Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis.

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 <1 month) of whom 55 required inotropes and/or mechanical circulatory support (FM) and the remaining 132 were hemodynamically stable (NFM). We also performed a subanalysis in 130 adult patients with acute viral myocarditis and viral prodrome within 2 weeks from the onset, which includes 34 with FM and 96 with NFM. Patients with giant-cell myocarditis, eosinophilic myocarditis, or cardiac sarcoidosis and those <15 years of age were excluded from the subanalysis. 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<0.0001). Long-term heart transplantation-free survival at 9 years was lower in FM than NFM (64.5% versus 100%, log-rank P<0.0001). Despite greater improvement in LVEF during hospitalization in FM versus NFM forms (median, 32% [interquartile range, 20%-40%] versus 3% [0%-10%], respectively; P<0.0001), the proportion of patients with LVEF <55% at last follow-up was higher in FM versus NFM (29% versus 9%; relative risk, 3.32; 95% confidence interval, 1.45-7.64, 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.

FAM111A mutations result in hypoparathyroidism and impaired skeletal development.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.

A real-life prospective blinded evaluation of placental biometry and macroscopic morphology from 1008 unselected consecutive pregnancies.

INTRODUCTION: The study of the macroscopic appearance of the placenta may represent a useful tool to understand the pathophysiology of adverse pregnancy outcomes. The aim of this study was to evaluate biometry and morphology of placentas in relation to maternal, neonatal and pregnancy course characteristics. METHODS: Clinical and placental data (biometry and macroscopic features of chorionic disk and adnexa) from unselected consecutive singleton pregnancies were recorded at the same Institution. Placental efficiency was approximated as ratio between fetal and placental weight (FPR). The total population was grouped according to the presence of any maternal comorbidity or pregnancy complication (group 1), neonatal complications diagnosed only at birth (2) and absence of any comorbidity (3). Multi-adjusted general linear and logistic regression models were performed to analyze associations between groups and placental biometry and morphology. RESULTS: The study population counted 1008 pregnancies: 576 (57.2 %) classified as group 1, 76 (7.5 %) as group 2 and 356 (35.3 %) uncomplicated controls (group 3). In multivariate models adjusted for confounding factors, no significant differences in placental biometry and macroscopic features were observed among the three groups. Maternal BMI was significantly associated with higher placental and birth weight and lower FPR; moreover FPR was significantly higher in pregnancies carrying males compared to female neonates. DISCUSSION: Maternal comorbidity or pregnancy disease was not associated with significant changes in placental macroscopic biometry and morphology. Conversely, maternal pregestational BMI and fetal sex impact on placental biometry and efficiency, suggesting different intrauterine adaptations in obese mothers and in male and female fetuses.

Histological findings following use of CoSeal in a patient with a left ventricular assist device.

Adhesions are a formidable challenge in patients undergoing reoperative cardiac surgery, particularly in those supported by an intracorporeal left ventricular assist device (LVAD) and undergoing heart transplantation. This report describes the pathological findings following the clinical use of a surgical sealant (CoSeal, Baxter Healthcare, Fremont, CA), in a patient who underwent LVAD implantation. On the treated surfaces, a minimal amount of adhesions were observed, whereas in untreated surfaces adhesions were present.

Methodology for Biometrical Analysis of the Placenta: Feasibility and Reproducibility.

The role of a healthy placenta as the interface between mother and fetus, which regulates the intrauterine environment and affects fetal and pregnancy outcomes, points to placental examination as a potentially useful diagnostic tool. Placental macroscopic and microscopic patterns are routinely evaluated when pregnancy complications occur. Moreover, placental measures particularly the ratio between fetal and placental weight have been reported to correlate with maternal characteristics, such as BMI as well as with birth-weight and fetal gender. Our pilot study evaluates the feasibility of the placental measures' reproducibility intra-operators. We enrolled 50 consecutive singleton pregnancies including physiological pregnancies and any pre-existing maternal disease or maternal and fetal complication. We conducted a macroscopic analysis of fetal adnexa with four different operators assessing pathological findings or other abnormalities. Intra-class correlation coefficient (ICC) and Cohen and Fleiss kappa coefficient were used to assess the degree of consistency between operators. The results of our study show that the placental morphometric analysis is a reproducible method.

Persistent left ventricular dysfunction after acute lymphocytic myocarditis: Frequency and predictors.

