains are medium-sized, monosulcate, finely striate with differently directed striations on distal and proximal surfaces. The aperture is usually broadly open with rounded ends. The ectexine is composed of a thick tectum, granular infratectum, and thin foot layer. The endexine shows fine lamellation in its outer part. Reported association of Lagenella martini with Stachyotaxus reproductive structures needs a more detailed investigation of the morphology and ultrastructure of the found pollen to make reliable conclusions. A comparison with known fossil and modern non-saccate striate pollen has shown that the studied pollen grains share a number of characters with some gymnosperms and angiosperms with most similarity to Vittatina-like pollen.

BACKGROUND: Late gadolinium enhancement (LGE) assessed with cardiovascular magnetic resonance (CMR) correlates with ventricular arrhythmias and survival in patients with structural heart disease. Whether some LGE characteristics may specifically improve prediction of arrhythmic outcomes is unknown. HYPOTHESIS: We sought to evaluate scar characteristics assessed with CMR to predict implantable cardioverter‐defibrillator (ICD) interventions in dilated cardiomyopathy of different etiology. METHODS: 96 consecutive patients evaluated with CMR received an ICD. Biventricular volumes, ejection fraction, and myocardial LGE were evaluated. LGE was defined as “complex” (Cx‐LGE) in presence of ≥1 of the following: ischemic pattern, involving ≥2 different coronary territories; epicardial pattern; global endocardial pattern; and presence of ≥2 different patterns. The primary endpoint was occurrence of any appropriate ICD intervention. A composite secondary endpoint of cardiovascular death, cardiac transplantation, or ventricular assist device implantation was also considered. RESULTS: During a median follow‐up of 75 months, 30 and 25 patients reached the primary and secondary endpoints, respectively. Cx‐LGE was correlated with a worse primary endpoint survival (log‐rank P < 0.001). Cx‐LGE and right ventricular end‐diastolic volume were independently associated with the primary endpoint (HR: 3.22, 95% CI: 1.56–6.65, P = 0.002; and HR: 1.06, 95% CI: 1.00–1.12, P = 0.045, respectively), but not with the secondary endpoint. CONCLUSIONS: Cx‐LGE identified at CMR imaging seems promising as an independent and specific prognostic factor of ventricular arrhythmias requiring ICD therapy in dilated cardiomyopathy of different etiologies.

OBJECTIVE The aim of this study was to compare myocardial T2* assessment with region-based (RB) T2* multiecho technique (CMRtools) with the pixel-wise (PW) inline myocardial T2* mapping (Siemens) in patients with thalassemia major for myocardial iron characterization. MATERIALS AND METHODS Forty-three thalassemia major patients were examined on a 1.5-T scanner using conventional gradient multiecho sequence. All the images were analyzed using both RB and PW T2* mapping. Coefficients of reproducibility (CRs) were used to assess the interoperator and intraobserver variability of each software. RESULTS The mean (SD) myocardial T2* values using RB and PW software resulted significantly different (30.7 [15] milliseconds [range, 4.8-52.6 milliseconds] vs 24.3 [10.5] milliseconds [range 4.6-38.2 milliseconds]; P < 0.0001). Interestingly, we found that SD had exponential relationship with T2* with evidence of increase in SD for T2* values greater than 20 milliseconds. For myocardial T2* values less than 20 milliseconds, intraobserver CR was 1.2 milliseconds for RB and 1.8 milliseconds for PW T2* mapping, and the interoperator CR was 3.4 and 1.6 milliseconds for RB and PW T2* mapping, respectively. Comparing iron overload classification by both software, we found that 7 patients (16%) were differently categorized using the standard T2* thresholds. CONCLUSIONS Our data show that RB and PW T2* mapping can be used interchangeably to measure severe myocardial and hepatic iron overload, whereas for borderline T2* values, we observed differences among the 2 methods causing different categorization.

