Danielle Fortuna

Severe human parechovirus type 3 myocarditis and encephalitis in an adolescent with hypogammaglobulinemia

Human parechovirus (HPeV) belongs to the Picornaviridae family of RNA viruses. HPeV infections can be asymptomatic, lead to mild respiratory and/or gastrointestinal symptoms, or less frequently cause severe diseases such as sepsis, meningitis, encephalitis, and myocarditis. Severe neurological HPeV infections occur most commonly in infants and neonates. There are currently 16 recognized types of HPeV. HPeV type 3 (HPeV3) has been the predominant type associated with severe central nervous system disease in neonates and newborns since its discovery in 1999. Although HPeV-related infections have been reported in adults, symptomatic HPeV3 infections in adolescents and adults are uncommon. A case of severe HPeV3 myocarditis and encephalitis in an adolescent is described.

Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis

Background Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution. Patients and methods We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors. Results CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes. Conclusions In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.

Human parechovirus and enterovirus initiate distinct CNS innate immune responses: Pathogenic and diagnostic implications

BACKGROUND Human parechovirus (HPeV) and enterovirus (EV) cause a range of human diseases including serious CNS infections. Little is known regarding the immune response to HPeV meningitis compared to EV meningitis or how the immune response to HPeV reflects its pathogenesis. OBJECTIVE To characterize the innate immune response to HPeV CNS infection in order to increase our understanding of HPeV pathogenesis and possibly help identify HPeV in the clinical setting. STUDY DESIGN CSF samples from 13 patients with HPeV meningitis, 7 patients with EV meningitis, and 11 patients negative for CNS infections were analyzed for chemokines/cytokines using multiplex ELISA assays. RESULTS CSF levels of the majority of cytokines/chemokines analyzed were significantly higher in patients with EV meningitis (EV group) compared to patients with HPeV meningitis (HPeV group) and controls. In the HPeV group, a small number of cytokine/chemokine levels were higher than controls; however, these levels were either significantly lower or not significantly different compared to the EV group. IL-6 levels were lower in HPeV than in both EV and controls. CONCLUSIONS The immune response to HPeV CNS infection differs from that of EV. Distinct patterns of cytokine/chemokine expression in HPeV infections suggest HPeV-mediated modulation of the immune response. HPeV disrupts the interferon cascade and seems to interfere with early inflammatory signaling. Although HPeV elicits a predominantly muted immune reaction, a partial, general infectious-type cytokine/chemokine response does occur. Beyond providing insight into HPeV pathogenesis, the identified cytokine/chemokine profile may aid in early detection of HPeV infection.

Diagnostic Challenges of Cryptococcus neoformans in an Immunocompetent Individual Masquerading as Chronic Hydrocephalus

Cryptococcus neoformans can cause disseminated meningoencephalitis and evade immunosurveillance with expression of a major virulence factor, the polysaccharide capsule. Direct diagnostic assays often rely on the presence of the cryptococcal glucuronoxylomannan capsular antigen (CrAg) or visualization of the capsule. Strain specific phenotypic traits and environmental conditions influence differences in expression that can thereby compromise detection and timely diagnosis. Immunocompetent hosts may manifest clinical signs and symptoms indolently, often expanding the differential and delaying appropriate treatment and diagnosis. We describe a 63-year-old man who presented with a progressive four-year history of ambulatory dysfunction, headache, and communicating hydrocephalus. Serial lumbar punctures (LPs) revealed elevated protein (153–300 mg/dL), hypoglycorrhachia (19–47 mg/dL), lymphocytic pleocytosis (89–95% lymphocyte, WBC 67–303 mg/dL, and RBC 34–108 mg/dL), and normal opening pressure (13–16 cm H2O). Two different cerebrospinal fluid (CSF) CrAg assays were negative. A large volume CSF fungal culture grew unencapsulated C. neoformans. He was initiated on induction therapy with amphotericin B plus flucytosine and consolidation/maintenance therapy with flucytosine, but he died following discharge due to complications. Elevated levels of CSF Th1 cytokines and decreased IL6 may have affected the virulence and detection of the pathogen.

Identification of a novel metabolic-related mutation (IDH1) in metastatic pancreatic cancer.

