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The aim of this study was to assess whether the chronic preoperative administration of intranasal corticosteroids (INCs) in chronic rhinosinusitis with/without nasal polyposis (CRSwNP/CRSsNP, respectively) could significantly influence bleeding during functional endoscopic sinus surgery (FESS). We prospectively enrolled 109 patients (56 CRSwNP and 53 CRSsNP) candidate for FESS who underwent clinical evaluation and anamnestic data collection. They were allocated to 2 groups depending on whether or not they were chronic INC users, as declared at their first medical evaluation: chronic “INC users” represented the treated group, while “INC nonusers” formed the control group. Lund-Mackay and American Society of Anesthesiology (ASA) scores, blood loss expressed both in milliliters and using the Boezaart scale, operation time in minutes, pre- and postoperative 22-item Sino Nasal Outcome Scores (SNOT-22) were collected. Each sample underwent histopathological evaluation. The results showed that anamnestic information, Lund-Mackay, and SNOT-22 scores were similar between the 2 groups ( P > .05). The average blood loss expressed in milliliters and operative time were slightly, but not significantly, higher in the INC user group, while the Boezaart scores proved significantly higher in the INC users ( P = .038). No differences emerged between CRSwNP and CRSsNP within each group in terms of bleeding. The pathologist described common features in the majority (78%) of INC group samples: ectatic venules embedded in a fibrous stroma and hypertrophy of the arterial muscular layer. In our experience, despite the presence of NP, chronic preoperative administration of INCs was associated with increased intraoperative bleeding according the Boezaart scale although objective recordings of blood loss were not statistically different between the INC users and nonusers.

Introduction Lymphoid neoplasms of the urinary tract and male genital organs are relatively rare, comprising less than 5% of all primary extranodal lymphomas; only a handful of small case series and isolated case reports have been published to describe their predominant sites and subtypes. Material and Methods We searched our institution's electronic archive of pathology reports from 2001 to 2012. We considered lymphoid neoplasms involving the kidney, bladder, testes and prostate. Patient age at diagnosis, sex, clinical history, and outcome were recorded using the relevant electronic medical records. Results We identified 25 patients with lymphoid neoplasms of the urogenital tract. 11 cases out of 40 were primary genitourinary lymphomas. Mean age at diagnosis was 61.7 years (range 13–87 years). Among bladder lymphomas cases, a male predominance was noted. As regards the types of lymphoid neoplasms, the following subtypes were observed: diffuse large B-cell lymphoma (32%), chronic lymphocytic leukemia (24%), small lymphocytic lymphoma (20%), Malt lymphoma (8%), Burkitt lymphoma (4%), follicular lymphoma (4%); diffuse large B-cell ALK+ (4%) and lymphoblastic lymphoma (4%). Conclusions Genitourinary tract lymphomas most commonly occurred in the kidney. B-cell non-Hodgkin's lymphomas were predominant, with diffuse large B-cell lymphoma being the most common subtype in the entire group. Although this study confirms the predominance of diffuse large B-cell lymphoma in extranodal sites, the findings also highlight the variety of lymphomas that may occur in the genitourinary tract. This diversity of subtypes affirms the importance of fully characterizing lymphomas by immunohistochemistry and other modalities, which are indispensable for accurate diagnosis.

Background The outcomes of patients presenting with acute myocarditis and life-threatening ventricular tachyarrhythmias (LT-VA) are unclear. The aim of this study was to assess incidence and predictors of recurrence of major arrhythmic events (MAEs) after hospital discharge in such patients. Methods and results We retrospectively analysed 156 patients (median age 44 years; 77% males) discharged with a diagnosis of acute myocarditis and LT-VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or on the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death (SCD) or ventricular fibrillation defibrillated successfully or sustained ventricular tachycardia (sVT) requiring implantable cardioverter-defibrillator therapy or synchronized external cardioversion. Median follow-up period was 23 months (first to third quartile [Q1-Q3] 7-60). Fifty-eight (37.2%) patients experienced MAEs after discharge, at a median time of 8 months (Q1-Q3 2.5-24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated to MAEs were presentation with sVT (hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38-6.11); late gadolinium enhancement (LGE) involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39-8.53); and absence of positive short-tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40-4.79) at first CMR. Conclusions Among patients discharged with the diagnosis of myocarditis and LT-VA, 37.2% had recurrences of MAEs during follow-up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmic recurrence.

Background Persistent left ventricular (LV) systolic dysfunction in patients with acute lymphocytic myocarditis (LM) is widely unexplored. Objectives To assess the frequency and predictors of persistent LV dysfunction in patients with LM and reduced LVEF at admission. Methods and results We retrospectively evaluated 89 consecutive patients with histologically-proven acute myocarditis enrolled at three Italian referral hospitals. A subgroup of 48 patients with LM, baseline systolic impairment and an available echocardiographic assessment at 12 months (6–18) from discharge constituted the study population. The primary study end-point was persistent LV dysfunction, defined as LVEF

Objective Despite growing evidence about myocardial injury in hospitalized COronaVIrus Disease 2019 (COVID-19) patients, the mechanism behind this injury is only poorly understood and little is known about its association with SARS-CoV-2-mediated myocarditis. Furthermore, definite evidence of the presence and role of SARS-CoV-2 in cardiomyocytes in the clinical scenario is still lacking. Methods We histologically characterized myocardial tissue of 40 patients deceased with severe SARS-CoV-2 infection during the first wave of the pandemic. Clinical data were also recorded and analyzed. In case of findings supportive of myocardial inflammation, histological analysis was complemented by RT-PCR and immunohistochemistry for SARS-CoV-2 viral antigens and in situ RNA hybridization for the detection of viral genomes. Results Both chronic and acute myocardial damage was invariably present, correlating with the age and comorbidities of our population. Myocarditis of overt entity was found in one case (2.5%). SARS-CoV-2 genome was not found in the cardiomyocytes of the patient with myocarditis, while it was focally and negligibly present in cardiomyocytes of patients with known viral persistence in the lungs and no signs of myocardial inflammation. The presence of myocardial injury was not associated with myocardial inflammatory infiltrates. Conclusions In this autopsy cohort of COVID-19 patients, myocarditis is rarely found and not associated with SARS-CoV-2 presence in cardiomyocytes. Chronic and acute forms of myocardial damage are constantly found and correlate with the severity of COVID-19 disease and pre-existing comorbidities. Graphic abstract