Traditional echocardiography is unable to detect neither the early stages of iron overload cardiomyopathy nor myocardial iron deposition. The aim of the study is to determine myocardial systolic strain indices in thalassemia major (TM), and assess their relationship with T2*, a cardiac magnetic resonance index of the severity of cardiac iron overload. 55 TM cases with recent cardiac magnetic resonance (CMR-T2*) underwent speckle tracking analysis to assess regional myocardial strains and rotation. The results were compared with a normal control group (n = 20), and were subsequently analyzed on the basis of the CMR-T2* values. Two TM groups were studied: TM with significant cardiac iron overload (“low” T2*, ≤20 ms; n = 21), and TM with normal T2* values (“normal” T2*, >20 ms; n = 34). TM patients show significant, uniform decrease in circumferential and radial strain (P

The availability of three iron chelators improved the scenario of chelation therapy for transfusion-dependent thalassemia (TDT) patients, allowing tailoring of drugs according to the goals expected for each patient. The use of Deferiprone/Deferoxamine (DFP/DFO) combined in different schemes has been reported since many years. Only recently data from combination of Deferasirox/Deferoxamine (DFX/DFO) have been reported showing that it can be safe and efficacious to remove iron overload, particularly in patients who do not respond adequately to a single chelating agent. We investigated the efficacy, tolerability and safety of combined DFX/DFO in thalassemia major patients. Ten TDT patients have started DFX/DFO for different reasons: 1) lack of efficacy in removing liver/cardiac iron with monotherapy; 2) agranulocytosis on DFP; and 3) adverse events with elevated doses of monotherapies. The study design included: cardiac and hepatic T2* magnetic resonance (CMR), transient elastography evaluation (Fibroscan), biochemical evaluation, and audiometric and ocular examinations. The drugs' starting doses were: DFO 32 ± 4 mg/kg/day for 3-4 days a week and DFX 20 ± 2 mg/kg/day. Seven patients completed the one-year follow-up period. At baseline the mean pre-transfusional Hb level was 9.4 ± 0.4 g/dl, the mean iron intake was 0.40 ± 0.10mg/kg/day, the median ferritin level was 2254 ng/ml (range 644-17,681 ng/ml). Data available at 1 year showed no alteration of renal/hepatic function and no adverse events. A marked reduction in LIC (6.54 vs 11.44 mg/g dw at baseline) and in median ferritin (1346 vs 2254 ng/ml at baseline) was achieved. A concomitant reduction of non-transferrin-bound iron (NTBI) at six months was observed (2.1 ± 1.0 vs 1.7 ± 1.2 μM). An improvement in cardiac T2* values was detected (26.34 ± 15.85 vs 19.85 ± 12.06 at baseline). At 1 year an increased dose of DFX was administered (27 ± 6 mg/kg/day vs 20 ± 2 mg/kg/day at baseline, p=0.01) with a stable dose of DFO (32 ± 4 mg/kg/day). Combined or alternated DFX/DFO can be considered when monotherapy is not able to remove the iron overload or in the presence of adverse events.

The ADAMTS proteinases are a family of secreted, matrix-associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma (e.g., Porter et al., Int J Cancer 2006;118:1241-7). We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF-7 breast cancer cells by stable expression of either a wild-type (wt) or metalloproteinase-inactive (E362A) protein. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. These studies indicate that extracellular ADAMTS-15 has multiple actions on tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve syndecan-4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche-dependent.

We report the description of a cardiac mass occupying almost the entire right atrium in a young man who developed paroxysmal supraventricular tachycardia during endovascular treatment of intracranial arteriovenous fistulas. The mass was detected at echocardiographic examination, its tissue characteristics were defined with cardiac magnetic resonance and it was successfully surgically removed. The histopathological findings were consistent with a mixed type cavernous-capillary hemangioma of the heart. The intriguing co-existence of cardiac hemangioma and cerebral arteriovenous fistulas, to the best of our knowledge, has not been previously reported in English Literature.

