Angela Pucci

Fibrosis in chronic hepatitis C acquired in infancy: is it only a matter of time?

Abstract Objective The natural history of chronic hepatitis C acquired in infancy is not well understood. The progression of fibrosis was analyzed in untreated children with chronic hepatitis C virus infection and no other hepatotoxic cofactors. Methods A total of 112 pediatric patients (13 with paired liver biopsies) were considered. Fibrosis was assessed by METAVIR score (i.e., stage F1 to F4). The ratio between the stage of fibrosis (METAVIR units) and the presumed duration of infection represented the “estimated” rate of fibrosis progression per year. In patients with paired biopsies, the “observed” rate of fibrosis progression was defined as the difference between the stage of fibrosis in the two biopsies divided by the time interval between them. Results Both age of patients at biopsy and duration of infection correlated with stage of fibrosis (p Conclusions Chronic hepatitis C acquired in childhood is a progressive, slow-moving, fibrotic disease. Fibrosis progression inferred on the basis of linear mathematical models should be critically evaluated in the clinical practice.

Recurrence of hepatitis D (delta) in liver transplants: Histopathological aspects

BACKGROUND The viral/pathological correlates of recurrent hepatitis delta virus (HDV) disease in orthotoptic liver transplants are reported. METHODS We examined the histological features of recurrent HDV disease in nine patients with transplants for terminal HDV cirrhosis were examined; intrahepatic HDV and hepatitis B virus (HBV) antigens were detected by immunoperoxidase techniques. Sera were tested for the battery of HDV and HBV markers. RESULTS In four patients, HDV reinfection was accompanied by the recurrence of an HBV infection with features of active viral replication. In the other five, HDV reinfection was accompanied by an atypical recurrence of HBV infection without evidence of active HBV replication (no expression of intrahepatic hepatitis B core antigen). In four of the latter patients, the atypical HBV pattern changed during the follow-up into a pattern of active viral replication accompanied by chronic necroinflammation detected during histology. CONCLUSION The pattern of recurrent HBV infection can influence the pathological aspects of the relapses of HDV disease in liver grafts.

Cytokeratin profile and neuroendocrine cells in the glandular component of cardiac myxoma

Glandular cardiac myxomas are very rare tumors of uncertain histogenesis that display glandular structures within otherwise typical myxomatous tissue. The origin of the glands has been attributed to epithelial differentiation of a totipotent cardiomyogenic precursor cell or to entrapped embryonal rests in the tumor. We studied four cases of glandular myxomas (three sporadic and one familial) to define the immunophenotypic profile of the glandular elements. The glands were either single and located within the myxoma cell islands (three cases) or in groups embedded in the myxomatous matrix. In the latter case, the glands featured villous projections, irregular profile, active inflammation or focal reactive cellular atypia (case 3) and had acidic and neutral mucins (mostly sialomucins). The cytokeratin expression profile (cytokeratin 7 and 20 co-expression) was similar to that of foregut derivatives. Scattered chromogranin-positive neuroendocrine cells were observed in case 3. Our findings indicate that the glandular component in cardiac myxoma is morphologically heterogeneous. In some cases, the scattered glands may derive from a divergent (epithelial) differentiation of myxoma cells; in others, entrapment of embryonic gastrointestinal rests (with mature neuroendocrine and mucous cell populations) could be the case.

Thrombopoietin modulates cardiac contractility in vitro and contributes to myocardial depressing activity of septic shock serum

Thrombopoietin (TPO) is a humoral growth factor that has been shown to increase platelet activation in response to several agonists. Patients with sepsis have increased circulating TPO levels, which may enhance platelet activation, potentially participating to the pathogenesis of multi-organ failure. Aim of this study was to investigate whether TPO affects myocardial contractility and participates to depress cardiac function during sepsis. We showed the expression of the TPO receptor c-Mpl on myocardial cells and tissue by RT-PCR, immunofluorescence and western blotting. We then evaluated the effect of TPO on the contractile function of rat papillary muscle and isolated heart. TPO did not change myocardial contractility in basal conditions, but, when followed by epinephrine (EPI) stimulation, it blunted the enhancement of contractile force induced by EPI both in papillary muscle and isolated heart. An inhibitor of TPO prevented TPO effect on cardiac inotropy. Treatment of papillary muscle with pharmacological inhibitors of phosphatidylinositol 3-kinase, NO synthase, and guanilyl cyclase abolished TPO effect, indicating NO as the final mediator. We finally studied the role of TPO in the negative inotropic effect exerted by human septic shock (HSS) serum and TPO cooperation with TNF-α and IL-1β. Pre-treatment with the TPO inhibitor prevented the decrease in contractile force induced by HSS serum. Moreover, TPO significantly amplified the negative inotropic effect induced by TNF-α and IL-1β in papillary muscle. In conclusion, TPO negatively modulates cardiac inotropy in vitro and contributes to the myocardial depressing activity of septic shock serum.