Background Juvenile idiopathic inflammatory myopathies (JIIMs) are a group of heterogenous, acquired, autoimmune disorders that affect the muscle. While the association between IIMs and malignancy has been widely reported in adults, cancer-associated myositis (CAM) is rare in children, so that routine malignancy screening is not generally performed. This report shows a case of severe CAM in a child. Case presentation An 11-years-old girl presented with worsening dyspnea after a 3-weeks history of progressive proximal weakness, myalgia, dysphagia, and weight loss. Her past history was remarkable for a type I Arnold-Chiari malformation associated with an anterior sacral meningocele. Physical examination showed severe hypotony and hypotrophy. Pulse oximetry and blood test showed a type II respiratory failure (SpO2 88%, pCO2 68 mmHg) and increased muscle enzyme levels (CPK 8479 U/L, AST 715 U/L, ALT 383 U/L, LDH 1795 U/L). The patient needed invasive mechanical ventilation. Inflammatory myositis was considered and treatment with intravenous methylprednisolone (30 mg/Kg/day for 3 days followed by 2 mg/Kg/day) and IVIG (1 g/kg/day for 2 days) was started. Muscle biopsy showed endomysial and perimysial necrosis and inflammation. The presence of serum anti-TIF1-γ antibody positivity led to a malignancy screening. Whole-body MRI showed a mature teratoma underneath sacral meningocele and both lesions were surgically removed. Given the histological and clinical severity of the myopathy, mycophenolate (500 mg twice a day) and rituximab (360 mg/m2, 4 weekly infusions) were added. Due to extreme muscular wasting, severe malnutrition and intolerance to enteral feeding the patient needed a transient tracheostomy and parenteral nutrition, followed by physiotherapy, speech therapy and nocturnal non-invasive ventilation. A complete remission was achieved 3 months after. Conclusions Among cancer-associated autoantibodies (CAAs) in adult patients, anti-TIF1-γ carries the highest risk of CAM, which recognizes with a high likelihood a paraneoplastic pathogenesis. In children, anti-TIF1-γ antibody has been associated with severe cutaneous disease, lipodystrophy, and chronic disease course, but not with CAM, which is overall rare in younger patients. Severe onset of a JIIM, especially if anti-TIF1-γ antibody positive, should prompt suspect of a CAM and lead to a screening for malignancy.

Objective: To estimate the prevalence of metastasis in the perimarginal nodes (PMNs) (also known as perifacial, preglandular and retroglandual nodes) in head and neck cancer. Methods: We recruited 136 patients affected by cancers of the oral cavity, lip, oropharynx, skin and by cáncer of unknown primary (CUP), who were candidates for level IB dissection. PMNs were identified and sent separately for histological analysis. Correlation between metastasis to the PMNs and characteristics of the primary tumour were reported. Results: The incidence of metastasis was 17% from oral cancer, 50% from lip cancer and 12.5% from skin cancer. No metastases were reported for oropharynx cancer or CUP. The only factor that correlated with the incidence of metastases was origin of the tumour from the upper part of oral cavity. Conclusion: PMNs represent a frequent site of metastasis in oral and lip cancers. In cancer of the oropharynx, their involvement has not been not reported, while their role in skin cancers remains to be clarified.

A 59-year-old man with a severe pneumonia due to coronavirus disease 2019 (COVID-19) died in multiple organ failure caused by a postoperative septic shock subsequent to a hemicolectomy for a right colon infarction occurred two weeks earlier.

ObjectiveTo date, no useful prognostic biomarker exists for patients with oral squamous cell carcinoma (OCSCC), a tumour with uncertain biological behaviour and subsequent unpredictable clinical course. We aim to investigate the prognostic significance of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of telomerase reverse transcriptase (TERT) gene and the impact of TERT single nucleotide polymorphism (SNP) rs2853669 in patients surgically treated for OCSCC.MethodsThe genetic frequencies of rs2853669, -124 C>T and -146 C>T as well as the telomere length were investigated in 144 tumours and 57 normal adjacent mucosal (AM) specimens from OCSCC patients.ResultsForty-five tumours harboured TERT promoter mutations (31.3%), with -124 C>T and -146 C>T accounting for 64.4% and 35.6% of the alterations respectively. Patients with -124 C>T TERT promoter mutated tumours had the shortest telomeres in the AM (p=0.016) and showed higher risk of local recurrence (hazard ratio [HR]:2.75, p=0.0143), death (HR:2.71, p=0.0079) and disease progression (HR:2.71, p=0.0024) with the effect being potentiated by the co-occurrence of T/T genotype of rs2853669.Conclusion-124 C>T TERT promoter mutation as well as the T/T genotype of the rs2853669 SNP are attractive independent prognostic biomarkers in patients surgically treated for OCSCC, with the coexistence of these genetic variants showing a synergistic impact on the aggressiveness of the disease.

Background Intraventricular masses are a relatively rare condition ranging from asymptomatic to potentially life-threatening situations. Case summary Herein, we report a case of a 49-year-old woman under investigation for a massive right ventricular (RV) mass who underwent complete investigation for possible differential diagnosis, in the suspect of RV tumour. Multimodality imaging with cardiac computed tomography and magnetic resonance imaging showed the presence of a massive thrombus partially obliterating the right ventricle. Surgical removal of the mass showed a large area of stratified thrombosis with an underlying area of endocardial fibrosis. The patient has been then discharged in good clinical condition and with lifetime oral anticoagulation. Discussion Massive RV thrombosis is a rare yet potentially fatal condition. Invasive management is preferable and lifetime anticoagulation is required to reduce possible downstream thrombotic complications.

Aim: We examined evidence on infective and non-infective endocarditis obtained from a database of 50,403 clinical autopsies performed at an Italian general hospital between January 1983 and December 2006. Materials and Methods: Out of 814 endocarditis cases, 409 were of infective endocarditis (IE) and 405 non-infective (NIE). The median age at the time of death was 78 years for those with IE and 83 for those with NIE. Data were collected on gender, clinical history, comorbidities, kind of affected valve (non-prosthetic/mechanical/biological), pathological features of endocarditis, endocarditis complications and microbiological agents. Results: The diagnosis of IE was frequently missed and these conditions were often complicated by cardiovascular events. IE was more common among patients with prior valve infection or cardiovascular surgery, while malignancies were frequent comorbidities of NIE. Conclusion: In general, we found several data that differ from those generally present in the scientific literature, and this could be explained by the fact that data on IE and NIE are generally obtained from surgical and clinical databases, while we analysed only autoptic cases.

Background Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Women with endometriosis have an increased risk of different types of malignancies, especially ovarian cancer and non-Hodgkin's lymphoma. Though there are several theories, researchers remain unsure as to the definitive cause of endometriosis. Our objective was to test the validity of the theory of müllerianosis for endometriosis, that is the misplacing of primitive endometrial tissue along the migratory pathway of foetal organogenesis Methods We have collected at autopsy 36 human female foetuses at different gestational age. We have performed a morphological and immunohistochemical study (expression of oestrogen receptor and CA125) on the pelvic organs of the 36 foetuses included en-block and totally analyzed. Results In 4 out of 36 foetuses we found presence of misplaced endometrium in five different ectopic sites: in the recto-vaginal septum, in the proximity of the Douglas pouch, in the mesenchimal tissue close to the posterior wall of the uterus, in the rectal tube at the level of muscularis propria, and in the wall of the uterus. All these sites are common location of endometriosis in women. Conclusion We propose that a cause of endometriosis is the dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis.

Objective The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS). Methods Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1. Results Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064). Conclusions These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome. Electronic supplementary material The online version of this article (10.1007/s00011-020-01413-2) contains supplementary material, which is available to authorized users.

Purpose of Review Myocarditis is a polymorphic disease, both in its presentation and clinical course. Recent data suggests that the genetic background, interacting with environmental factors, could be diriment both in the susceptibility and evolution of myocarditis in different clinical presentations. The aim of this paper is to expose the current available evidences and the evolving concepts on this topic, in order to provide insight for improving the clinical management of those patients. In this regard, the main goal is an optimal characterization of each patient’s risk, with the purpose of individualizing the treatment and the follow-up. Recent Findings The latest research highlights the possible prognostic role of some pathogenic mutations that could create a vulnerable myocardium prone to myocardial inflammation and also to the development of a long-lasting cardiomyopathy. Summary The identification of these genetic defects and of myocarditis patients requiring genetic testing is emerging as a challenge for the future. In fact, identifying a possible genetic background responsible for a particularly high-risk profile could be of extreme importance in improving management of myocarditis. This and many other aspects in the genetics of myocarditis remain uncovered, and further studies are expected based to refine our daily clinical practice.