We report the histopathologic correlates of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) in a patient with heart transplant who died for graft failure a few months after the scan. Extensive late enhancement was present at CMR, and it correlated with extensive fibrosis at histology. To our knowledge, this is the first time the findings on contrast enhancement CMR are compared to the histology of the whole heart in a heart transplantation patient, and the correspondence between LGE and fibrosis, demonstrated in other cardiac pathologies, is confirmed also in this particular setting.

353 ISSN 1758-1923 10.2217/BMT.13.36 © 2013 Future Medicine Ltd Breast Cancer Manage. (2013) 2(5), 353–356 Matrix metalloproteinases as cancer targets Breast cancer 5-year survival rates in the UK have improved up to 85% over the last decade due to earlier detection, better diagnosis and an increasing range of treatment options. Today, the majority of breast cancer-related deaths are due to the spread of tumor cells in the body. Therefore, the search for markers of aggressive disease and tumor cell dissemination is ongoing, along with ways to prevent or treat invasive spread. Matrix metalloproteinases (MMPs) have long been regarded as potential targets for anticancer therapy. In humans, the MMPs are a family of 24 secreted endopeptidases that can collectively degrade all protein components of the extracellular matrix. Although they play important roles in normal physiological processes, including wound healing and embryonic development, they are also often found to be expressed at higher levels in cancer tissues compared with their normal counterparts. Numerous studies have demonstrated their involvement in tumor invasion and metastasis in various cancer types [1]. The tumorspecific upregulation of MMPs, together with their prominent roles in cancer dissemination and a high protein sequence homology at their catalytic sites, led to the development in the 1980s and 1990s of smallmolecule active site-directed inhibitors for cancer therapy [2]. Initial preclinical studies had generated promising findings and these broadspectrum inhibitors went into clinical trials accompanied by great optimism. Unfortunately, these trials proved disappointing, with some of the inhibitors in fact promoting tumor progression and decreasing survival rates in some types of cancer [3,4]. Subsequent in-depth analysis of in vitro and in vivo studies revealed a number of factors that may in part explain the limited beneficial effects of treatment with broad-spectrum MMP inhibitors. The discrepancy in preclinical and clinical efficacy of these drugs is most probably related to the different disease stages used. While in vivo animal studies were most

Summary Although pulmonary function abnormalities in thalassaemia major (TM) were described in 1980, the pathogenetic mechanism is not clear and data are contradictory, probably because of study heterogeneity and the multifactorial nature of the pathogenesis. We retrospectively analysed 73 adult TM patients to evaluate the prevalence of pulmonary dysfunction in adult TM and investigate relationships with iron load. All patients underwent body plethysmography and carbon monoxide diffusion (DLCO) was assessed in 63, in addition to blood tests, echocardiogram and T2* myocardial and liver magnetic resonance imaging. Restrictive lung disease was present in 26 (35·6%) patients. Serum ferritin levels were higher in patients with restrictive pattern (1526 μg/l vs. 975 μg/l, P = 0·05). Restrictive lung disease did not correlate with cardiac or liver iron overload. However, considering only patients with serum ferritin >2500 μg/l, those with restrictive pattern also had heart (T2* 14·28 ± 9·99 ms vs. 31·59 ± 7·43 ms) and liver iron overload (LIC 16·02 ± 8·44 mg vs. 5·02 ± 2·69 mg Fe/g dry weight) compared to those without restrictive pattern. Twenty-five patients (39·7%) had decreased DLCO. No correlation was observed with iron parameters. In our data restrictive pattern was predominant; we observed a relationship with serum ferritin levels suggesting that iron, particularly its chronic effect, could play a role in the pathogenesis of pulmonary disease.

