An Emergent Form of Cardiotoxicity: Acute Myocarditis Induced by Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. ICIs have shown great promise in the treatment of several advanced malignancies. However, therapy with these immunomodulatory antibodies may lead to a wide spectrum of immune-related adverse events in any organ and any tissue. Cardiologic immune-related events include pericarditis, pericardial effusion, various types of arrhythmias including the occurrence of complete atrioventricular block, myocardial infarction, heart failure, and myocarditis. Although relatively rare, myocarditis is associated with a very high reported mortality in comparison to other adverse events. Myocarditis often presents significant diagnostic complexity and may be under-recognized. When confronted with an unexpected change in the clinical picture, the physician must differentiate between immune-related adverse events, cancer worsening, or other causes unrelated to the cancer or its therapy. However, this is not always easy. Therefore, with the increasing use of checkpoint inhibitors in cancer, all providers who care for patients with cancer should be made aware of this rare, but potentially fatal, cardiologic immune-related adverse event, and able to recognize when prompt consultation with a cardiologist specialist is indicated. In this review, we evaluate currently available scientific evidence and discuss clinical manifestations and new potential approaches to the diagnosis and therapy of acute myocarditis induced by ICIs. Temporary or permanent discontinuation of the ICIs and high-dose steroids have been administered to treat myocarditis, but symptoms may worsen in some patients despite therapy.

A rare mutation in MYH7 gene occurs with overlapping phenotype.

Mutations in the beta-myosin heavy chain gene (MYH7) cause different muscle disorders. The specific molecular pathobiological processes that cause these different phenotypes remains unexplained. We describe three members of a family with an autosomal dominant mutation in the distal rod of MYH7 [c.5401G> A (p.Glu1801Lys)] displaying a complex phenotype characterized by Laing Distal Myopathy like phenotype, left ventricular non compaction cardiomyopathy and Fiber Type Disproportion picture at muscle biopsy. We suggest that this overlapping presentation confirm the phenotypic variability of MYH7 myopathy and may be helpful to improve the genotype phenotype correlation.

Fatal intrahepatic hemorrhage after nadroparin use for total hip arthroplasty.

Low-molecular-weight heparins have become the predominant choice for deep venous thrombosis prophylaxis and treatment. However, their use may cause bleeding complications. Intrahepatic bleeding is exceptional and only very few cases have been described. The authors present a unique case of fatal intrahepatic hematoma complicating nadroparin use in a 65-year-old woman with a hepatic cyst who was admitted to hospital for unilateral total hip arthroplasty. At autopsy, hemoperitoneum (2,000 ml of blood and clots) was evident. A ruptured sub-capsular hematoma involving the right lobe of the liver was observed. The hemorrhage within the cyst induced by the nadroparin use was likely responsible for the subsequent hepatic hematoma, liver rupture, and death. This case highlights the need for pathologists and surgeons to be aware of the possibility of intrahepatic hematoma in patients who have received low-molecular-weight heparins, undergone major surgery and present postoperative hemodynamic instability, especially in those with preoperative diagnosis of hepatic cyst.

Short tandem repeat analysis of host's hepatocellular carcinoma by laser microdissection confirms the validity of safety procedures in liver transplantation: a forensic case.

BACKGROUND: To limit the chimerism typical of transplanted organs, which constantly reveals mixed profiles, laser microdissection (LCM) has been hypothesized as a valid tool in comparison with manual dissection. CASE REPORT: A 42-year-old man with end-stage HBV/HDV liver cirrhosis and single hepatocellular carcinoma (HCC) underwent liver transplantation. Four months later hepatic nodules were diagnosed. The histological investigation showed an HCC. Despite therapy, the man died as a result of metastatic carcinoma 9 months later. On behalf of the public prosecutor, we performed short tandem repeat analysis on the hepatic nodules to determine whether the carcinoma had originated from the transplanted liver. CONCLUSIONS: The manually dissected samples revealed a high degree of chimerism that did not allow a clear diagnosis. Instead, the detected chimerism was very low in the microdissected samples, where the tumor origin was clearly diagnosable as a recurrence of the recipient's primitive HCC. Accordingly, the application of LCM improved the quality of the results leading to an exclusion of medical liability profiles, confirming the high quality safety procedure of the Italian system in solid organ transplantation, and showing at the same time how useful this technique may be in selected forensic cases.

Parallel improvement of left ventricular geometry and filling pressure after transcatheter aortic valve implantation in high risk aortic stenosis: comparison with major prosthetic surgery by standard echo Doppler evaluation.

PURPOSE: The effect of Transcatheter Aortic Valve Implantation (TAVI) on left ventricular (LV) geometry and function was compared to traditional aortic replacement (AVR) by major surgery. METHODS: 45 patients with aortic stenosis (AS) undergoing TAVI and 33 AVR were assessed by standard echo Doppler the day before and 2 months after the implantation. 2D echocardiograms were performed to measure left ventricular (LV) mass index (LVMi), relative wall thickness (RWT), ejection fraction (EF) and the ratio between transmitral E velocity and early diastolic velocity of mitral annulus (E/e' ratio). Valvular-arterial impedance (Zva) was also calculated. RESULTS: At baseline, the 2 groups were comparable for blood pressure, heart rate, body mass index mean transvalvular gradient and aortic valve area. TAVI patients were older (p<0.0001) and had greater LVMi (p<0.005) than AVR group. After 2 months, both the procedures induced a significant reduction of transvalvular gradient and Zva but the decrease of LVMi and RWT was significant greater after TAVI (both p<0.0001). E/e' ratio and EF were significantly improved after both the procedure but E/e' reduction was greater after TAVI (p<0.0001). TAVI exhibited greater percent reduction in mean transvalvular gradient (p<0.05), Zva (p<0.02), LVMi (p<0.0001), RWT (p<0.0001) and E/e' ratio (p<0.0001) than AVR patients. Reduction of E/e' ratio was positively related with reduction of RWT (r = 0.46, p<0.002) only in TAVI group, even after adjusting for age and percent reduction of Zva (r =0.43, p<0.005). CONCLUSIONS: TAVI induces a greater improvement of estimated LV filling pressure in comparison with major prosthetic surgery, due to more pronounced recovery of LV geometry, independent on age and changes of hemodynamic load.