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 <50% at 1-year, and was observed in 27/48 patients (56.3%). Higher LV end-diastolic diameter at admission (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.04-1.43, p = 0.002), non-fulminant presentation (OR 8.46, 95% CI 1.28-55.75, p = 0.013) and presence of a poor lymphocytic infiltrate (OR 12.40, 95% CI 1.23-124.97, p = 0.010) emerged as independent predictors of persistent LV dysfunction at multivariate analysis (area under the curve 0.91, 95% CI 0.82-0.99). Pre-discharge LVEF was lower in patients with persistent LV dysfunction compared to the others (32%±8 vs. 53%±8, p <0.001), and this single variable showed the best accuracy in predicting the study end-point (area under the curve 0.95, 95% CI 0.89-1.00). CONCLUSIONS: More than half of patients presenting with acute LM and LVEF <50% who survive the acute phase show persistent LV dysfunction after 1-year from hospital discharge. Features of subacute inflammatory process and of established myocardial damage at initial hospitalization emerged as predictors of this end-point.

Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support. A single-center study found that a patient with FM had better outcomes than those with acute nonfulminant myocarditis (NFM) presenting with left ventricular systolic dysfunction, but otherwise hemodynamically stable. This was recently challenged, so disagreement still exists. OBJECTIVES: This study sought to provide additional evidence on the outcome of FM and to ascertain whether patient stratification based on the main histologic subtypes can provide additional prognostic information. METHODS: A total of 220 patients (median age 42 years, 46.3% female) with histologically proven acute myocarditis (onset of symptoms <30 days) all presenting with left ventricular systolic dysfunction were included in a retrospective, international registry comprising 16 tertiary hospitals in the United States, Europe, and Japan. The main endpoint was the occurrence of cardiac death or heart transplantation within 60 days from admission and at long-term follow-up. RESULTS: Patients with FM (n = 165) had significantly higher rates of cardiac death and heart transplantation compared with those with NFM (n = 55), both at 60 days (28.0% vs. 1.8%, p = 0.0001) and at 7-year follow-up (47.7% vs. 10.4%, p < 0.0001). Using Cox multivariate analysis, the histologic subtype emerged as a further variable affecting the outcome in FM patients, with giant cell myocarditis having a significantly worse prognosis compared with eosinophilic and lymphocytic myocarditis. In a subanalysis including only adults with lymphocytic myocarditis, the main endpoints occurred more frequently in FM compared with in NFM both at 60 days (19.5% vs. 0%, p = 0.005) and at 7-year follow up (41.4% vs. 3.1%, p = 0.0004). CONCLUSIONS: This international registry confirms that patients with FM have higher rates of cardiac death and heart transplantation both in the short- and long-term compared with patients with NFM. Furthermore, we provide evidence that the histologic subtype of FM carries independent prognostic value, highlighting the need for timely endomyocardial biopsy in this condition.

Analysis of histological and immunohistochemical patterns of benign and malignant adrenocortical tumors by computerized morphometry.

Diagnosis of benign and purely localized malignant adrenocortical lesions is still a complex issue. Moreover, histology-based diagnosis may suffer of a moment of subjectivity due to inter- and intra-individual variations. The aim of the present study was to assess, by computerized morphometry, the morphological features in benign and malignant adrenocortical neoplasms. Eleven adrenocortical adenomas (ACA) were compared with 18 adrenocortical cancers (ACC). All specimens were stained with H&E, cellular proliferation marker Ki-67 and reticulin. We generated a morphometric model based on the analysis of volume fractions occupied by Ki-67 positive and negative cells (nuclei and cytoplasm), vascular and inflammatory compartment; we also analyzed the surface fraction occupied by reticulin. We compared the quantitative data of Ki-67 obtained by morphometry with the quantification resulting from pathologist's visual reading. The volume fraction of Ki-67 positive cells in ACCs was higher than in ACAs. The volume fraction of nuclei in unit volume and the nuclear/cytoplasmic ratio in both Ki-67 negative cells and Ki-67 positive cells were prominent in ACCs. The surface fraction of reticulin was considerably lower in ACCs. Our computerized morphometric model is simple, reproducible and can be used by the pathologist in the histological workup of adrenocortical tumors to achieve precise and reader-independent quantification of several morphological characteristics of adrenocortical tumors.

Oral ulcer as an exclusive sign of gastric cancer: report of a rare case.