In their remarkable study, Lurz et al. [(1)][1] were able to perform cardiac magnetic resonance (CMR) using several protocols of acquisition (both on 1.5-T and 3-T scans) and biventricular endomyocardial biopsies within 36 h of hospital admission in patients with suspected myocarditis [(1)][1]. Two

Background Isolated ventricular non-compaction (IVNC) is frequently, but not invariably, associated with left ventricular (LV) systolic dysfunction. Factors impacting on regional and global LV function are unknown. The aim of the study was to apply magnetic resonance imaging (MRI) to evaluate the impact of extent and severity of ventricular non-compaction on LV systolic function in patients with IVNC. Methods Sixteen adult patients with IVNC as defined by previously validated MRI criteria [ratio between end-diastolic thickness of non-compacted and compacted myocardium (NC/C ratio) > 2.3 in ≥ 1 LV segment] were enrolled. Short-axis cine images were employed for analysis. Applying a 16-segment LV model, regional systolic performance was assessed qualitatively (wall motion score, WMS; 1 = normal, 2 = mild hypokinesia, 3 = moderate-to-severe hypokinesia, and 4 = a/dyskinesia) as well as quantitatively [fractional wall thickening, FWT (%) = 100 × (end-diastolic wall thickness − end-systolic wall thickness) / end-diastolic wall thickness)]. Results Mean LV ejection fraction was 43.8 ± 15.4% (range, 17–68%). Regional disease severity, as expressed by the NC/C ratio, revealed a significant correlation with WMS (r = 0.26; p = 0.018) and FWT (r = − 0.30; p = 0.006). The total number of non-compacted segments/patient (NoNC) as an index of disease extent was a significant independent correlate of LV ejection fraction by multivariate regression analysis (β = −5.24; p = 0.038) and an excellent predictor of global LV dysfunction (ROC analysis, AUC = 0.98; p Conclusions In patients with IVNC, disease severity correlates with the degree of LV dysfunction at a regional level. The extent of myocardial non-compaction is an independent predictor of global LV dysfunction.

The morphology and exine ultrastructure of Classopollis torosus, C. meyeriana and Geopollis zwolinskae are studied from the Cotham Member of the Lilstock Formation (Penarth Group) in southern England. The palynological assemblage that allows dating the deposits to the Rhaetian is outlined. Although the Circumpolles pollen grains under study show variations in the exine ultrastructure, some common characters support their origin from the same plant group, the Cheirolepidiaceae. An infratectum formed by large granulae arranged mostly in one row and sandwiched between the tectum and endexine is considered as the key character of the pollen grains under study. Ultrastructural transformations within Circumpolles are discussed. The origin of Classopollis-producing plants from any plant group with saccate pollen and alveolate ectexine is considered much less probable than from a group with non-saccate pollen with granular ectexine.

A common clinical practice during single-point Doppler analysis is to measure the centerline maximum velocity and to recover the time-averaged flow rate by exploiting an assumption on the shape of velocity profile (a priori formula), either a parabolic or a flat one. In a previous study, we proposed a new formula valid for the peak instant linking the maximum velocity and the flow rate by including a well-established dimensionless fluid-dynamics parameter (the Womersley number), in order to account for the hemodynamics conditions (Womersley number-based formula). Several in silico tests confirmed the reliability of the new formula. Nevertheless, an in vivo confirmation is missing limiting the clinical applicability of the formula. An experimental in vivo protocol using cine phase-contrast MRI (2-D PCMRI) technique has been designed and applied to ten healthy young volunteers in three different arterial districts: the abdominal aorta, the common carotid artery, and the brachial artery. Each PCMRI dataset has been used twice: 1) to compute the value of the blood flow rate used as a gold standard and 2) to estimate the flow rate by measuring directly the maximum velocity and the diameter (i.e., emulating the intravascular Doppler data acquisition) and by applying to these data the a priori and the Womersley number-based formulae. All the in vivo results have confirmed that the Womersley number-based formula provides better estimates of the flow rate at the peak instant with respect to the a priori formula. More precisely, mean performances of the Womersley number-based formula are about three times better than the a priori results in the abdominal aorta, five times better in the common carotid artery, and two times better in the brachial artery.

