Organ Biopsy Research Articles

A case of VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome presenting as progressive multisystem involvement with parenchymal infiltrates following infection with Epstein Barr virus

AbstractVEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, and somatic) syndrome is a rare multisystem disease affecting predominantly males over 50 and manifesting as widespread progressive inflammatory sequelae and haematological dysfunction. We describe a patient who presented with systemic symptoms of fevers, night sweats and weight loss, and developed progressive inflammatory sequelae including cutaneous lesions, haematological dysfunction, lymphadenopathy, migratory inflammatory arthropathies, with new pulmonary infiltrates, following infection with Epstein Barr Virus. Laboratory investigations, bronchoscopy, bone marrow biopsy and imaging were consistent with an inflammatory aetiology. The constellation of organ system involvement, laboratory, biopsy, and imaging results were suspicious for VEXAS syndrome, and this diagnosis was confirmed by identification of a somatic mutation in the UBA1 gene following extensive exclusion of infectious and autoimmune causes. Interestingly the onset of the VEXAS syndrome coincided with serological confirmation of Epstein Barr Virus raising the importance of further exploration into the underlying aetiology of VEXAS syndrome.

Gadoxetate disodium (Gd-EOB-DTPA) contrast-enhanced magnetic resonance imaging for differentiation between benign and malignant splenic lesions in dogs.

Malignant splenic lesions in dogs are common, with hemangiosarcoma diagnosed most frequently, and there have been no consistent clinicopathologic, gross, or imaging characteristics identified that differentiate malignant from benign splenic lesions. Histopathology is required for definitive diagnosis, and given the poor long-term prognosis of malignant splenic lesions, a noninvasive tool to aid in diagnosis would be valuable. This prospective cohort study utilized gadoxetate disodium, a liver-specific contrast agent (Gd-EOB-DPTA; Eovist), to identify the general lesion and pre- and postcontrast signal characteristics of benign and malignant splenic and hepatic lesions in dogs with naturally occurring disease. Twenty-five dogs were enrolled, Eovist-enhanced MRI was performed, and dogs were taken to surgery for splenectomy and other organ biopsy. All histopathology and MRI studies were evaluated by a single pathologist and a single radiologist, respectively. The associations between the tumor type and numerous variables defined on MRI were evaluated using Fisher's exact tests, and the significance was identified at a P-value of.05. Malignant splenic masses were identified in 11/25 (44%) dogs, and 5/11 malignancies represented hemangiosarcoma. The presence of abdominal effusion (P=.017) and the presence of hepatic nodules on MRI (P=.009) were associated with splenic malignancy. There were no benign T2 hyperintense and no malignant T2 hypointense lesions (P=.021). Utilization of the T2 W MRI sequence may aid in the identification of malignant splenic lesions, particularly when accompanied by abdominal effusion and hepatic lesions.

Clinical Impact of Community-Acquired Respiratory Viruses in Patients With Solid Organ Transplants

Community-acquired respiratory viruses (CARVs) are associated with poor outcome in solid organ transplant recipients. We reviewed some of these outcomes such as respiratory support, length of stay, admission to the intensive care unit, steroid use, and 30-day all-cause mortality. Multihospital, single center, retrospective review of electronic health records from January 1, 2014, to December 31, 2019. Twenty-three solid organ transplant recipients (20 male and 3 female) who tested positive for CARVs were identified. The mean age at admission was 60 years, average length of stay was 8 days with 2 patients needing >2 weeks. Six patients required intensive care unit and 8 required supplemental oxygen support. CARV distribution was rhinovirus in 48%, parainfluenza in 29%, metapneumovirus in 12%, respiratory syncytial virus in 0.03%, adenovirus in 0.03%, and non-novel coronavirus in 0.06%. All patients were immunosuppressed, intravenous immunoglobulins were used in 3 patients, antivirals in 7 patients (ribavirin in 6 and oseltamivir in 1), and steroids in 10 patients. Twelve patients had transplant organ biopsy with 5 showing acute cellular rejection. Thirty-five percent of patients died within 1 year (2 during the same admission). Transplant recipients are at a high risk of infections, especially CARVs, which may increase morbidity and mortality. In our observational study, we assessed patients with solid organ transplants who were admitted and tested positive for CARVs, and the associated impact on their clinical course. Careful analysis of the results will help us to emphasize the importance of timely diagnosis and treatment in specific populations.

