Abnormal immunothrombosis and lupus anticoagulant in a catastrophic COVID-19 recalling Asherson's syndrome.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a complex disease with many clinicopathological aspects, including abnormal immunothrombosis, and the full comprehension of its pathogenetic mechanisms is urgently required. METHODS/RESULTS: By means of a multidisciplinary approach, we here report a catastrophic COVID-19 in a 44-year-old Philippine male patient, discovered lupus anticoagulant (LAC)-positive shortly before death, occurred 8 days after hospitalization in a clinical scenario refractory to standard high acuity care recalling Asherson's syndrome (catastrophic antiphospholipid syndrome). CONCLUSION: A parallelism between this severe form of COVID-19 and Asherson's syndrome can be so drawn. Both the diseases in fact exhibit hypercytokinemia, thrombotic microangiopathy, disseminated intravascular coagulation and multiple organ failure, they show a relationship with viral infections, and they are burdened by a high mortality rate. A genetic predisposition to develop these two overlapping conditions may be supposed.

In Vivo Uptake of Rare Earth Metals by Triple-Negative Breast Cancer Cells.

Rare earth metals (REM) are a group of 17 chemical elements in the periodic table, namely scandium (Sc), yttrium (Y) and the lanthanides. In relation to atomic volume and geological behavior, the lanthanides are further subdivided into light, medium and heavy REM. They find many applications in the technological field; however, their impact on the human health is still conflicting and, for many aspects, unknown. During a research program carried on 113 cases of female breast cancer, immunohistochemically categorized in Her2-positive (29 cases), Her2-negative (57 cases) and triple negative (27 cases), aimed to evaluate the role of environmental particulate in carcinogenesis by elemental microanalysis, for the first time in literature we have detected a REM uptake, in detail europium (Eu), dysprosium (Dy) and praseodymium (Pr), inside the neoplastic cells belonging to a single triple negative breast cancer. Curiously, the woman affected by this form of malignancy had worked in the ceramic industry, a well-known source of REM, during her life, and she was the one and only patient of our series to be dedicated to this activity. The medical repercussions of our findings are here discussed: in fact, a REM detection in only 1 of 113 examined cases seems to exclude active roles in breast carcinogenesis and discloses new possibilities for therapeutic developments in triple negative breast cancer.

Lethal cardiotoxicity from quaternary ammonium compounds contained in an unguarded household detergent at a psychiatric facility.

Here, referred for the first time in literature, we present the forensic case of death, with suicidal intent, following ingestion of a conspicuous amount of quaternary ammonium compounds contained in an unguarded bottle of household detergent. The deceased person was a young female patient at a psychiatric facility; the cause of death was acute heart failure due to spotty infiltration of neutrophils, lymphocytes and plasma cells in the myocardial tissue, observable in the course of toxic myocarditis. The dominant pathogenetic factors involved are direct damage of myocardial cells and a superimposed immune response extending to the epicardial perivascular spaces. This rare form of acute myocarditis has never been previously described. Moreover, this fatal event emphasizes the need for planned clinical risk-management measures and for guidelines to prevent future adverse events of this kind in psychiatric facilities.

State-of-the-art nanopathological diagnostics.

The nanopathological diagnostics (ND) is an ultra-specialized branch of pathological anatomy aimed to identify the nanoparticles of metallic, semimetallic, or nonmetallic elements in the inorganic particulate matter present inside pathological tissues, even on the nanometer scale. ND exploits an environmental scanning electron microscope, connected to an X-ray microprobe mounted on an energy-dispersive spectrometer. The searching of nanoparticles can be performed on paraffin-embedded material, omitting emissions of black overlay and plating procedures. The technique is highly sensitive and specific, reproducible and rapid, covering an entire operating cycle in few hours. Nowadays, ND finds many applications: (I) intratumor detection of heavy metals and endocrine metal disruptors; (II) identification of pathogenic nanoparticles in medical or veterinary drugs and devices, cosmetics, household products, and foodstuffs; (III) differential diagnosis of sarcoid-type granulomas (berylliosis, baritosis) and foreign body granulomas (prosthetic, iatrogenic); (IV) attestation of occupational disease correlating the datum with the occupational risk (anthracosis, asbestosis, bauxite fibrosis, byssinosis, chalicosis, siderosis, silicosis, stannosis, talcosis); and (V) forensic investigations to ascertain a causal link between disease and environmental, military, or work exposure. In addition to filling a knowledge gap, ND offers to the pathologist a current research field, with particular reference to the impact of occupational and environmental pollution on the human health and cancer.