Transient elastography (TE) is a valuable noninvasive technique of measuring liver stiffness and a reliable tool for predicting hepatic fibrosis in patients with chronic liver disease. The role of TE in patients with beta-thalassemia has not been extensively investigated. The present study aimed to evaluate the role of TE in the assessment of hepatic fibrosis in 115 adult patients with beta-thalassemia major (TM) (#59) or intermedia (TI) (#56). TE was performed according to current practice. Histologic data were obtained in 14 cases. Liver iron concentration was assessed by atomic absorption spectrometry and T2 magnetic resonance. In patients with TM, the proportion of anti-HCV positive viremic patients, median serum ferritin levels, and TE values were significantly higher than in TI. In the group of 14 patients who underwent liver biopsy, a significant positive correlation was observed between liver stiffness and fibrosis stage (r = 0.73, P = 0.003). Severe fibrosis is diagnosed with a sensitivity of 60% and a specificity of 89%, whereas cirrhosis is detected with a sensitivity of 100% and a specificity of 92%. At multivariate analysis, the variables independently associated with TE were ALT, GGT, and bilirubin levels in both groups and, in patients with TM, HCV RNA positivity. In beta-thalassemia patients, TE is a reliable tool for assessing liver fibrosis even if the influence of iron overload has to be clarified.

The molecular interactions leading to organised, controlled extracellular matrix degradation are of central importance during growth, development and tissue repair, and when deregulated contribute to disease processes including cancer cell invasion. There are two major pathways for collagen degradation: one dependent on secreted and membrane-bound collagenases, the other on receptor-mediated collagen internalisation and intracellular processing. Despite the established importance of both pathways, the functional interaction between them is largely unknown. We demonstrate here, that the collagen internalisation receptor Endo180 (also known as CD280, uPARAP, MRC2) is a novel regulator of membrane-bound matrix metalloproteinase (MT1-MMP) activity, MT1-MMP-dependent MMP-2 activation and urokinase plasminogen activator (uPA) activity. We show close correlation between Endo180 expression, collagen accumulation and regulation of MT1-MMP cell-surface localisation and activity. We directly demonstrate, using collagen inhibition studies and non-collagen-binding mutants of Endo180, that the molecular mechanism underlying this regulation is the ability of Endo180 to bind and/or internalise collagens, rather than by acting as an interaction partner for pro-uPA and its receptor uPAR. These studies strongly support a functional interaction between two distinct collagen degradation pathways, define a novel mechanism regulating MT1-MMP activity and might have important implications for organised collagen clearance in the pericellular environment.

BACKGROUND Acute renal failure (ARF) following percutaneous coronary intervention (PCI) has been shown to be associated with a worse outcome. Whether this event should be considered as a marker of disease severity or an independent contributor to mortality is still unclear. METHODS In a multicenter, prospective cohort study we investigated the predictive variables and the impact of postprocedural ARF on 2-year all-cause mortality in 2860 consecutive patients (50% with stable angina and 50% with non-ST-elevation acute coronary syndromes) undergoing PCI. Serum creatinine determinations were made immediately before and 24 h after PCI. ARF was defined as an increase in serum creatinine of > or =0.5 mg/dl over baseline. RESULTS One hundred and six patients (3.7%) experienced ARF. At logistic regression analysis, ARF was associated with pre-existing low values of estimated glomerular filtration rate, reduced left ventricular ejection fraction, hypertension, and prior coronary bypass surgery. Mortality data at 2 years were available for all patients: 119 patients (4.16%) had died, 3.9% of those without and 11.3% of those with ARF (univariate hazard ratio 3.16; 95% confidence interval 1.68-5.94; P = 0.0004). At Cox regression analysis, the significant predictors of mortality were age, ejection fraction, preprocedural estimated glomerular filtration rate, PCI failure, atrial fibrillation, diabetes mellitus, and fluoroscopy time. In this comprehensive mortality model, ARF maintained a borderline statistical significance (hazard ratio 1.83, 95% confidence interval 0.98-3.44; P = 0.06). CONCLUSIONS ARF following PCI occurs almost exclusively in patients with chronic kidney disease or left ventricular dysfunction. These risk factors are also among the most powerful predictors of long-term mortality and are likely to explain most of the association between postprocedural ARF and long-term mortality. After correction for clinical determinants, however, postprocedural ARF maintains a clinically significant impact on mortality that must be taken into account for benefit vs. risk evaluation of PCI in individual patients.