CD19-CAR T-cell therapy induces deep tissue depletion of B cells

ObjectivesCD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue...

Extracellular vesicles: A potential new way to assess cholestasis.

Extracellular vesicles (EVs) are small, nonreplicating, lipid-encapsulated nanoparticles that carry protein and nucleic acid cargo derived from their tissue of origin. Due to their capacity to provide comparable insights to solid organ biopsy through a minimally invasive collection procedure, EVs provide an attractive biomarker source. This review will provide an insight, how EVs in circulation may provide a novel way to assess cholestasis and will address the possibility of getting a better understanding of the mechanisms of cholestasis of pregnancy through the use of serial hepatic-specific EVs as a window.

MethOxyfluraNe in InTerventiOnal Radiology (MONITOR): Arandomised controlled trial.

Procedural sedation and pain management in interventional radiology (IR) are of critical importance to successful outcomes but remain under-researched. Methoxyflurane has been previously used in some minor procedures with several advantages including rapid onset and offset and a good safety profile. The purpose of this study was to evaluate methoxyflurane for procedures in IR. A randomised, double-blind, placebo-controlled trial was performed between October 2021 and November 2022. Patients presenting for portacath insertion, portacath removal or solid organ biopsy were randomised to either methoxyflurane or placebo. Three hundred and fourteen patients were enrolled in total. Patients were supplied with one Penthrox inhaler containing either 3 mL methoxyflurane or placebo. The primary endpoints of the study were change in pain and anxiety scores compared with baseline, measured on a standardised visual analogue scale (VAS) pre-procedure, at 5-min intervals during the procedure and post-procedure. Baselines scores were controlled for in the statistical analysis. Safety analysis was also performed. One hundred and sixty-nine patients received methoxyflurane and 145 received placebo. Baseline characteristics were similar between the two groups. The methoxyflurane group had lower pain and anxiety scores throughout the procedure (P < 0.001) with 2.5 times less pain (VAS 1.08/10) and 1.6 times less anxiety (VAS 0.97/10) on average. Lower post-procedure pain (mean 0.72 vs 1.44; P < 0.001) and anxiety (mean 0.55 vs 1.13; P = 0.008) were also observed with methoxyflurane. There were no drug or major procedure-related adverse events. The results of this study suggest that methoxyflurane provides safe and effective analgesia and anxiolysis for some procedures in IR.

Fabry disease in W162C mutation: a case report of two patients and a review of literature

BackgroundFabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement.Case presentationThe cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases.ConclusionsThree main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.

Oral manifestations of amyloidosis and the diagnostic applicability of oral tissue biopsy.

Amyloidosis exhibits a variable spectrum of systemic signs and oral manifestations that can be difficult to diagnose. This study aimed to characterize the clinical, demographic, and microscopic features of amyloidosis in the oral cavity. This collaborative study involved three Brazilian oral pathology centers and described cases with a confirmed diagnosis of amyloidosis on available oral tissue biopsies. Clinical data were obtained from medical records. H&E, Congo-red, and immunohistochemically stained slides were analyzed. Twenty-six oral biopsies from 23 individuals (65.2% males; mean age: 59.6 years) were included. Oral involvement was the first sign of the disease in 67.0% of cases. Two patients had no clinical manifestation in the oral mucosa, although the histological analysis confirmed amyloid deposition. Amyloid deposits were distributed in perivascular (88.0%), periacinar and periductal (80.0%), perineurial (80.0%), endoneurial (33.3%), perimuscular (88.2%), intramuscular (94.1%), and subepithelial (35.3%) sites as well as around fat cells (100.0%). Mild/moderate inflammation was found in 65.4% of cases and 23.1% had giant cells. Amyloid deposits were consistently found in oral tissues, exhibiting distinct deposition patterns. Oral biopsy is less invasive than internal organ biopsy and enables the reliable identification of amyloid deposits even in the absence of oral manifestations. These findings corroborate the relevance of oral biopsy for the diagnosis of amyloidosis.