Cardiac lymphomas are rare extranodal lymphomas involving primarily and secondarily the heart and/or pericardium. Here we describe three cases of cardiac involvement from lymphoma with specific peculiarities: two primary cardiac Diffuse Large B-cell Lymphomas and one secondary involvement from Marginal Zone Lymphoma (MZL). The first case highlights the issue of early CNS relapse and the possible role for CNS prophylaxis; the second case demonstrates the difficulties of interpretation and possible mistakes of different radiologic techniques adopted to evaluate cardiac involvement by lymphoma during follow-up; the third is a unique case of MZL with cardiac involvement. Our aim is to share the findings observed in these cases putting them in relation with data from the literature.

To investigate the prognostic significance of the stratification of extranodal extension (ENE) into ENE minor (ENEmi, up to 2 mm) and ENE major (ENEma, over 2 mm) in non-HPV-related squamous cell cancers of the head and neck, we retrospectively reviewed microscopic slides from neck dissection specimens of ENE-positive patients and subcategorised them into ENEmi and ENEma. We then compared the two groups in terms of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Forty-four patients with pathologically positive necks had ENE in the histological report. Twenty-six had ENEmi and 18 ENEma. The three-year OS was 46% in the ENEmi group and 38.9% in the ENEma group. DSS and DFS were 80.8% and 80.8%, respectively, in the ENEmi group and 61.1% and 77.8%, respectively, in the ENEma group. None of the comparisons revealed any statistically significant difference. The results of our survival analysis seem to show a trend towards better survival rates in the ENEmi group, particularly regarding OS. Nonetheless, extension of the tumour outside the lymph node capsule by more than 2 mm was not found to be significantly associated with any of the explored survival outcomes.

Latest statements from European and American societies recommend to rule out viral presence in endomyocardial biopsy (EMB) via polymerase chain reaction (PCR) analysis before starting immunosuppression or immunomodulation in acute lymphocytic myocarditis presenting with life-threatening scenarios. However, recommendations in myocarditis are mostly based on heterogeneous studies enrolling patients with inflammatory cardiomyopathies and established heart failure rather than acute myocarditis. Thus, definitive evidence of a survival benefit from immunomodulation guided by viral presence is currently lacking. Finally, distinguishing innocent bystanders from causative agents among EMB-detected viruses remain challenging and a major goal to achieve in the near future. Therefore, considerable divergence remains between official recommendations and clinical practice, including the possibility of starting immunosuppressive therapy empirically, without knowing viral PCR results. This review systematically discusses the unsolved issues of immunomodulation guided by viral presence in acute lymphocytic myocarditis, namely (i) virus epidemiology and prognosis, (ii) variability of viral presence rates, (iii) the role of potential viral bystander findings, and (iv) the main results of immunosuppression controlled trials in lymphocytic myocarditis. Furthermore, a practical approach for the critical use of viral presence analysis in guiding immunomodulation is provided, highlighting its importance before starting immunosuppression or immunomodulation. Future, multicentre studies are needed to address specific scenarios such as fulminant lymphocytic myocarditis and a virus-tailored management as for parvovirus B19.

Objective: To evaluate if limiting factors of intrauterine magnetic resonance imaging (iuMRI) performed in the early second trimester of pregnancy (19–23 weeks) affect its accuracy in comparison to post-mortem MRI (pmMRI) in fetuses that underwent termination of pregnancy (TOP) for central nervous system (CNS) defects. Study design: This is a secondary analysis of a 10 years prospective observational study. Cases of TOP < 23 weeks for CNS malformation that had undergone neurosonography (NSG), iuMRI, pmMRI and autopsy were included. The agreement between iuMRI and pmMRI was calculated. The autopsy represented the gold-standard. Results: Overall, 143 TOPs for fetal congenital anomaly underwent the post-mortem diagnostic protocol. Of these, 31 cases underwent iuMRI and pmMRI for CNS abnormality. Three cases were excluded due to brain autolysis at autopsy. Corpus callosum defects were the most represented (16/28; 57 %). In only one case of posterior fossa defect, pmMRI identified the presence of vermian hypoplasia not diagnosed at iuMRI. In 2 cases (7%), iuMRI added clinically relevant additional findings to NSG, that were posteriorly confirmed by pmMRI. Conclusions: The study shows that, at 19–23 weeks and for CNS defects, limiting factors that might influence the performance of iuMRI have little influence on iuMRI accuracy. This finding is particularly important for professionals who work in countries with legal bound for TOP in the early second trimester.

Background: Tissue Doppler imaging (TDI) indices of left ventricular (LV) diastolic function provide incremental prognostic information on mortality and morbidity in the general population and in several clinical scenarios. Their independent, additional role in outpatients with normal LV ejection fraction (LVEF) and without heart failure (HF) is undefined. Methods: We reviewed clinical and echocardiographic records of 2628 consecutive outpatients 52.8% male, median age 71 years) with LVEF > 50% without concurrent or prior HF, from the Cardiovascular Center of Trieste. We analyzed septal early mitral annular velocity (e’) and its combination with mitral peak early filling velocity (E/e’) in relation to the composite end-point of death and cardiovascular hospitalizations. Results: During follow-up of 26 months (interquartile range: 12–41), 392 (15%) patients experienced the endpoint (88 deaths). Increasing E/e’ showed an overall association with the clinical end-point (log rank p < 0.02), but with no prognostic difference between the middle and upper tertile. Decreasing e’ also showed an association with the end-point, with a more balanced stepwise risk increase for increasing tertiles (log rank p < 0.01 for all contrasts). At multivariable analysis, E/e’ (either in tertiles or dichotomized according to the threshold of 15) was no longer associated with clinical outcome, whereas e’ independently predicted the combined endpoint [hazard ratio 0.73 (0.53-0.94), p = 0.04]. The prognostic value of e’ was incremental to that of other clinical and echocardiographic variables (p = 0.04). Conclusions: In outpatients with normal LVEF and without HF, e’ and E/e’ are both associated with clinical end-points, though only e’ is an independent and incremental predictor of outcome. These findings suggest a potential role for e’ as a prognosticator, and spread a cautionary word about the utilization of septal E/e’ alone as a surrogate for a comprehensive assessment of diastolic function in this context.