Asymptomatic inflammatory myofibroblastic tumor of the heart: immunohistochemical profile, differential diagnosis, and review of the literature

BACKGROUND Inflammatory myofibroblastic tumor (IMT) is an uncommon lesion, mainly occurring in children and young adults and extremely rare in the heart. IMTs are composed of differentiated myofibroblastic cells accompanied by inflammatory cells. Cardiac IMTs are considered biologically benign, but they may have fatal consequences depending upon the peculiarity of site. Because of their rarity in the heart, most knowledge is based on extracardiac lesions that have uncertain behaviour. METHODS AND RESULTS We investigated the morphologic features and the immunohistochemical profile of an intracardiac IMT, arising in the right outflow tract of an asymptomatic 11-month-old boy, by using a large panel of antibodies, many of them previously reported in extracardiac IMTs only. Results were compared with data of literature. After complete surgical excision of the tumor, the patient is disease-free at 1 year of follow-up. CONCLUSIONS The present case showed morphologic and immunohistochemical features characteristic of IMT. Immunohistochemistry was helpful for characterization and differential diagnosis. The immunoreactivity pattern (including calponin expression) was similar to that of extracardiac IMTs except for anaplastic lymphoma kinase 1 immunoreactivity, lacking in this benign intracardiac IMT but usually associated to favourable prognosis in extracardiac IMTs.

PPARγ in coronary atherosclerosis: In vivo expression pattern and correlations with hyperlipidemic status and statin treatment

OBJECTIVE Peroxisome proliferator-activated receptor-γ (PPARγ) is involved in regulation of macrophage inflammation and in atherosclerosis. Herein we investigate the influence of statin treatment on PPARγ expression in coronary artery disease. METHOD PPARγ expression was investigated in coronary atherosclerotic atherectomies (N=48) and arteries (N=12) from patients with stable or unstable coronary syndromes or undergoing cardiac transplantation for end-stage ischemic cardiomyopathy, respectively, by immunohistochemistry. Plaque components and tissue factor immunoreactivity were also investigated. Atherectomies were obtained from de novo culprit lesions of hypercholesterolemic (16 statin-treated and 16 untreated) and normolipidemic (N=16) patients. Furthermore, PPARγ expression was evaluated in patients peripheral blood monocytes and in monocytic U937 cells after atorvastatin incubation, by Western blot analysis. RESULT PPARγ expression was higher in coronary plaques and peripheral blood monocytes of statin-treated patients, and it significantly increased in monocytes after 24h atorvastatin incubation (p<0.05). Intra-plaque macrophage content, atheroma, neoangiogenesis and hemorrhage, and circulating CRP levels were lower in statin-treated than untreated hypercholesterolemic patients and comparable with normolipidemic subjects. PPARγ immunoreactivity was localized to neointima and media, its distribution pattern being different from that of tissue factor. CONCLUSION PPARγ expression was enhanced in statin-treated patients with different distribution and behavior as compared to atheroma, macrophage content, tissue factor immunoreactivity and serum CRP. In vitro studies showed increased PPARγ expression in monocytes after atorvastatin incubation. These findings provide further evidence as to the protective role of statins in coronary artery disease and their influence on PPARγ expression in coronary plaques and on the inflammatory status of patients.