Background Hereditary hemochromatosis, thalassemia and myelodysplastic syndromes represent disease models with evidence of iron-related heart failure. Non-Transferrin Bound Iron (NTBI) induces cardiac toxicity through the production of reactive oxygen species and lipid peroxidation. In ST-elevation acute myocardial infarction (STEMI) with evidence of microvascular obstruction (MVO) and hemorrhage (HEM), HEM may be a source of iron-related cardiac toxicity through NTBI and pro-inflammatory mediators. Aim of the study The study aims to assess NTBI in patients with STEMI and its possible relationship with MVO and HEM. Methods and results NTBI, LPO–Malondialdehyde (MDA) and interleukin-6 (IL-6) were assessed in 15 patients with STEMI immediately before primary percutaneous coronary intervention (PPCI) and at 3, 6, 9, 12, and 24h post-PPCI. Cardiac Magnetic Resonance (CMR) was performed at 5days and 6months after STEMI. Myocardial edema and HEM were assessed by T2 and T2* mapping. MVO and necrotic area were assessed by early and late gadolinium enhancement (LGE). NTBI was detected in 13/15 patients with the highest values in 4 patients with evidence of MVO and HEM. NTBI levels were significantly related to CK-MB and troponin T values. NTBI kinetics appeared to be different in patients with MVO and HEM (7/15 patients), with a peak value at 6h after PCI, in comparison with those with no evidence of MVO and HEM, in whom NTBI values were lower and remained indeterminable after the first 24h. Conclusions The detection of elevated NTBI values in patients with STEMI, MVO and HEM suggests a possible role of iron cardiotoxicity in myocardial damage.

Background Hereditary hemochromatosis, thalassemia and myelodysplastic sindromes represent iron toxicity models with evidence of iron-related heart failure. Non-TransferrinBound Iron (NTBI), plays a key role in the pathogenesis of cardiac toxicity leading to the production of reactive oxygen species which increase lipid peroxidation (MDA). In acute myocardial infarction (MI) microvascular obstruction (MVO) and hemorrhage (HEM) are independent predictors of left ventricular (LV) remodelling. HEM may be a source of iron toxicity through NTBI and pro-inflammatory mediators (IL-6) , which can directly contribute to acute impairment of myocardial function and adverse LV remodelling. The aim of the study was to assess NTBI in a consecutive cohort of patients (pts) prospectively enrolled with ST-elevation MI (STEMI).and its relationship with MVO and HEM.