Predictors of early and late failure of pericardiectomy for constrictive pericarditis (CP) have not been established. Early and late outcomes of a cumulative series of 81 (mean age 60 years; mean EuroSCORE II, 3.3%) consecutive patients from three European cardiac surgery centers were reviewed. Predictors of a combined endpoint comprising in-hospital death or major complications (including multiple transfusion) were identified with binary logistic regression. Non-parametric estimates of survival were obtained with the Kaplan–Meier method. Predictors of poor late outcomes were established using Cox proportional hazard regression. There were 4 (4.9%) in-hospital deaths. Preoperative central venous pressure > 15 mmHg (p = 0.005) and the use of cardiopulmonary bypass (p = 0.016) were independent predictors of complicated in-hospital course, which occurred in 29 (35.8%) patients. During follow-up (median, 5.4 years), preoperative renal impairment was a predictor of all-cause death (p = 0.0041), cardiac death (p = 0.0008), as well as hospital readmission due to congestive heart failure (p = 0.0037); while partial pericardiectomy predicted all-cause death (p = 0.028) and concomitant cardiac operation predicted cardiac death (p = 0.026), postoperative central venous pressure

The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual introduces "depth of invasion" and "extranodal extension" into the head and neck section, and our aim was to find out if these changes have an impact on prognosis. We evaluated 174 patients who had had oral squamous cell carcinomas (SCC) resected between 2003 and 2012. The clinical records were reviewed, the patients' tumours restaged according to the 8th edition of the AJCC, and we analysed five-year survival to verify whether different correlations were made between the T and N stages and disease-specific survival using the 7th and 8th editions. We excluded seven cases because information was incomplete, and the final sample was 167 patients. The five-year overall survival was 68% and the five-year disease-specific survival was 78%. The variable pT was upstaged in 51 patients (31%), and no tumour was downstaged. When we used the 7th edition, the pT category did not correlate with survival (p=0.055), but when we used the 8th edition, there was a significant association between increased pT categories and disease-specific survival (p=0.01). In the pN category 23 cases were upstaged (14%) and this affected disease-specific survival using both the 7th and the 8th editions (p=0.001). When patients were restaged, there was an improvement in discrimination between T categories in relation to disease-specific survival, and confirmation of the prognostic impact of the variable pN. T stage and depth of invasion are complementary predictors of disease-specific survival, and their combination results in the new AJCC staging system giving a better prognosis.

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Background Progressive lung involvement in Filamin A (FLNA)-related cerebral periventricular nodular heterotopia (PVNH) has been reported in a limited number of cases. Case presentation We report a new pathogenic FLNA gene variant (c.7391_7403del; p.Val2464Alafs*5) in a male infant who developed progressive lung disease with emphysematous lesions and interstitial involvement. Following lobar resection, chronic respiratory failure ensued necessitating continuous mechanical ventilation and tracheostomy. Cerebral periventricular nodular heterotopia was also present. Conclusions We report a novel variant of the FLNA gene, associated with a severe lung disorder and PNVH. The lung disorder led to respiratory failure during infancy and these pulmonary complications may be the first sign of this disorder. Early recognition with thoracic imaging is important to guide genetic testing, neuroimaging and to define optimal timing of potential therapies, such as lung transplant in progressive lung disease.

Background: Statins and sildenafil have been shown to exert beneficial effects in cardiac injury. We hypothesized that antenatal maternal administration of simvastatin and/or sildenafil might also promote benefits in cardiac remodeling of congenital diaphragmatic hernia (CDH). Therefore, we performed micro-CT image analysis and histology of the heart after antennal treatment in experimental nitrofen-induced CDH. Methods: At 9.5 days post conception (dpc), pregnant rats were exposed to nitrofen. At 16 and 20 dpc fetuses were treated with simvastatin and/or sildenafil. At 21 dpc postmortem micro-CT and autopsy were performed. Results: All nitrofen-treated fetuses had a lower birth weight compared to controls; in the simvastatin-treated group, a significant improvement in CDH was noted. Impairment of the lung and liver was also noted in CDH. Compared to controls, CDH rats showed lower ventricular mass, with greater left ventricular thickness; simvastatin decreased the ventricular mass and improved wall thickness. CDH rats exhibited myocardial hypotrophy, severe vascular depression in the left ventricle, and intense interstitial edema compared to controls and nitrofen-exposed animals without CDH. In CDH, the cardiac morphology appeared deformed with left ventricular wall verticalization. Simvastatin improved cardiac myocyte appearance and heart morphology. Conclusion: The potential to treat CDH with antenatal simvastatin may improve the management of this malformation.

Riassunto Obiettivi Il rabdomiosarcoma e un tumore maligno dei tessuti molli che origina dal muscolo scheletrico; e stato inizialmente descritto nel 1854 e rappresenta piu del 50% dei sarcomi dei tessuti molli nei giovani pazienti. Diagnosticare un rabdomiosarcoma e spesso difficile dato che, clinicamente, non ha caratteristiche patognomoniche e univoche. Materiali e metodi Si riporta il caso di un rabdomiosarcoma facilmente confondibile con una lesione di origine odontogena, diagnosticato a un giovane di 24 anni. Per giungere alla diagnosi finale sono state necessarie piu fasi e tecniche quali l’istopatologia, l’immunoistochimica e l’imaging, in aggiunta all’aspetto clinico. Risultati e conclusioni La diagnosi precoce delle lesioni maligne del cavo orale riveste un ruolo determinante per la prognosi. E necessario adottare un atteggiamento critico e consapevole per non incorrere in errori diagnostici e, conseguentemente, terapeutici. Inoltre e opportuno che i casi sospetti o dubbi siano tempestivamente inviati a strutture specializzate di riferimento per ottimizzare la gestione del piano diagnostico-terapeutico.

Introduction: We assessed the post-mortem micro-CT utility to evaluate fetal cardiac impairment in nitrofen-induced congenital diaphragmatic hernia (CDH). Methods: At 9.5d postconception (dpc), pregnant rats were exposed to nitrofen. At +18 and +21dpc, fetuses were harvested by cesarean section. Postmortem micro-CT and autopsy were performed. Fetuses were assigned to three experimental groups: Control group (C), Nitrofen group (N, exposition to nitrofen without CDH), CDH group. Cardio-pulmonary indices were evaluated. Results: An accurate morphological evaluation of the lung and heart was obtained. Early cardiac impairment was present in the N and CDH groups. At term pregnancy, an increased maximum diameter and decreased minimum diameter of the ventricles and increased interventricular septal thickness were noted in CDH. Histology showed a myocardial “disarray” and an high density of mitotic myocytes in CDH at midgestation. Conclusions: The potential utility of post-mortem fetal micro-CT examination in CDH was introduced. The results highlighted the presence of cardiac adaptation in affected fetuses.