Expert opinion on bleeding risk from invasive procedures in cirrhosis

Despite several recent international guidelines, no consensus exists on the bleeding risk nor haemostatic parameter thresholds that define the safety of invasive procedures in patients with cirrhosis. The aim of this study was to establish a position paper on the bleeding risk associated with invasive procedures in patients with cirrhosis among the experts involved in various guidelines. All experts involved in recent guidelines on the management of invasive procedures in patients with cirrhosis were invited to classify 80 procedures as "high risk" or "low risk" with respect to bleeding. Procedures were considered high risk when the estimated risk of major bleeding was 1.5% or more, or when even minor bleeding might lead to significant morbidity or death. The experts were also asked to choose safety thresholds for laboratory test values at which elective invasive procedures could be safely performed. The predetermined threshold considered as "consensus" was ≥75% agreement. Fifty-two experts participated in the study. Out of 80 procedures, a consensus opinion was reached for 52 procedures (65%): 17 procedures were classified as "high risk", primarily interventional endoscopic procedures, percutaneous organ biopsies, or procedures involving the central nervous system; and 35 as "low risk", primarily "diagnostic" procedures. The lowest platelet counts at which performance of a low-risk procedure or a high-risk procedure/surgery were deemed acceptable were 30×109/L and 50×109/L, respectively. Experts did not believe that international normalised ratio should be considered before performing low-risk procedures; 71% also indicated that it should not be considered before performing high-risk procedures. This experience-based classification may be helpful to refine future study designs and to guide clinical decision making regarding invasive procedures in patients with cirrhosis. Several risk classifications and management guidelines for invasive procedures in patients with cirrhosis have been proposed, but with conflicting recommendations. By providing a position paper, based on the opinion of a broad panel of experts, on the bleeding risk associated with 52 invasive procedures in patients with cirrhosis, this survey will help to provide a framework for future study design. The consensus on platelet count, international normalised ratio, fibrinogen and activated partial thromboplastin time identified in this survey will inform physicians regarding the laboratory test values considered acceptable by the experts prior to the performance of an elective invasive procedure in patients with cirrhosis.

Immunoglobulin light chain amyloidosis: 2024 update on diagnosis, prognosis, and treatment.

Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or MGUS." Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for the diagnosis of AL amyloidosis. Organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. N-terminal pro-brain natriuretic peptide (NT-proBNP or BNP), serum troponin T(or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four stages; 5-year survivals are 82%, 62%, 34%, and 20%, respectively. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first-line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a ≥VGPR. In patients failing to achieve this depth of response options for consolidation include pomalidomide, stem cell transplantation, venetoclax, and bendamustine. Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure. Trials of antibodies to deplete deposited fibrils are underway.

Clinical Characterization of Hepatic Light Chain Amyloidosis in the Chinese Population: A Single-Center Retrospective Analysis

CONCLUSION Hepatic light chain amyloidosis is caused by malignant plasma cells that abnormally secrete immunoglobulin light chains, which undergo a conformational change to a β-pleated sheet configuration and are deposited in the liver. The amyloid fibrils are deposited mainly in the hepatic sinusoids, the space of Disse and the walls of blood vessels. Previous autopsy studies have shown that the proportion of systemic light chain amyloidosis with liver involvement is extremely high; however, there are fewer systematic analyses of the clinical features in the Chinese population. Therefore, this study retrospectively analysed the clinical data of patients with hepatic lightchain amyloidosis in our center to further explore the clinical characteristics of this disease. A total of 40 patients with hepatic light chain amyloidosis were included in the analysis from 2007 to 2022. Inclusion criteria were positive liver tissue biopsy or positive biopsy of other organs with alkaline phosphatase (AKP) greater than 1.5 times the upper limit of normal or total liver span &amp;gt;15 cm in the absence of heart failure. The median age of these patients was 58±10 years and 80% were male. Of these 40 patients, 66% had light-chain amyloidosis secondary to myeloma and the remainder had primary amyloidosis. The proportion of patients with symptoms related to liver injury as the initial clinical presentation was 33%. Symptoms included malaise, abdominal distention, or jaundice. 40% of patients with symptoms related to abnormal heart function, such as chest tightness, severe shortness of breath, and dizziness. 25% of the patients were first seen for symptoms related to impaired renal function, such as proteinuria with lower limb edema or hypourocrinia. κ-type was found in 28% of the patients and λ-type in 73%. All patients had other sites of involvement, 95% with cardiac involvement (72.9%, Mayo 2004 stage III) and 48% with renal involvement. AKP was elevated in 100% of patients, r-GT in 95%, liver enzymes in 33%, total bilirubin in 44%, and the maximum anteroposterior diameter of the right lobe of the liver was 16.6±1.7 cm (upper limit of normal was 10 cm). In this cohort of patients, 80% received a 2- to 3-drug combination regimen based on proteasome inhibitors and 5% received a 2-drug combination regimen based on melphalan, with a median survival time of 6.5±31.3 months, and patients with a normal total bilirubin level had an overall survival time 2.4 times longer than those with an elevated level (p&amp;lt; 0.05,Figure 1). Contrary to previous reports of hepatic light chain amyloidosis, λ light chain amyloidosis was predominant in our center; elevated total bilirubin was an independent risk factor for survival.