Sudden, unexpected death due to glioblastoma: report of three fatal cases and review of the literature.

Sudden death from an undiagnosed primary intracranial neoplasm is an exceptionally rare event, with reported frequencies in the range of 0.02% to 2.1% in medico-legal autopsy series and only 12% of all cases of sudden, unexpected death due to primary intracranial tumors are due to glioblastomas. We present three cases of sudden, unexpected death due to glioblastoma, with different brain localization and expression. A complete methodological forensic approach by means of autopsy, histological and immunohistochemical examinations let us to conclude for an acute central dysregulation caused by glioblastoma and relative complication with rapid increase of intracranial pressure as cause of death. Although modern diagnostic imaging techniques have revolutionized the diagnosis of brain tumors, the autopsy and the careful gross examination and section of the fixed brain (with coronal section) is still the final word in determining exact location, topography, mass effects and histology and secondary damage of brain tumor and contributed the elucidation of the cause of death. Immunohistochemistry and proteomic analysis are mandatory in such cases. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1218574899466985.

Sudden death due to primary atrial neoplasms: report of two cases and review of literature.

Primary cardiac tumours are very uncommon lesions with an estimated incidence of less than 0.03% during autoptic examination. Among these, about 75% are benign, mainly myxomas. The intracardiac tumours occur over a wide range of ages and can progress silently or have many clinical presentations, such as valvular dysfunction, cardiac compression and embolic accidents, mostly in case of atrial localization. Primary atrial tumours often progress asymptomatically. Sudden death could represent the "first symptom" of these pathological findings. Indeed, cardiac neoplasms may cause disorders of atrioventricular or intraventricular conduction, which are manifested by fatal arrhythmias. Two cases of sudden death due to atrial tumours are reported. A complete autoptic examination, with histologic and immunohistochemical study of cardiac lesions, confirmed that these neoplasms were primary. Very few cases of sudden death due to right atrial tumours have been described in forensic literature, a fact which emphasizes their rarity.

Simultaneous determination of disulfiram and bupropion in human plasma of alcohol and nicotine abusers.

An isocratic high-performance liquid-chromatographic method has been developed for the simultaneous determination of disulfiram and bupropion in human plasma samples. Analyses were carried out on a C(8) reversed-phase column using a mobile phase composed of 50% acetonitrile and 50% aqueous phosphate buffer, containing triethylamine. Diode-array detection was used, operating at a wavelength of 250 nm. For the clean-up of plasma samples, a solid phase extraction procedure, based on C(2) cartridges, was implemented. Extraction yields of the analytes were satisfactory, being always higher than 84%. The calibration curve was linear over the 5-500 ng mL(-1) plasma concentration range for both disulfiram and bupropion. The method showed a high sensitivity (limit of detection of 1.5 ng mL(-1)) and satisfactory precision, selectivity and accuracy. The application to human plasma samples obtained from some alcohol and nicotine abusers also gave good results.

Death caused by toxic epidermal necrolysis (Lyell syndrome).

Toxic epidermal necrolysis (TEN) is characterized by fever, scalded appearance of the skin, and epidermolysis associated to blister formation and exfoliation, and it is caused by hypersensitivity reaction to a drug. The authors report two cases of death as a result of TEN; both referred to old aged women treated with a polytherapy including allopurinol. Both patients displayed erythematous skin lesions similar to scald burns and epidermolysis at the face, chest, and abdomen and died shortly after hospitalization. Autopsy findings and histological examinations revealed epidermal necrolysis and confirmed the clinical diagnosis. A strict time-correlation between allopurinol administration and symptoms was evidenced. Because of its iatrogenic origin, TEN often arises suspicions of medical liability; however, because of its unpredictable nature, the occurrence of this syndrome cannot be ascribed to the medical staff whose main task is the rapid diagnosis and the correct management.

A "de novo" mutation of the LDL-receptor gene as the cause of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a common genetic disorder caused by mutations of the LDL-receptor gene and transmitted as a co-dominant trait. However, there are some forms of hypercholesterolemia which have a recessive type of transmission. We have identified a subject with the clinical phenotype of heterozygous FH whose parents had normal plasma lipid values, suggesting a recessive type of transmission. The analysis of the LDL-receptor gene revealed that the patient was heterozygous for a G>C transversion in exon 4, which results in a serine for cysteine substitution at position 88 (C88S) of the receptor protein. Since this novel mutation was not found in the proband's parents and non-paternity was excluded, we concluded that the patient was a carrier of a "de novo" mutation. Haplotype analysis of LDL-receptor locus indicated that this "de novo" mutation occurred in the paternal germ line. The C88S mutation is the likely cause of LDL-receptor defect as it was present in the proband's hypercholesterolemic son and was not found in 200 chromosomes of control subjects.