Acutemyocarditisisanin flammatorydisorderoftheheartmuscleinwhichtheseverityofinjurydependsbothonthenatureoftheoffendingagent(i.e.virus)andontheensuinginflammatoryresponse.Thede fini-tion excludes, however, the response to ischemic or toxic injury. Theheart, however, like other organs, may provide a stereotyped responsetoinjury.Followingischemicinjury,theformationoftheinfl ammasomein the heart promotes heart failure [1].Theinflammasome is a macro-molecular structure activated during injury that amplifies the responseby processing Interleukin-1β (IL-1β) and IL-18, and promotion of celldeath [2]. Viral infections may lead to either death of the virus and thecell (pyroptosis), or survival of both cell and virus with persistence ofthe infection through inhibition of the inflammasome (evasion) [3].Therearenoreportsoftheinflammasomeinacutemyocarditis.Wehy-pothesize that the viral infection or the ensuing cellular destructionleads to the formation of the inflammasome, providing an opportunityto explore inflammasome-related markers for diagnostic or prognosticpurposes. Furthermore at present day, there are no specific treatmentsfor acute myocarditis, and thus inhibitors of the inflammasome couldrepresent a new therapeutic approach.We studied samples obtainedthrough endomyocardialbiopsy in11patients with acute lymphocytic myocarditis (b4 weeks of symptomsonset) in Trieste, Italy. The diagnosis was based upon pathology exam-ination and clinical scenario (Table 1). As a comparison group westudied autopsy samples of 11 patients with acute myocarditis diag-nosed post mortem, and 5 control subjects who had died withoutacute myocarditis or other acute cardiac conditions.Weemployedimmunofluorescencestainingtodetectin flammasomeaggregatesusingantibodiesraisedagainstthescaffoldprotein,ApoptosisSpeck-like protein containing a caspase-1 recruiting domain (ASC), and/or the effector protein, caspase-1, as previously described [1].Tocharac-terizethetypeofcell,weusedadoublestainingtechniquewithantibod-ies against cardiac actin to identify cardiomyocytes, S100A4 to identifyfibroblasts, andCD31 forendothelialcells. To overcomefor the auto fluo-rescence of sarcomeric proteins, we used a solution of 1% Sudan black in70% ethanol for 5 min. Images of samples were acquired with an IX70microscope and cellSens Dimension di gital imaging software (Olympus,Central Valley, PA) using a 40× objective (400× magnification). Filtersets for each separate fluorescence-conjugated antibody were layeredtorenderacompositeimage.Theinflammasome “specks” were countedby cell type (cardiomyocyte, leukocytes, fibroblasts and endothelialcells) per high power field of view (40×). Data are presented as medianand interquartile range and non-parametric Mann–Whitney test wasused.Intracellularaggregates of ASC and/ or caspase-1 indicative of the for-mation of the inflammasome were seen in leukocytes, cardiomyocytes,fibroblasts and endothelial cells in heart biopsy samples of all 11 cases(100%), and in heart samples of 10 of 11 post-mortem cases (91%), andin none of the controls (0%, P b 0.002)(Fig. 1). ASC aggregates co-localized with caspase-1 aggregates in virtually all cases. The numberof inflammasomes was variable across cases ranging between 3 and 14specks in biopsies, and between 0 and 45 specks per field in autopsies,without statistically significant differences (data not shown). Some

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p

Il 23 febbraio 2013 un paziente di 66 anni giunge presso l’Ambulatorio di Medicina e Patologia orale della Clinica Odontoiatrica e Stomatologica di Trieste lamentando algia alla masticazione in sede mandibolare destra. Il paziente, portatore di protesi rimovibile, era incapace di indossarla a causa del dolore. Nonostante il consulto con il proprio odontoiatra, che aveva molato e ribasato la protesi inferiore per due volte, il dolore persisteva da più di un mese. La raccolta dell’anamnesi patologica svela una storia clinica di pregresso carcinoma della prostata nel 2010, del polmone nel 2011 e della tiroide nel 2012, tutti risolti dopo terapia combinata chirurgica e chemioterapica. Il paziente nega di avere allergie o altre comorbilità ma riferisce di assumere i seguenti farmaci: pregabalin (25 mg, 2/die), liotironina sodica (20 μg, 1 cpr/2 die), colecalciferolo (10.000 UI, 25 gtt/settimana), tramadolo (20 gtt, 3/die). All’esame obiettivo il paziente appare edentulo, con importante atrofia sia mascellare sia mandibolare, tuttavia senza alcuna lesione né discontinuità mucosa. I linfonodi laterocervicali, omolaterali al dolore riferito, risultano ingrossati e di consistenza aumentata. Dopo accurata palpazione della cresta edentula del quarto quadrante, che scatena importante dolore al paziente, si percepisce un’irregolarità dell’osso. In seguito all’esecuzione di una radiografia ortopanoramica (fig. 1) si osserva un’ampia lesione radiotrasparente a margini irregolari in sede quarto quadrante, accompagnata da una piccola lesione osteolitica controlaterale. Nella stessa giornata, dopo aver ottenuto il consenso informato scritto da parte del paziente, si esegue un’incisione marginale nella sede dove si percepisce discontinuità ossea e, dopo adeguato scollamento dei tessuti molli, si individua la presenza di un’area di 4 cm infarcita di tessuto molle, arrossato e fibroso, la quale è stata parzialmente prelevata e inviata all’anatomia patologica. Il report istopatologico, ottenuto dopo 7 giorni, riferisce quanto segue: “Frammenti di tessuto osseo caratterizzati dalla sostituzione delle trabecole con tessuto fibroso. Visibili aree di agglomerati cellulari. Compatibile con metastasi da carci- noma tiroideo. Immunofenotipizzazione positiva per TTF1 (fattore di trascrizione tiroideo), tireoglobulina e CK7 (citocheratina)” (fig. 2a,b). Il paziente viene riferito alla Clinica otorinolaringoiatrica per la valutazione chirurgica del caso. La tomografia computerizzata evidenzia la presenza della lesione osteolitica in sede mandibolare destra, accompagnata da discontinuità dell’osso corticale e coinvolgimento del nervo alveolare inferiore. Controlateralmente, la lesione osteolitica risulta di minori di- mensioni e caratterizzata da una perfetta continuità dell’osso corticale. Su richiesta dei colleghi ORL, la lesione controlatera- le viene comunque sottoposta a biopsia, escludendo definitivamente che si tratti di un’ulteriore metastasi. Il referto istopatologico recita quanto segue: “Frustoli di tessuto osseo con assottigliamento delle trabecole e sostituzione da parte di tessuto fibroblastico. Nel materiale inviato non risultano documentabili aspetti coerenti con la presenza di localizzazioni secondarie”. Successivamente il paziente viene sottoposto a emimandibulectomia (fig. 3) con ricostruzione a mezzo lembo mi- crovascolarizzato con prelievo di fibula, contestualmente allo svuotamento omolaterale dei linfonodi del collo. L’anatomopatologo conferma la diagnosi di metastasi da tumore tiroideo e definisce i margini di resezione come liberi da malattia. Dopo 3 mesi dall’intervento il paziente viene nuovamente riferito all’Ambulatorio di Medicina e Patologia orale dove è riabilitato con una protesi totale superio- re e inferiore. Attualmente risulta libero da malattia e in buone condizioni generali. Nonostante i tumori solidi metastatizzino raramente al distretto oro-maxillofacciale, il riconoscimento precoce della lesione e un’adeguata diagnosi differenziale vanno eseguiti per aumentare le probabilità di un trattamento efficace. L’approfondimento diagnostico risulta importante in casi come questo nel quale, nonostante l’apparente assenza di problematiche, una semplice radiografia panoramica ha permesso di evidenziare la lesione. Questo caso clinico pone l’accento su quanto sia importante non sottovalutare mai i sintomi riferiti dal paziente e affrontare l’approccio al dolore del cavo orale in maniera razionale e consapevole.