Hemostasis disorders in patients with systemic AL-amyloidosis

To analyze the frequency and nature of hemorrhagic and thrombotic complications in patients with systemic AL-amyloidosis and compare with laboratory changes in the hemostasis system. The prospective study included 40 patients with newly diagnosed AL-amyloidosis. To detect amyloid, all patients underwent bone marrow trephine biopsy and duodenal biopsy, and 28 (70%) patients underwent biopsy of the affected organ. Before the start of therapy, all patients were determined the platelet count, activated partial thromboplastin time, thrombin time, fibrinogen concentration, time of XIIa-dependent fibrinolysis, antithrombin III, D-dimer, activity of blood coagulation factors VIII, X and vWF. The statistical part of the study was carried out using the IBM SPSS Statistics 2017 system software (SPSS, Chicago, IL, USA). In 20 (50%) patients, hemorrhages on the skin and mucous membranes were diagnosed as vascular purpura. Before the start of therapy, 7 (17.5%) patients had thrombosis, including leg vein thrombosis (5 patients), ischemic stroke (2 patients). There was a direct correlation between thrombotic complications and cutaneous hemorrhagic syndrome (p=0.007). In 15 (75%) cases, cutaneous hemorrhagic syndrome was accompanied by hypercoagulable shifts in the hemostasis system. Of the 20 patients with cutaneous hemorrhagic syndrome, 19 (95%) patients had kidney damage, including 15 patients with nephrotic syndrome. Hematoma type of bleeding, as well as heavy bleeding was not observed, including after a biopsy of the internal organs. According to the totality of hemostasis indicators, hypercoagulation syndrome was more often observed (in 23; 56% of patients). Hypocoagulation was diagnosed only in 2 (5%) patients with liver damage, 16 (39%) patients had normocoagulation. Cutaneous hemorrhagic syndrome is the most common clinical manifestation of disorders in the hemostasis system in patients with AL-amyloidosis. The relationship of hemorrhages on the skin with nephrotic syndrome has been established, which may indicate a single pathogenetic mechanism. Cutaneous hemorrhagic syndrome is associated with hypercoagulable shifts in hemostasis and a high risk of thrombotic complications.

An Unaccustomed Presentation of Besnier-Boeck-Schaumann Disease

Eliminating other potential causes of granulomatous inflammation helps to diagnose the mysterious sarcoidosis. All clinicians face a diagnostic dilemma because of the clinical polymorphism and the multisystemic sarcoidosis symptoms. After the lungs, the skin is the organ most frequently impacted by sarcoidosis. Before, during, or after systemic involvement, dermatological symptoms can occur, and the kind of skin lesion can have a bearing on the prognosis. Additionally, compared to a biopsy of visceral organs, a skin lesion biopsy is easier to perform and less intrusive. Therefore, there are some instances in which cutaneous symptoms can help with the diagnosis and outlook of a systemic illness. A high index of clinical suspicion is needed for early diagnosis and timely management, which can improve the quality of life for those patients and reduce morbidy and mortality due to this disease. This article has emphasised the prevalence, clinical characteristics, and treatment of the common skin lesions of sarcoidosis.