Testosterone Aromatization to Estradiol in Course of Ovarian Functioning Brenner Tumor Associated With Endometrial Carcinoma and Endometriosis (Roncati-Manenti Triad).

OBJECTIVE: Aromatization is the biochemical process in which aromatase catalyzes the conversion of testosterone into estradiol, the fundamental pathway for the synthesis of estrogens. When enhanced, it can lead to hyperestrogenism, a well-known risk factor for gynecological cancers. METHODS: The surgical specimens, coming from 2 postmenopausal women with hyperestrogenism on pap smear and bioptic diagnosis of endometrial endometrioid carcinoma, were fixed in 10% neutral buffered formalin, paraffin embedded, and then submitted for routine hematoxylin/eosin staining and immunohistochemical characterization for antiestrogen, antiprogesterone, antitesterone, anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6. RESULTS: The presence of an undescribed triad represented by ovarian functioning Brenner tumor, endometrial carcinoma, and pelvic endometriosis has been ascertained. The immunohistochemical investigation proved a normal expression of the DNA mismatch repair proteins and revealed a bimodal hormonal status in the pathological tissues, that is, the Brenner tumor cells showed a high expression of testosterone, contrariwise endometrioid carcinoma and endometriosis a high estrogen and progesterone immunolabeling. CONCLUSIONS: This synchronous triad underlines the importance of aromatization and hyperestrogenism in the development of gynecological malignancies in which the immunohistochemical detection of an active source of hormone production - to always keep in consideration during synchronous diseases - can guide subsequent antihormone chemotherapy based on aromatase inhibitors.

Loss of CDKN2A Promoter Methylation Coincides With the Epigenetic Transdifferentiation of Uterine Myosarcomatous Cells.

Leiomyosarcoma is the most common type of uterine sarcoma and usually displays typical morphology. Heterologous leiomyosarcoma is the rarest variant, in which the tumor contains liposarcomatous, osteosarcomatous, or rhabdomyosarcomatous components. We have investigated the largest series of uterine leiomyosarcoma with a rhabdomyosarcomatous component and we have disclosed a molecular finding, which coincides to the process of transdifferentiation from smooth muscle into striated muscle phenotype. The surgical specimens of 5 rare cases of uterine leiomyosarcoma with a rhabdomyosarcomatous component were formalin fixed and paraffin embedded. In addition to hematoxylin/eosin stains, phosphotungstic acid hematoxylin staining, immunohistochemistry, and methylation-specific polymerase chain reaction the CDKN2A promoter region were performed. Leiomyosarcomatous cells were found to be strongly immunoreactive for both desmin and α-smooth muscle actin. Rhabdomyosarcomatous cells were immunoreactive for sarcomeric actin, desmin, vimentin, CD10, and p16. The methylation-specific polymerase chain reaction revealed the presence of a methylated allele and an unmethylated allele in the microdissected samples, coming from leiomyosarcomatous cells. On the contrary, 2 unmethylated alleles, molecular expression of a loss of heterozygosity, were detected in all the microdissected samples in the rhabdomyosarcomatous cells. The loss of heterozygosity methylation in the promoter region of the CDKN2A gene, occurred only in the rhabdomyosarcomatous cells with increases in both p16 and p14 expression. This event may result in an inhibition of cdk4/cdk6 activity, stabilizes the tumor suppressor protein p53, and coincides with the transdifferentiation from smooth muscle into striated muscle.

The first investigative science-based evidence of Morgellons psychogenesis.