The hemopexin-like domain of membrane-type matrix metalloproteinase-1 (MT1-MMP) enables MT1-MMP to form oligomers that facilitate the activation of pro-matrix metalloproteinase-2 (pro-MMP-2) at the cell surface. To investigate the role of the MT1-MMP hemopexin domain in the trafficking of MT1-MMP to the cell surface we have examined the activity of two MT1–MT4-MMP chimaeras in which the hemopexin domain of MT1-MMP has been replaced with that of human or mouse MT4-MMP. We show that MT1-MMP bearing the hemopexin domain of MT4-MMP was incapable of activating pro-MMP-2 or degrading gelatin in cell based assays. Furthermore, cell surface biotinylation and indirect immunofluorescence show that transiently expressed MT1–MT4-MMP chimaeras failed to reach the plasma membrane and were retained in the endoplasmic reticulum. Functional activity could be restored by replacing the MT4-MMP hemopexin domain with the wild-type MT1-MMP hemopexin domain. Subsequent analysis with an antibody specifically recognising the propeptide of MT1-MMP revealed that the propeptides of the MT1–MT4-MMP chimaeras failed to undergo proper processing. It has previously been suggested that the hemopexin domain of MT4-MMP could exert a regulatory mechanism that prevents MT4-MMP from activating pro-MMP-2. In this report, we demonstrate unambiguously that MT1–MT4-MMP chimaeras do not undergo normal trafficking and are not correctly processed to their fully active forms and, as a consequence, they are unable to activate pro-MMP-2 at the cell surface.

A morphological study of dispersed Circumpolles pollen grains from the Upper Triassic of the Southern Alps has been initiated with the genus Duplicisporites. Individual pollen grains were studied by means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Seen with SEM the pollen surface is finely verrucate with low verrucae of different sizes. A sub-equatorial continuous rimula is clearly visible. The proximal trilete scar is small and indistinct. TEM images reveal a bi-layered exine. The ectexine is formed by numerous small, closely packed, granulae subdivided by irregularly-spaced cavities. In the region of the subequatorial canal, the ectexine becomes thinner, about 1/3 of the usual thickness. At places, the ectexine is slightly separated from the underlying endexine. The endexine is prominent and significantly darker than the ectexine. It is homogeneous and of constant thickness. On the basis of its older age, with respect to Classopollis, the present ultrastructural dataset provides information on the possible origin of cheirolepidiaceous-type

The palynological analysis on a continuous shallow-marine succession of the western Tethys realm allows a better characterization of the Carnian (late Triassic) paleofloristic and paleoclimatic scenario. The classic succession of the “Raibl Group”, once the “Raibler Schichten”, in the Southern Alps (northern Italy) was investigated. Ammonoids and conodonts constrain the age of the fossil-rich terrigenous-carbonate sequence to the Julian and Tuvalian, the Julian/Tuvalian boundary lying in the upper part of the Tor Formation. In order to document the pollen biostratigraphy and the paleoecologic trends of this late Triassic interval, results of qualitative and quantitative spore and pollen analysis are presented. The new combination Converrucosisporites tumulosus (Leschik) Roghi is proposed. The recognition of three palynological assemblages facilitates realistic regional palynostratigraphical correlation of Carnian successions in the Southern Alps. Quantitative analysis of the pollen/spore assemblages is used to confirm humid environmental conditions during latest Julian and earliest Tuvalian times.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is an integral type I transmembrane multidomain zinc-dependent endopeptidase involved in extracellular matrix remodelling in physiological as well as pathological processes. MT1-MMP participates in the regulated turnover of various extracellular matrix components as well as the activation of secreted metalloproteinases and the cleavage of various cell membrane components. MT1-MMP expression has been reported to correlate with the malignancy of various tumour types and is thought to be an important mediator of cell migration and invasion. Recently, it has been proposed that internalisation of the enzyme from the cell surface is a major short-term level of MT1-MMP regulation controlling the net amount of active enzyme present at the plasma membrane. In this paper we show that, in HT1080 fibrosarcoma cells, MT1-MMP is internalised from the cell surface and colocalises with various markers of the endocytic compartment. Interestingly, we observed that in these cells, internalisation occurs by a combination of both clathrin-mediated and -independent pathways, most probably involving caveolae. In addition, internalised MT1-MMP is recycled to the cell surface, which could, in addition to downregulation of the enzymatic activity, represent a rapid response mechanism used by the cell for relocalising active MT1-MMP at the leading edge during migration.