P09 A catastrophic decline: a significant skin rash in a patient presenting with catastrophic antiphospholipid syndrome

P09 A catastrophic decline: a significant skin rash in a patient presenting with catastrophic antiphospholipid syndrome

Tartrazine Modifies the Activity of DNMT and HDAC Genes-Is This a Link between Cancer and Neurological Disorders?

In recent years, artificial additives, especially synthetic food colorants, were found to demonstrate wider properties compared to their natural equivalents; however, their health impact is still not totally mapped. Our study aimed to determine the long-term (30 and 90 days) exposure effect of one of the commonly used artificial food colorants, tartrazine, on NMRI mice. The applied dose of tartrazine referred to the human equivalent dose for acceptable daily intake (ADI). Further, we evaluated its impact on the transcription of a range of epigenetic effectors, members of the DNA methyltransferase (DNMT) as well as histone deacetylase (HDAC) families. Following the exposure, organ biopsies were collected from the lungs, kidneys, liver, and spleen, and the gene expression levels were determined by real-time quantitative reverse transcription PCR (RT-qPCR). Our results demonstrated significant upregulation of genes in the tested organs in various patterns followed by the intake of tartrazine on ADI. Since DNMT and HDAC genes are involved in different steps of carcinogenesis, have roles in the development of neurological disorders and the effect of dose of everyday exposure is rarely studied, further investigation is warranted to study these possible associations.

Epidemiology, Clinical Characteristics and Risk Factors for Severity of Chronic Disseminated Candidiasis in Jerusalem, Israel.

Chronic disseminated candidiasis (CDC) occurs mostly in patients with acute hematologic malignancy and its clinical manifestations derive from immune reconstitution following neutrophil recovery. The aim of this study was to describe epidemiological and clinical characteristics of CDC and define risk factors for disease severity. Demographic and clinical data were collected from medical files of patients with CDC hospitalized in two tertiary medical centers in Jerusalem between 2005 and 2020. Associations between different variables and disease severity were evaluated, as well as characterization of Candida species. The study included 35 patients. CDC incidence slightly increased during study years and the average number of involved organs and disease duration was 3 ± 1.26 and 178 ± 123days, respectively. Candida grew in blood in less than third of cases and the most common isolated pathogen was Candida tropicalis (50%). Histopathological or microbiological workup in patients who underwent an organ biopsy demonstrated Candida in about half of the patients. Nine months after starting antifungals, 43% of the patients still didn't have resolution of organ lesions in imaging modalities. Factors associated with protracted and extensive disease were prolonged fever prior to CDC and absence of candidemia. A C- Reactive Protein (CRP) cutoff level of 7.18mg/dL was found to predict extensive disease. In conclusion, CDC incidence is increasing and the number of involved organs is higher than previously described. Clinical factors such as fever duration prior to CDC and absence of candidemia can predict severe course of disease and assist in treatment decisions and follow-up planning.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

P207 DIAGNOSTIC PATHWAY OF CARDIAC AMYLOIDOSIS. INSIGHTS FROM CUNEO HOSPITAL

Abstract Introduction In the last fifteen years, thanks to the refinement of non–invasive diagnostic techniques, there has been a clear increase in the diagnosis of amyloidosis. From this need arises the establishment of a specific out–patients department in order to guarantee the best path of diagnosis and treatment. Methods Since 2018 we have begun to suspect cardiac amyloidosis in hospitalized patients with heart failure with preserved ejection fraction and clinical and/or instrumental red flags: left ventricular hypertrophy unexplained by other causes, biatrial enlargement, minimal pericardial effusion, history of carpal tunnel, low voltages in peripheral leads, elevated values ​​of cardiac biomarkers. In these patients we excluded AL amyloidosis by searching for monoclonal components and at the same time we performed a myocardial scintigraphy with diphosphonates. In the case of positive scintigraphy, patients are taken care of at our cardiology rare disease outpatient clinic. We believe that this collaboration is essential for the correct management of the patient with amyloidosis, especially in an area like ours where there is a high prevalence of a mutation, val30met, with prevailing initial neurological involvement. Results From 2019, 156 patients underwent bone scintigraphy with diphosphonates. The average age is 78 years. 87 scintigraphies were positive (Perugini 2–3), 47 patients were diagnosed with TTRwt amyloidosis, 3 with TTRv amyloidosis, 38 are awaiting genetic testing. 34% underwent organ biopsy (of which 10 patients underwent salivary gland biopsy, 3 patients underwent periumbilical fat biopsy and 1 patient underwent BEM at another center. 25% underwent cardiac MRI. 7 patients underwent started in Tafamidis. Conclusions Amyloidosis is a frequently underdiagnosed disease. An early diagnosis is crucial to undertake, in cases that allow it, a specific therapy: chemotherapy in the case of AL amyloidosis or disease–modifying drugs in the case of TTR. The experience of our center has shown us how a multidisciplinary approach and a specific diagnostic path are crucial to achieve an early diagnosis in order to establish therapeutic paths that can modify natural history of the disease.