Background: Multivessel coronary disease after myocardial infarction is a major risk factor for unfavorable cardiac remodeling and death due to pump failure, but underlying pathophysiologic mechanisms are still uncompletely established. Post-infarction myocardial apoptosis has been recently implicated as a cause of ongoing cell loss leading to cardiac failure. Our aim was to assess the role of post-infarction myocardial apoptosis and pro-apoptotic factor expression in the non-infarcted remote myocardium of subjects with multivessel coronary disease. Methods: Twenty-one males dying after recent myocardial infarction with permanent occlusion of the infarct-related artery were selected at autopsy. Apoptosis was assessed at viable myocardial regions remote from infarction by co-staining for in situ end-labeling of DNA fragmentation and cleaved caspase-3. Expression of pro-apoptotic factor bax and hypoxia-induced factor-1alpha was evaluated by immunohistochemistry. Results: Subjects with multivessel disease (N = 11) showed a significantly two-fold higher myocardial apoptosis in comparison to subjects with single vessel disease (N = 10) (0.9% vs. 0.5%, p = 0.013). Similarly, myocardial bax expression was increased in patients with multivessel disease (3.0% vs. 1.4%, p = 0.029). Stratification for the number of diseased coronary vessels confirmed the association between extent of coronary disease and apoptotic rates (p = 0.022). Even in subjects dying over 30 days after infarction multivessel disease remained predictive of enhanced myocardiocyte apoptosis at remote regions (p = 0.033). Conclusions: Post-infarction myocardial apoptosis and bax expression in remote left ventricular regions are significantly increased in male patients with multivessel coronary disease in comparison to those with isolated infarct-related artery occlusion. These findings suggest that apoptotic cell loss in the viable non-infarcted myocardium, possibly due ongoing ischemia, may play a relevant role in the unfavorable clinical course typical of multivessel disease after myocardial infarction. © 2004 Published by Elsevier Ireland Ltd.

Heart failure is a complex syndrome characterized by impaired emptying and/or impaired filling of the heart chambers. The use of parameters of diastolic function has provided novel tools for risk stratification and management of patients with heart failure. This study evaluated the potential correlation between apoptosis at time of death and left ventricular (LV) diastolic function after acute myocardial infarction. We selected, at routine postmortem examination, 14 subjects who died 10 to 62 days after an acute myocardial infarction and had an available echocardiographic report from the most recent hospital admission. The apoptotic rate was calculated at the region bordering the infarct, using co-localization of in situ end-labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3. Transthoracic echocardiographic studies were retrospectively reevaluated and pulse-wave Doppler spectra of mitral inflow were analyzed. LV diastolic function was assessed by measuring the ratio of E peak velocity to A peak velocity and E-wave deceleration time; a ratio of E peak velocity to A peak velocity ≥2 and deceleration time

BACKGROUND: There are few articles in the literature reporting the histological changes of groin structures affected by inguinal hernia. A deeper knowledge of this matter could represent an important step forward in the identification of the causes of hernia protrusion. This study aimed to recognise the pathological modifications of muscular structures in autopsy specimens excised from tissues surrounding the hernia orifice. METHODS: Inguinal hernia was identified in 30 autopsied cadavers, which presented different varieties of hernia, including indirect, direct and mixed. Tissue specimens were resected for histological study from structures of the inguinal area surrounding the hernia opening, following a standardised procedure. The histological examination was focussed on the detection of structural changes in the muscle tissues. The results were compared with biopsy specimens resected from corresponding sites of the inguinal region in a control group of 15 fresh cadavers without hernia. RESULTS: Significant modification of the muscular arrangement of the inguinal area was recognized. Pathological alterations such as atrophy, hyaline and fibrotic degeneration, as well as fatty dystrophy of the myocytes were detected. These findings were observed consistently in the context of multistructural damage also involving vessels and nerves. In cadavers with hernia these alterations were always present independent of hernia type. No comparable damage was found in control cadavers without hernia. CONCLUSIONS: The high degree of degenerative changes in the muscle fibres in the inguinal area involved in hernia protrusion described in this report seems to be consistent with chronic compressive damage. These alterations could embody one important factor among the multifactorial sources of hernia genesis. Conjectures concerning its impact on the physiology and biodynamics of the inguinal region are made. The relationship between the depicted degenerative injuries and the genesis of inguinal hernia is also a focus of discussion in this article.

BACKGROUND: Few scientific reports to date describe the histological modification of structures outlining a hernia opening. This article is focused on the identification of the pathological changes in vascular structures in tissues excised from cadavers with inguinal hernia. A deeper comprehension of this topic could lead to essential improvements in the detection of hernia genesis. MATERIALS AND METHODS: Different kinds of hernia, including indirect, direct and mixed, were identified in 30 autopsied subjects. Tissue samples were resected for histological study from abdominal wall structures close to the hernia opening. Histological examination focused on the detection of structural changes in arteries and veins. The results were compared with tissue specimens excised from equivalent sites of the inguinal area in a control group of 15 fresh cadavers without hernia. RESULTS: Significant modification of vascular structures were identified in the tissue specimens examined. The veins demonstrated parietal fibrosis, perivascular edema and vascular dilation due to congestion and stasis. The arterial structures detected showed thickening of the media due to medial hyperplasia, ranging from luminal sub-occlusion to a manifest artery occlusion. These findings are present independent of hernia type in cadavers with inguinal hernia. These pathological changes were lacking in the control group of cadavers without hernia. CONCLUSIONS: The notable changes in vascular structures described in the report could be the result of a steady compressive effect exerted by the abdominal viscera in the inguinal area. These pathological changes could represent one of the factors involved in the weakening of the inguinal region leading to hernia protrusion.

BACKGROUND: The histological study of the herniated inguinal area is rare in the literature. This report is focused on the detection of structural changes of the nerves within tissues bordering the inguinal hernia of cadavers. Their physiopathological consequences are hypothesized. MATERIALS AND METHODS: Primary inguinal hernia was diagnosed in 30 fresh cadavers. Tissue specimens from the inguinal region close to and around the hernia opening were excised for histological examination. A control of the data was achieved through tissue samples excised from equivalent sites of the inguinal region in 15 cadavers without hernia. RESULTS: The detected nerves in the inguinal area demonstrated pathological changes such as fibrotic degeneration, atrophy, and fatty dystrophy of the axons. The thickening of the perineural sheath was constantly seen. These findings were consistently present, independent of the hernia type. CONCLUSIONS: The detected nerve alterations lead us to imagine a worsening, or even the cessation, of the nervous impulse to the muscles, leading to atrophy and weakening of the abdominal wall. This could represent one of the multifactorial causes of hernia genesis.

Acute myocarditis is an acute inflammatory syndrome characterized by acute myocardial damage and dysfunction followed by a variable recovery over time with some patients progressing toward severe dilated cardiomyopathy. Cardiomyocyte apoptosis, a key pathologic feature of heart failure, may play a critical role in functional recovery in patients with acute myocarditis. The aim of the study was to investigate whether apoptosis predicts functional recovery in patients with acute myocarditis. Sixteen patients with biopsy-documented acute myocarditis were followed for 1 year with serial transthoracic echocardiography. Functional recovery was defined as 12-month left ventricular ejection fraction >40%. Cardiomyocyte apoptosis, leukocyte infiltration, and cell proliferation was assessed in all samples. A group of cases in which the diagnosis of acute myocarditis was made after death was also selected for comparison, and morphologically normal hearts from patients who died from a noncardiac cause were selected as controls. Six patients (38%) had functional recovery at 12 months, whereas 10 (62%) did not. The 2 groups had similar characteristics except for lower baseline left ventricular ejection fraction in the group with functional recovery. Apoptotic rate was found to be significantly higher in patients with acute myocarditis than in control hearts, and, unexpectedly, patients with functional recovery had significantly higher apoptotic rates than patients without recovery (3.2% vs 0.5%, p = 0.001). None of the patients with apoptotic rates below the median had functional recovery versus 86% of patients with apoptotic rates above the median (p