Characterization of mitochondrial DNA in primary cardiomyopathies

With the aim of studying the involvement of the mitochondrial genome in the impairment of heart function, mitochondrial DNA was analyzed by modified primer shift-polymerase chain reaction in a panel of young patients affected by primary cardiomyopathies. Mitochondrial DNA molecules harboring the 7436 bp deletion were specifically found in cardiomyopathic patients as compared with a panel of control subjects. The 4977 bp deletion was commonly detected among the subjects analyzed whereas none of the specific tRNA gene point mutations generally associated with the cardiomyopathic trait were detected. The presence of the 7436 bp deletion as a consequence of a premature aging of the heart muscle, secondary to heart dysfunction, is discussed.

Incidental Epstein-Barr virus associated atypical lymphoid proliferation arising in a left atrial myxoma: a case of long survival without any postsurgical treatment and review of the literature

We report a case of left atrial cardiac myxoma harbouring an incidental atypical B-cell lymphoid proliferation. Histology disclosed classic myxoma cells embedded in a mucopolysaccharide-rich matrix and a micronodular atypical lymphoid proliferation under the surface of the mass. Myxoma cells were immunoreactive for calretinin, while lymphoid cells expressed B lineage markers (CD 20+, CD79a), without evidence of clonality. Moreover, they were LMP1 positive; EBNA2 negative; KSHV/HHV8 negative; and, by in situ hybridization, EBER/Epstein-Barr virus (EBV) positive and Kappa and Lambda negative. According to the 2008 WHO schemes, the present case shares close similarities either with diffuse large B-cell lymphomas growing in the context of long-standing chronic inflammation or with primary effusion lymphomas, solid variant, both associated with EBV infection. This is the sixth case of incidental atypical lymphoid proliferation discovered in a cardiac myxoma reported so far. The optimal treatment of such lesions remains undefined, but their clinical course is indolent. After an accurate staging workup, without any postsurgical treatment, the patient we observed has been well with no recurrence of the disease at 6 years of follow-up.

Incomplete and Atypical Kawasaki Disease: A Clinicopathologic Paradox at High Risk of Sudden and Unexpected Infant Death

Incomplete Kawasaki disease (IKD) and atypical Kawasaki disease (AKD) represent rare conditions. Two cases of unexpected or sudden infant death are reported. The diagnosis for a 3-month-old girl was determined by echocardiography, and the child unexpectedly died despite appropriate treatment, whereas autopsy determined the diagnosis of AKD for a 4-month-old boy. In both patients, giant coronary artery aneurysms with thrombosis and vasculitis, myocarditis, and coagulative necrosis were shown at autopsy. These rare forms of IKD and AKD carry a poor prognosis and represent a paradox between the severe cardiovascular damage and the clinical presentation that mimics common and usually self-limiting exanthematic infectious disease in infancy.

Life-Threatening Tumors of the Heart in Fetal and Postnatal Age

OBJECTIVES To evaluate the role of histology in diagnosis and management of biologically benign heart tumors causing life-threatening symptoms and even death in children and fetuses. The clinical impact of a multidisciplinary approach including 2-D echocardiography, histology, genetics, and cardiac surgery has not yet been fully elucidated. STUDY DESIGN Forty-one consecutive antenatal (n = 17) or postnatal (n = 24) detected cardiac masses were evaluated by 2-D echocardiography (in alive patients) or at autopsy, and 12/41 cases with definite histologic diagnosis of primary and benign cardiac tumor were entered in this study. RESULTS Rhabdomyomas (n = 6), hemangiomas (n = 3), central fibrous body chondroma (n = 1), fibroma (n = 1), or left atrial myxoma (n = 1) were histologically diagnosed in 4 fetuses and in 8 children. Death occurred in 6 patients showing diffuse or infiltrative tumors, 2/6 experiencing intrauterine death or sudden and unexpected infant death. Seven patients underwent surgery, 4/7 are alive and well at >5 years follow-up, whereas 3 deaths followed partial tumor resection. Two fetuses with extensive tumor/s were aborted. Tuberous sclerosis complex gene mutations were seen in patients with rhabdomyomas. CONCLUSIONS Histology represents the best diagnostic approach in life-threatening pediatric cardiac tumors allowing definite diagnosis in cases other than rhabdomyoma and in sudden deaths, influencing clinical management and counselling. 2-D echocardiography remains the main tool for early clinical diagnosis and follow-up. A multidisciplinary approach is advisable because of rarity, difficult management, and possible associations with inheritable diseases.