BACKGROUND: The oral cavity is a rare but occasional target for metastases, which may masquerade as various benign and inflammatory lesions, and sometimes also be asymptomatic. Oral metastatic lesions have been described in various cancers, particularly lung, breast and kidney carcinoma. CASE PRESENTATION: We here describe an uncommon case of a hard palate mucosa and gingival metastasis from gastric carcinoma that was originally diagnosed as a periodontal disease. Histopathological examination of a biopsy of the lesion revealed a signet-ring cell carcinoma, and a subsequent biopsy of an ulcerated stomach lesion showed a poorly differentiated gastric carcinoma. The patient underwent gastric resection but died of heart failure on the tenth postoperative day; a post-mortem examination revealed a residual bilateral ovarian infiltration by gastric carcinoma (Krukenberg's tumor). CONCLUSION: An occult carcinoma of the stomach may rarely metastasise to the oral cavity even as a first and exclusive manifestation; it is important to bear this possibility in mind because such conditions may mimic a benign disease.

Predictive value of computerized morphometric analysis of steatosis in donor livers.

OBJECTIVE: To describe, by computerized morphometry, the degree and the type of steatosis in liver transplants that developed primary nonfunction and to compare the results with the quantification by pathologist. STUDY DESIGN: Twelve patients who developed primary nonfunction after liver transplantation were matched with 23 transplanted patients with a regular postoperative clinical course. Morphology of the liver biopsy included many stereological parameters; all cases were evaluated by an operator blinded to the diagnosis and to the clinical history. The assessment of steatosis by morphometry was compared with the pathologist's evaluation. Moreover, to assess the reproducibility of the morphometric model, another operator applied the morphometric model in a blinded fashion to a randomly selected sample of cases. RESULTS: The percentage of hepatocytes with microsteatosis and the ratio of macro/microsteatosis were higher in primary nonfunction. The pathologist's evaluation of steatosis showed a marked overestimation when compared to morphometry. Lastly, the comparison between the results of 2 blinded operators of morphometric analysis showed a high reproducibility with a low interobserver variability. CONCLUSION: Our quantitative estimation of the degree and the quality of steatosis avoids interobserver interpretations. Moreover, our analysis shows that the quantification of steatosis in liver transplantation by the current assessment must be reviewed in order to reevaluate the real impact of steatosis.

Coronary and atrial compression by a giant cardiac hemangioma.

A 57-year-old asymptomatic man showed a round echo-dense mass, partially occupying the left atrium on echocardiography. Magnetic resonance localized the mass in the atrioventricular groove, inside the pericardial space, and showed a large hepatic mass too. Computed tomography revealed significant compression of the left main coronary artery and of the left pulmonary veins outlet. The tumor was surgically removed and diagnosed as hemangioma. Heart hemangiomas are extremely rare; they are usually asymptomatic but sometimes they grow rapidly, causing various symptoms. In our case, life-threatening compression of the left main coronary artery and of the pulmonary veins warranted the intervention.

Postsurgical intrapericardial adhesions: mechanisms of formation and prevention.

Postsurgical intrapericardial adhesions are still considered an unavoidable consequence of cardiothoracic operations. They increase the technical difficulty and the risk of reoperations. The pathogenesis of postsurgical adhesions is a multistep process, and the main key players are (1) loss of mesothelial cells, (2) accumulation of fibrin in areas devoid of mesothelial cells, (3) loss of normal pericardial fibrinolysis, and (4) local inflammation. Today, very promising methods to reduce adhesions are available for clinical use. This report reviews the process of formation of adhesions and the methods to prevent them, classified according to the mechanism of action.

Morphometric analysis of hepatocellular nodular lesions in HCV cirrhosis.

We generated a computerized morphometric model to evaluate and quantify the morphological features in large regenerative nodules (LRN), high-grade dysplastic nodules (HGDN) and hepatocellular carcinoma (HCC). Sixteen LRN, 10 HGDN and 16 HCC in HCV-cirrhotic livers were stained with H&E, smooth muscle actin, CD34, CD31 and reticulin to evaluate volume and surface fractions. On H&E stains, the most discriminatory features between LRN, HGDN and HCC were volume fraction and the number of hepatocyte nuclei in unit volume and hepatocyte nuclear/cytoplasmic ratio. On immunohistochemistry, volume fractions of capillarised sinusoids, capillary units and isolated arteries were significantly different among all groups and highest in HCC; surface fraction of reticulin was markedly decreased in HCC. Our morphometric model is an objective method for quantification of the morphological changes of the nodular lesions, and it could be applied to studies involving histological evaluation of the spectrum of nodular lesions arising in the cirrhotic liver.