Background: T-lymphocyte activation within atherosclerotic plaque, and widespread to the myocardium, has been shown in patients with acute coronary syndromes. Objective: To investigate the presence of T-lymphocyte infiltrate at different stages of acute coronary syndromes by studying patients with sudden coronary death, acute myocardial infarction (AMI) and healed infarction, in comparison with patients with myocarditis and patients with non-ischaemic heart failure. Methods: 72 cases were studied at autopsy: 12 dying of sudden coronary death (group 1), 12 dying 4 months after AMI (group 3), 12 with active lymphocytic myocarditis (group 4), 12 with hypertensive heart disease (group 5), and 12 control subjects (group 6). Light microscopy was performed to measure the number of activated T-lymphocytes (CD3+/DR+) in the myocardium and coronary artery wall, and intercellular adhesion molecule-1 (ICAM-1) expression in the myocardium. Results: Activated T-lymphocyte infiltrates and ICAM-1 myocardial expression in both remote and peri-infarction regions and activated T-lymphocytes within the epicardial coronary artery wall of both the infarct- and non-infarct-related arteries were found in groups 1, 2 and 3, whereas myocardial, but not coronary, infiltrates were found in groups 4 (p

Objectives: The aim of the study was to analyze the molecular mechanisms activated during postinfarction remodeling in human hearts. Background: The molecular mechanisms of initial response to ischemic insult in the heart and the pathways involved in compensation and remodeling are still largely unknown. Methods: Up-regulation or down-regulation of gene expression in the human viable peri-infarct (vs. remote) myocardial region was investigated by complementary deoxyribonucleic acid array technology and confirmed at a single-gene/protein level with reverse transcriptase polymerase chain reaction and immunohistochemistry. An in vitro model of cardiomyocyte hypoxia in HL1 cells was used to validate anti-apoptotic effects of the candidate gene/protein and to assess the associated downstream cascade. Finally, a mouse model of myocardial infarction was used to test the in vivo effects of exogenous transfection with the candidate gene/protein. Results: Protein disulfide isomerase (PDI), a member of the unfolded protein response, is 3-fold up-regulated in the viable peri-infarct myocardial region, and in a postmortem model, its expression is significantly inversely correlated with apoptotic rate and with presence of heart failure (HF) and biventricular dilatation. Induced PDI expression in HL1 cells conferred protection from hypoxia-induced apoptosis. Adenoviral-mediated PDI gene transfer to the mouse heart resulted in 2.5-fold smaller infarct size, significantly reduced cardiomyocyte apoptosis in the peri-infarct region, and smaller left ventricular end-diastolic diameter versus mice treated with a transgene-null adenoviral vector. Conclusions: These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF. © 2007 American College of Cardiology Foundation.

Apoptosis is a key pathologic feature in acute myocardial infarction and heart failure. Experimental animal studies have shown beneficial effects of inhibiting apoptosis. Understanding the mechanisms involved in the apoptotic cascade may be useful in better understanding of heart failure and its management. Not only in vivo detection of apoptosis may prove clinically useful in the diagnosis and risk stratification of patients with ischemic heart disease, but anti-apoptotic treatments (specific and non-specific) may be effective in the prevention and treatment of post-infarction remodelling and heart failure. © 2006 Elsevier Ltd. All rights reserved.

Heart failure (HF) is less prevalent and has a better prognosis in women than in men. Also, the outlook after acute myocardial infarction (AMI) is more favourable in elderly women.1 Such sex related differences are probably related to sex specific cardiac remodelling processes.2 However, despite several hypothetical pathogenetic mechanisms, there are no established explanations. Myocardial apoptosis is a pivotal determinant of left ventricular (LV) dysfunction and cardiac failure in experimental and clinical studies, including after AMI. Sex may indeed influence apoptosis, as shown in normal aging and in end stage HF.3 However, little is known about the role of sex in post-infarction apoptosis. We thus evaluated the influence of sex on expression of pro-apoptotic mediators and myocardiocyte apoptotic index (AI) in subjects dying after AMI. Using established methods,4 we selected six females who had died after AMI with permanent infarct related artery occlusion at necropsy (< 30 hours after death); 15 males with similar characteristics were selected during the same period. Three men and one woman dying from non-cardiac causes were included as controls. Re-infarction was excluded on clinicopathologic grounds in all cases. Infarct size was quantified at gross pathology on a four grade scale (small, moderate, moderate to extensive, and extensive). Tissue specimens were obtained at peri-infarct and remote sites. In situ end labelling of DNA fragmentation by transferase-mediated biotinylated UTP nick end labelling (TUNEL) was performed (Apoptag, Oncor) and sections were stained with antibodies against muscle actin (DAKO-Carpintera; dilution 1:50), and activated caspase-3 (Cell …

We report hypoxia-inducible factor-1 (HIF-1) expression in myocardium of patients with recent acute myocardial infarction (AMI), supporting the hypothesis of HIF-1 as a possible mediator of response to ischemia. A potential diagnostic role of determining tissue expression of HIF-1 as a marker of ischemia, and potential therapeutic implications by trying to modulate HIF-1 activity in order to promote beneficial effects of HIF-1 related genes (e.g. expression of vascular endothelial growth factor (VEGF)) may derive. © 2004 Elsevier Ireland Ltd. All rights reserved.

Aims: Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium. Methods and results: In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P = 0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P < 0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P = 0.42] Conclusion: Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences. © The European Society of Cardiology 2005. All rights reserved.

Background— Diffuse coronary vascular inflammation is associated with acute coronary syndromes. However, it is unknown whether inflammation also occurs within the myocardium. Therefore, this study was aimed at assessing the presence of activated cells in unaffected remote myocardium of patients with acute myocardial infarction (AMI), in comparison to the peri-infarct region from the same cases, and in comparison to myocardial specimens from control hearts. Methods and Results— Sixteen patients dying 1 to 12 weeks after AMI and 16 control subjects were selected at autopsy. Myocardial specimens were taken at remote unaffected viable regions and at peri-infarct regions in cases with AMI. Confocal microscopy was performed to measure the number of activated cells (DR+), T-lymphocytes (CD3+), and activated T-lymphocytes (CD3+/DR+). Activated cells and activated T-lymphocytes were found in remote unaffected regions in 11 of 16 cases (69%), in peri-infarct zone in all cases (100%), and in none of the control hearts (0%, P P Conclusions— This study for the first time shows the presence of activated T-lymphocytes in remote unaffected myocardial regions in approximately two thirds of patients with recent AMI. Because these cells are associated with persistent infarct-related artery occlusion, our data may suggest that an antigenic stimulus present also in the myocardium triggers an immune response that may be critical to precipitate artery occlusion. (Circulation. 2004;110:46-50.)