It is well known that bereavement can cause ominous cardiovascular events and elicit aggressive behavior in bystanders. A multidisciplinary approach in end-of-life care including communication and taking into account cultural, social, emotional, religious, spiritual preferences, and local differences needs further development and implementation in health-care systems worldwide. The direct effects of emotional stress on the cardiovascular system and cardiac diseases most frequently implicated in sudden cardiac death are discussed.

A 46 year old woman from Sri Lanka, underwent blood examination after her return to Italy and found high titers of uric acid (8.2 mg/dl), thus her family physician prescribed allopurinol 300 mg once daily. After 3 weeks she presented to the ER with fever and esantematic rash on the thorax and limbs, therefore allopurinol was stopped and began prednisone 25 mg/day. A week later she returned to the ER for a worsening of the cutaneous eruption, high fever and marked weakness. The admitting physician excluded an adverse drug reaction and was admitted to the Infectious diseases ward with altered liver function tests, high inflammation indices and eosinophilia. All the tests for infectious disease workup resulted negative, but her general condition worsened with high fever, anasarcatic status and neurological weakness. The total body CT scan showed lung and abdominal lymphadenopathy and pleural effusion. The bone marrow biopsy excluded a lympho myeloproliferative disorder and revealed two microgranulomas and 34% eosinophils. The hepatic biopsy showed a diffuse acute hepatitis with marked infiltrate of T-lymphocytes (CD3+) and eosinophils. Cardiac examination with EKG and echocardiography was normal but the cardiac MNR dimostrated a severe pericardial inflammation with effusion. Only when the eosinophilic blood concentration raised to 52% the diagnosis of DRESS was made. The patient also resulted positive for HLA-B*58:01. She began treatment with high glucocorticoid i.v. (1 mg/kg/day) and obtained rapid improvement of the general condition of weakness, skin healing by desquamation and normalization of eosinophilia and hepatic function. She was discharged after one month of hospital stay. Conclusion This is a particular case of DRESS with extensive histological, blood, and radiological examination. It is important to employ elevated levels of glucocorticoids in the treatment of DRESS. The normal cardiac screening by EKG and echocardiography may sometimes prove inadequate for identifying real cardiac injury. We believe that it’s important to undergo cardiac MR imaging since appropriate therapy may prevent progression of cardiac disease.

Background & objectives. The ADAMTS proteinases are a family of secreted, matrix-associated enzymes that have diverse roles in the regulation of tissue organization and vascular homeostasis. Several of the 19 human family members have been identified as having either tumor promoting or suppressing roles. We previously demonstrated that decreased ADAMTS15 expression correlated with a worse clinical outcome in mammary carcinoma. Methods. We have explored the effects of A Disintegrin and Metalloproteinase with Thrombospondin motifs-15 (ADAMTS-15) on the behavior of MDA-MB-231 and MCF 7 breast cancer cells by stable expression of either a wild type (wt) or metalloproteinase-inactive (E362A) protein. Results. No effects on mammary cancer cell proliferation or apoptosis were observed for either form of ADAMTS-15. However, both forms reduced cell migration on fibronectin or laminin matrices, though motility on a Type I collagen matrix was unimpaired. Knockdown of syndecan-4 attenuated the inhibitory effects of ADAMTS-15 on cell migration. In contrast to its effects on cell migration, wt ADAMTS-15 but not the E362A inactive mutant inhibited endothelial tubulogenesis in 3D collagen gels and angiogenesis in the aortic ring assay. In experimental metastasis assays in nude mice, MDA-MB-231 cells expressing either form of ADAMTS-15 showed reduced spread to the liver, though lung colonization was enhanced for cells expressing wt ADAMTS-15. Conclusiona. These studies indicate that extracellular ADAMTS-15 has multiple actions on tumor pathophysiology. Via modulation of cell-ECM interactions, which likely involve syndecan-4, it attenuates mammary cancer cell migration independent of its metalloproteinase activity; however, its antiangiogenic action requires catalytic functionality, and its effects on metastasis in vivo are tissue niche-dependent.