Morgellons disease is an infrequent syndromic condition, that typically affects middle-aged white women, characterized by crawling sensations on and under the skin, associated with itchy rashes, stinging sores, fiber-like filaments emerging from the sores, severe fatigue, concentrating difficulty, and memory loss. The scientific community is prone to believe that Morgellons is the manifestation of various psychiatric syndromes (Munchausen, Munchausen by proxy, Ekbom, Wittmaack-Ekbom). Up until now, no investigative science-based evidence about its psychogenesis has ever been provided. In order to close this gap, we have analyzed the filaments extracted from the skin lesions of a 49-year-old Caucasian female patient, by using a Field Emission Gun-Environmental Electron Scanning Microscope equipped with an X-ray microprobe, for the chemico-elemental characterization of the filaments, comparing them with those collected during a detailed indoor investigation, with careful air monitoring, in her apartment. Our results prove the self-introduction under the epidermis of environmental filaments. For the first time in the literature, we have scientifically demonstrated the self-induced nature of Morgellons disease, thereby wiping out fanciful theories about its etiopathogenesis.

The First 5-Year-Long Survey on Intrauterine Unexplained Sudden Deaths from the Northeast Italy.

PURPOSE: Sudden intrauterine unexplained death syndrome (SIUDS) represents one of the main open issues in the scientific and social setting of the modern medicine, and our efforts have aimed to understand its possible causes and risk factors. METHODS: A 43-case series of consecutive unexplained fetal deaths coming from Northeast Italy, collected in a 5-year period (2011-2015), has been submitted to an in-depth investigation, based on neuropathological and cardiopathological examinations, immunohistochemistry for neuronal nuclear antigen (NeuN), genetic characterization for the serotonin transporter (5-HTT) gene polymorphisms, and toxicological environmental analyses. RESULTS: The overall survey from the neuropathological findings highlights one or more congenital morphological abnormalities of the autonomic nervous system in 77% of cases of sudden fetal deaths. CONCLUSIONS: From our results emerges the need to perform a complete autopsy of all SIUDS victims with an in-depth examination of the neuronal centers of the brainstem, which modulate the vital functions.

A Novel Forensic Investigation Applied to Bone Remains Exhumed near to Quirra Interforce Firing Range.

The need to implement novel techniques, able to support a causal link between exposure and pathology, has been emerged over the recent years. The application of scanning electron microscope coupled with probe X-ray microanalysis (by means of an energy-dispersive spectroscopy) has been developed by our research group for the bone remains investigation. It was aimed to testify the exposure to microsized and nanosized pollutions, due to military activities in the Quirra interforce firing range, of a Sardinian shepherd, died of acute leukemia. Metallic debris with a combustive morphology and with an oncogenic potential has been surely detected inside his bone marrow canal. This novel technique has proved to be able to bring to light a source of past exposure preserved over time within the bone marrow canal. It can be useful for postmortem analyses, delivering a new avant-garde approach to modern forensic science.

The Uncontrolled Sialylation is Related to Chemoresistant Metastatic Breast Cancer.

Among the scientific communities, there is a convergence of results supporting a direct relationship between dysregulated sialylation and poor prognosis in many human cancers. For this reason, we have retrospectively investigated 169 cases of invasive ductal carcinoma of the breast, coming from female patients aged between 31 and 76 years old. The whole series was subdivided into two prognostic groups: the first group consisted of 138 patients, who showed a post-treatment survival time more than 5 years, while the second group was made up by 31 patients, died within 5 years despite of chemotherapy. All the surgical specimens were fixed in 10 % neutral buffered formalin, paraffin embedded and, then, submitted to routinely haematoxylin/eosin staining and to a further histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange), immunohistochemical (ST3GAL5 sialyltransferase, Ki67, c-erbB2, ER, PR) and chemico-elemental characterization. In the 31 cases of breast cancer belonging to the second group, an overexpression of sialomucins and sialyltransferases has been detected. Our results lead us to support that in aggressive chemoresistant breast cancers, the altered expression of sialic acid, due to an uncontrolled sialylation, creates an excessive negative charge on cell membranes, which stimulates repulsion between neoplastic cells and their subsequent access into the blood stream. This event implies an early metastatization and a rapid disease progression with fatal outcome. The early application of Alcian Blue stain on diagnostic biopsies of breast cancer is able to cheaply reveal the sialomucin accumulations, providing for the disease course.