Chronic Aichi Virus Infection As a Cause of Long-Lasting Multiorgan Involvement in Patients With Primary Immune Deficiencies.

Metagenomic next-generation sequencing (mNGS) was used to assess patients with primary or secondary immune deficiencies (PIDs and SIDs) who presented with immunopathological conditions related to immunodysregulation. Thirty patients with PIDs or SIDs who presented with symptoms related to immunodysregulation and 59 asymptomatic patients with similar PIDs or SIDs were enrolled. mNGS was performed on organ biopsy. Specific Aichi virus (AiV) reverse-transcription polymerase chain reaction (RT-PCR) was used to confirm AiV infection and screen the other patients. In situ hybridization (ISH) assay was done on AiV-infected organs to identify infected cells. Virus genotype was determined by phylogenetic analysis. AiV sequences were detected using mNGS in tissue samples of 5 patients and by RT-PCR in peripheral samples of another patient, all of whom presented with PID and long-lasting multiorgan involvement, including hepatitis, splenomegaly, and nephritis in 4 patients. CD8+ T-cell infiltration was a hallmark of the disease. RT-PCR detected intermittent low viral loads in urine and plasma from infected patients but not from uninfected patients. Viral detection stopped after immune reconstitution obtained by hematopoietic stem cell transplantation. ISH demonstrated the presence of AiV RNA in hepatocytes (n = 1) and spleen tissue (n = 2). AiV belonged to genotype A (n = 2) or B (n = 3). The similarity of the clinical presentation, the detection of AiV in a subgroup of patients suffering from immunodysregulation, the absence of AiV in asymptomatic patients, the detection of viral genome in infected organs by ISH, and the reversibility of symptoms after treatment argue for AiV causality.

Very Small Embryonic-Like Stem Cells Transform Into Cancer Stem Cells and are Novel Candidates for Detecting/Monitoring Cancer by a Simple Blood Test.

Cancer continues to remain a "Black Box" as there is no consensus on how it initiates, progresses, metastasizes, or recurs. Many imponderables exist about whether somatic mutations initiate cancer, do cancer stem cells (CSCs) exist, and if yes, are they a result of de-differentiation or originate from tissue-resident stem cells; why do cancer cells express embryonic markers, and what leads to metastasis and recurrence. Currently, the detection of multiple solid cancers through liquid biopsy is based on circulating tumor cells (CTCs) or clusters, or circulating tumor DNA (ctDNA). However, quantity of starting material is usually adequate only when the tumor has grown beyond a certain size. We posit that pluripotent, endogenous, tissue-resident, very small embryonic-like stem cells (VSELs) that exist in small numbers in all adult tissues, exit from their quiescent state due to epigenetic changes in response to various insults and transform into CSCs to initiate cancer. VSELs and CSCs share properties like quiescence, pluripotency, self-renewal, immortality, plasticity, enrichment in side-population, mobilization, and resistance to oncotherapy. HrC test, developed by Epigeneres, offers the potential for early detection of cancer using a common set of VSEL/CSC specific bio-markers in peripheral blood. In addition, NGS studies on VSELs/CSCs/tissue-specific progenitors using the All Organ Biopsy (AOB) test provide exomic and transcriptomic information regarding impacted organ(s), cancer type/subtype, germline/somatic mutations, altered gene expressions, and dysregulated pathways. To conclude, HrC and AOB tests can confirm the absence of cancer and categorize the rest of subjects into low/moderate/high risk of cancer, and also monitor response to therapy, remission, and recurrence.