ABSTRACT Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme implicated in cancer cell metabolic reprogramming. This is underscored by the detection of functional, somatic IDH1 mutations frequently found in secondary glioblastoma. To our knowledge, there has never been a reported, validated case of an IDH1 mutation in a pancreatic ductal adenocarcinoma (PDA). Herein, we present a case of a patient with metastatic PDA that harbored a potentially actionable, albeit rare, IDH1 mutation. As part of the Know Your Tumor project (Pancreatic Cancer Action Network), a 48-year-old female was diagnosed with metastatic PDA and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. This mutation was confirmed by an independent sequencing reaction from the tumor sample, and by immunohistochemistry using an antibody specific for the IDH1 R132H mutation. The patient subsequently received a mutant IDH1 inhibitor (AG-120, Agios Pharmaceuticals, Cambridge, MA), but with no response. IDH1 mutations are common in certain cancer types, but have not been reported in PDA. We report the first case of an IDH1 mutation in this tumor type, perhaps providing a rare opportunity for a targeted therapy as a treatment option for PDA.

Model analysis of effect of canagliflozin (Invokana), a sodium-glucose cotransporter 2 inhibitor, to alter plasma 1,5-anhydroglucitol.

BACKGROUND Renal reabsorption of 1,5-anhydroglucitol (AG) is competitively inhibited by elevated glucose and leads to depleted plasma AG in diabetes. Plasma AG recovery in diabetes normally correlates with improved glycemic control. However, use of sodium-glucose co-transporter 2 (SGLT2) inhibitors (e.g., canagliflozin) to treat diabetes by inhibition of renal glucose reabsorption can negate this correlation, via an indirect effect (increase of renal filtrate glucose concentration) to inhibit AG reabsorption by sodium-glucose co-transporter 4 (SGLT4). Conversely, then, AG measurement might be useful as an independent marker for SGLT2 inhibitor activity. METHODS Using an AG mass balance model, we analyzed literature data on plasma AG before and after initiation of canagliflozin therapy (CT) to quantitatively characterize the effect of CT on AG reabsorption. RESULTS According to model calculations, modest decreases (<5%) in fractional reabsorption of AG account for the drastic decrease in [AG] observed during CT. Decreases are predicted to be rapid (t1/2<3days) after CT initiation. CONCLUSION CT negates the usual premise of AG measurement (that [AG] should increase with improved glycemic control). However, according to model calculations, a substantial and likely rapid effect of CT on [AG] means that AG measurement might provide an early marker for CT activity.

Fibroepithelial Lesions of the Breast

Fibroepithelial lesions of the breast are a group of biphasic neoplasms, lesions characterized by proliferation of both mesenchymal and epithelial elements. On the whole, these lesions constitute one of the most commonly encountered neoplasms in routine practice and span the spectrum of biological significance from benign to malignant. Prototypic examples of these neoplasms include the fibroadenoma (FA) and phyllodes tumor (PT), with the phyllodes tumor requiring further subtyping into benign, borderline/intermediate, and malignant in accordance with the World Health Organization (WHO) recommendations [1]. These specific lesions within this group have diverse clinical behavior, natural history, and therapeutic implications, despite showing considerable morphologic overlap at times. Since many of the initial diagnoses are rendered in core biopsies, this can potentially compound a diagnostic challenge, and clinical-pathological correlation is imperative. Here, we present a review of fibroepithelial lesions with an emphasis on morphology and distinguishing features. Hamartomas, also considered a fibroepithelial lesion, is discussed below under the differential diagnosis section of fibroadenoma.

MCM2 expression in serrated polyps demonstrates aberrant cellular proliferation

In normal colonic epithelium, the proliferative zone is limited to the lower half of the colonic crypt. Evaluating the changes in the colonic epithelial proliferation can be useful in understanding pathophysiology of various diseases. Our aim was to investigate the proliferative compartment of serrated polyps (SPs) using MCM2, a protein involved in DNA replication, and assess for changes along the SP spectrum. Immunohistochemistry was performed on serrated polyps (16 microvesicular-type hyperplastic polyps (HP), 58 sessile serrated adenomas (SSA), 7 SSAs with dysplasia) and 6 sections of normal colon using anti-MCM2 antibody. Multiple sections of normal colon showed the following pattern for MCM2 and Ki-67 staining: positive nuclear staining of the lower half of the colonic crypts and/or slightly expanded to the lower two-thirds of the crypt. By MCM2, SPs show expansion of the proliferative compartments; 81.3% of HPs and 100% of SSAs showed some degree of full crypt MCM2 staining. SSAs with dysplasia showed consistent diffuse polyp staining. Aberrant staining in adjacent normal mucosa was also seen in SSAs with dysplasia and in a subset of non-dysplastic SSAs. By using MCM2, we show that serrated polyps exhibit changes in proliferation during progression along the pathway. HPs and SSAs show a similar highly proliferative profile. Aberrant proliferative cell staining patterns in adjacent normal colonic mucosa as seen in SSAs with dysplasia and a subset of SSAs suggest a field effect phenomenon. This indicates that changes in the colonic micro-environment may promote adenoma morphogenesis and predisposition to malignancy.