Prognostic Factors for Breast Cancer: an Immunomorphological Update.

The prognostic variability recorded within homogeneous groups of patients for anatomo-clinical disease stages has led to a more detailed biological characterization of breast cancer. Recently, the attention of the scientific community has focused on the role of tumor-infiltrating lymphocytes (TILs). Therefore, the need of an in-depth immunomorphological characterization of TILs has been emerged. The presence of TILs has been retrospectively investigated in 113 female cases of ductal carcinoma. An immunohistochemical investigation with CD3, CD4, CD8, CD20, CD56, granulysin, perforin-1, granzyme-B and TIA-1 was performed according to the standard procedures on all 17 cases with TILs evidence. TILs consisted of T and B lymphocytes: the prevalent population showed a T immunoprofile with a CD8-immunopositive killer subpopulation (Tk), close-linked to carcinomatous cells, and a CD4-immunopositive helper subpopulation (Th), inside the tumor. A time sequence (firstly T, then B) has been disclosed. Granulysin, perforin, granzyme-B and TIA-1 were expressed by Tk cells. The activated Tk cells secrete these mediators as a result of the binding to the tumor target cell, causing its lytic planned death. The cytotoxicity supported by Tk cells appears an important favorable prognostic factor. Therefore, a graduation system for TILs in breast cancer has been here proposed (absent, non-brisk, brisk).

Heavy Metal Bioaccumulation in an Atypical Primitive Neuroectodermal Tumor of the Abdominal Wall.

Heavy metals are able to interfere with the function of vital cellular components. Besides in trace heavy metals, which are essential at low concentration for humans, there are heavy metals with a well-known toxic and oncogenic potential. In this study, for the first time in literature, we report the unique adulthood case of an atypical primitive neuroectodermal tumor of the abdominal wall, diagnosed by histology and immunohistochemistry, with the molecular hybridization support. The neoplasia occurred in a patient chronically exposed to a transdermal delivery of heavy metal salts (aluminum and bismuth), whose intracellular bioaccumulation has been revealed by elemental microanalysis.

ESEM Detection of Foreign Metallic Particles inside Ameloblastomatous Cells.

Ameloblastoma is a borderline tumor of odontogenic origin, with a high recurrence rate and possible local aggressiveness. The etiopathogenetic factors involved in its occurrence are not still defined and our study has been precisely aimed to search for novel factors associated with its development. Sections cut from paraffin blocks, containing the representative specimens of 18 different ameloblastomas, collected in a 15-year period (1999-2014), have been observed by an environmental scanning electron microscope, in order to search micro- and nano-sized particles and to identify their composition. In all the neoplastic cases, micro- and nano-sized metallic debris, differing in size and composition, have been detected inside the ameloblastomatous cells. On the contrary, the total absence of metallic particles in the healthy control cases has been emerged. Our results reveal a relationship between ameloblastoma and metallic particulate. The cigarette smoke and the routine dental practice appear the most probable source for the presence of these biopersistant inorganic particles inside the neoplastic cells.

Pneumothorax-associated fibroblastic lesion in combination with localized pleural angiomatosis: A possible cause of juvenile spontaneous hemopneumothorax.

Spontaneous hemopneumothorax is an uncommon but potentially life-threatening condition, with a potential for a rapid ventilatory collapse and a large collection of hidden blood loss into the pleural cavity. Here, we report the first case in the literature on pneumothorax-associated fibroblastic lesion in combination with localized pleural angiomatosis in a 19-year-old Caucasian male, resulting in massive spontaneous hemopneumothorax and hypovolemic shock. Our findings support a causal link between this condition and pneumothorax. The possible superimposed hemothorax is explainable by the pleural involvement of large angiomatous vessels, prone to rupture.