Background: Cyclo-oxygenase-2 (COX-2) is induced in cardiomyocytes only in response to stress, such as ischaemia. Objective: To assess COX-2 expression at the site of recent myocardial infarction. Methods: COX-2 expression was evaluated by specific immunostaining in cardiomyocytes from 23 subjects who died 10–60 days after acute myocardial infarction. The relation between COX-2 myocardial expression and apoptotic rate was investigated. Cardiomyocyte apoptotic rate was defined as the number of cells co-expressing in situ end labelling of DNA fragmentation (TUNEL) and immunostaining for activated caspase-3. Results: COX-2 expression was found in cardiomyocytes at the site of infarction in nine of 23 cases (39%). It was associated with fivefold higher apoptotic rates (median 17.9% (interquartile range 11.0–25.4%) v 3.7% (0.6–12.8%); p = 0.016), and apoptotic rate increased progressively from mild to intense COX-2 staining (p for trend 0.009). COX-2 expression co-localised with TUNEL nuclear staining in myocytes, and there was a high concordance between COX-2 and hypoxia induced factor 1-α staining (78%, p = 0.021) and between COX-2 and bax (83%, p = 0.014). Subjects showing myocardial COX-2 expression were more likely to have enlarged hearts (p = 0.050), and intense COX-2 staining was strictly associated with symptomatic heart failure (p = 0.035). Conclusions: COX-2 is expressed in cardiomyocytes in nearly 40% of cases at the site of recent acute myocardial infarction, even late after the index event. Its expression was associated with extremely high apoptotic rates. These findings suggest a potential cause–effect link between COX-2 expression and enhanced myocardial apoptosis in ischaemic cardiomyopathy.

While demonstration of cells with DNA synthesis is common in postinfarction models, the true significance of these cells is questionable. As we find that these markers are closely linked to apoptosis and unfavorable cardiac remodeling, they are likely to represent either early or late events in the mitotic failure leading to cell death. Because the differentiation of dying myocardiocytes in oncotic, apoptotic and mitotic deaths is mostly academical, these markers should be considered unfavorable prognostic markers for cell loss, unless true demonstration of effective cell replication is presented. © 2003 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVES: The purpose of this study was to evaluate a potential correlation between apoptotic rate (AR), post-infarction left ventricular (LV) remodeling, and clinical characteristics in subjects who died late (≥10 days) after an acute myocardial infarction (AMI) with evidence of persistent occlusion of the infarct-related artery at autopsy. BACKGROUND: Apoptosis contributes to myocardiocyte loss in cardiac disease and may have a pathophysiologic role in post-infarction LV remodeling. METHODS: The AR was calculated at the site of infarction and in remote unaffected LV regions, using co-localization of in situ end labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3, in 14 subjects who died within two months after AMI. Correlation between AR and clinical characteristics such as age, site of AMI, transmural extension, multivessel coronary disease, and signs and/or symptoms of heart failure (HF), at the time of initial hospitalization for AMI or subsequently before death, was assessed using non-parametric statistical tests. Parameters of LV remodeling including diameters, free wall thickness, diameter-to-wall-thickness ratio, and mass were measured at gross examination at autopsy. Values are expressed as median (interquartile range). RESULTS: Among clinical variables, early symptomatic post-infarction HF (9 cases, 64%) was associated with nearly fourfold increased AR at the site of infarction (26.2% [24.5% to 28.8%] vs. 6.4% [1.9% to 13.3%], p = 0.001). Moreover, AR both at the site of infarction and in unaffected regions was significantly correlated with parameters of progressive LV remodeling (p < 0.05). CONCLUSIONS: Our data show that in patients dying ≥10 days after AMI, myocardial apoptosis is strongly associated with and may be a major determinant of unfavorable LV remodeling and early symptomatic post-infarction HF. © 2003 by the American College of Cardiology Foundation.

Background: Cardiac remodelling after acute myocardial infarction (AMI) is characterised by molecular and cellular mechanisms involving both left and right ventricles, and biventricular failure identifies patients with an extremely unfavourable prognosis. Aims: To assess whether a link exists between increased myocardial apoptotic rates (AR) at sites of recent infarction and patterns of unfavourable cardiac remodelling, such as biventricular enlargement after left ventricular (LV) infarction. Methods: Twelve patients with recent AMI involving the LV and not the right ventricle (RV) and with permanent infarct related artery occlusion were selected at necropsy. Gross pathological characteristics, such as LV and RV dilatation, and AR at site of infarction were assessed. Potential false positive results (DNA synthesis and RNA splicing) were excluded from the cell count. Results: RV enlargement, defined as a tricuspidal ring greater than 120 mm, was found in five cases and was associated with LV dilatation. These patients showed significantly higher AR than the others. When the subjects were divided into three groups according to progressive cardiac remodelling (absence of cardiac dilatation, isolated LV dilatation, and biventricular enlargement), the last group had significantly higher ARs than the other two groups, showing that myocardiocyte apoptosis is increased in more unfavourable forms of cardiac remodelling. Conclusion: Patients with severely unfavourable cardiac remodelling, such as biventricular enlargement, have extremely high myocardiocyte apoptosis at necropsy, even late after LV myocardial infarction, supporting the role of myocardiocyte loss in determining post-infarction adverse remodelling.

Background— Myocardial apoptosis persists beyond the acute phases of acute myocardial infarction (AMI) and is associated with left ventricular (LV) remodeling. Infarct-related artery (IRA) patency is considered a favorable prognostic factor after AMI and may be associated with more favorable LV remodeling because of reduced apoptosis at the site of AMI. The aim of this study was to assess the influence of IRA status on apoptotic rate (AR) in the hearts of subjects dying late after AMI. Methods and Results— We used colocalization for in situ end-labeling of DNA fragmentation and immunohistochemistry for caspase-3 to calculate the AR at time of death (12 to 62 days after AMI) in 16 hearts with persistently occluded IRAs and in 8 hearts with patent IRAs. No significant differences were found when comparing the clinical characteristics of the 2 groups. Occluded IRA was associated with significantly higher AR at site of infarction (25.8% [interquartile range 20.9% to 28.5%] versus 2.3% [interquartile range 0.6% to 5.0%], P P =0.003). Conclusions— A significantly higher AR was associated with persistent IRA occlusion late post-AMI. These data may suggest that the post-AMI benefits observed with a patent IRA (the “open-artery hypothesis”) may in part be due to reduced myocardial apoptosis.

Apoptosis is a common pathological feature in acute myocardial infarction (AMI), however, its role in the later phases (>10 days) of AMI and in post-infarction left ventricular remodeling has not been characterized. The aim of the study was to identify signs of ongoing cell apoptosis late post AMI. Sixteen hearts were collected at autopsy from subjects 12 to 62 days after the onset of AMI. In situ end-labeling of DNA fragmentation (TUNEL) and co-staining with caspase-3 were performed. Double-positive cells were defined as apoptotic and the apoptotic rate was calculated. Values are expressed as median and interquartile range. Co-stainings with muscle-actin, splicing factor (SC35), PCNA, bax and bcl-2 were also performed. Apoptotic rates at site of infarction [25.4% (17.0-28.4%)] were significantly higher v those at remote regions [0.7% (0.5-0.8%);P

The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of myocytes in the adult heart. Therefore, we studied the extent of mitosis among myocytes after myocardial infarction in humans.Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile rings, karyokinesis, and cytokinesis was also recorded.In the infarcted hearts, Ki-67 expression was detected in 4 percent of myocyte nuclei in the regions adjacent to the infarcts and in 1 percent of those in regions distant from the infarcts. The reentry of myocytes into the cell cycle resulted in mitotic indexes of 0.08 percent and 0.03 percent, respectively, in the zones adjacent to and distant from the infarcts. Events characteristic of cell division--the formation of the mitotic spindles, the formation of contractile rings, karyokinesis, and cytokinesis--were identified; these features demonstrated that there was myocyte proliferation after myocardial infarction.Our results challenge the dogma that the adult heart is a postmitotic organ and indicate that the regeneration of myocytes may be a critical component of the increase in muscle mass of the myocardium.