Search

Utilizing a comprehensive (3+1)D relativistic hydrodynamic framework with multiple conserved charge currents and charge-dependent lattice-QCD-based equation of state, we study the baryon and electric charge number deposition at midrapidity in isobar Ru+Ru and Zr+Zr collisions at the center of mass energy sqrt[s_{NN}]=200  GeV. Comparing our predictions with upcoming experimental data from the Relativistic Heavy Ion Collider will shed light on the existence of baryon junctions.

Germ line mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). Patients with FPD frequently show clonal expansion of premalignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the premalignant bone marrow (BM) is not well-understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase in the number of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the BM. Furthermore, the expression of CD48, another inflammation-response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild-type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, using 3 mouse models. These studies establish a novel murine FPDHM model and demonstrate that germ line Runx1 mutations induce a premalignant phenotype marked by BM inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Thymomas are rare tumors characterized by a broad range of morphologic appearances that can sometimes give rise to difficulties for classification. We have studied a series of 120 thymoma patients in whom the tumors were characterized by sheets of atypical epithelial cells with squamoid and/or spindle cell features. They occurred in 63 men and 57 women and presented as a discrete mass in the anterior mediastinum measuring 2-23 cm (mean: 8.2 cm). Patients' ages ranged from 14 to 86 years (mean: 57.8) and most had symptoms referable to a mass lesion. 20 patients had myasthenia gravis or other autoimmune disorder. 76 cases were characterized by a predominant population of round to polygonal tumor cells while 32 cases were characterized by atypical oval or spindle cells. 12 cases showed mixed features and 16 cases showed the development of thymic carcinoma arising from thymoma. All cases were positive for p40/p63 and cytokeratin AE1/AE3. 23 cases were positive for CD5 (25%), and 13 for CD117 (14%). MIB1 showed a significant increase in proliferative activity (mean = 11.6%). Next generation sequencing in 47 cases did not disclose any variants amenable to current targeted therapies. Clinical follow up ranging from 2 to 29 years showed a progressive increase in aggressive behavior and fatality rate with advancing stage. Overall survival was 87% at 5 years, 67% at 10 years, and 23% at 20 years. Completeness of resection and staging were the most significant parameters for survival. The more aggressive tumors followed a protracted clinical course with multiple recurrences and metastases over a long period of time (mean = 19.8 years from time of initial relapse to death). Atypical thymomas are a distinct category of thymic epithelial neoplasm characterized by a slowly progressive clinical course with increased potential for metastases, transformation to a higher-grade malignancy, and fatal outcome in some cases., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

A study of 80 cases of spindle cell thymoma in which the spindle cell component was overshadowed by massive numbers of stromal lymphocytes is presented. The patients were 38 women and 42 men, aged 8 to 81 years (mean=54 y). All tumors presented as an anterior mediastinal mass; 5 patients had myasthenia gravis and one had Good syndrome. The tumors were well-circumscribed, encapsulated, and measured 2.9 to 26.0 cm in greatest diameter (mean=7.3 cm). Using modified Masaoka staging, 66 tumors were stage I, 10 were stage IIa, 2 were stage III and 1 was stage IV. Histologically the tumors were characterized by a predominant lymphocytic population admixed with scattered small spindle epithelial cells. The neoplastic spindle cells in these tumors demonstrated 2 major growth patterns: in 33 cases, the tumors were exclusively composed of dense sheets of lymphocytes containing scattered spindle cells resembling a lymphocyte-rich thymoma (WHO type B1); in the remaining cases the tumors showed admixtures of a predominantly lymphocytic component with areas that were lymphocyte-poor and contained a pure spindle cell population similar to WHO type A. Immunohistochemical stains and electron microscopy corroborated the spindle cell morphology in both types. The GTF2I p.L424H variant was identified in 53 of 63 (84%) cases analyzed. Clinical follow-up in 27 cases showed that most of the tumors behaved in an indolent manner. Our study expands the spectrum of spindle cell thymoma by demonstrating the existence of cases that are predominantly composed of lymphocyte-rich elements and lack areas with a pure (lymphocyte poor) spindle cell morphology., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The expression of immunohistochemical markers has been extensively investigated in thymomas to assist in the differential diagnosis. We have studied six select markers to determine their utility in the evaluation of these tumors. A series of 126 thymomas including 33 type A, 27 type AB, 20 type B1, 22 type B2, and 24 type B3, were examined utilizing a tissue microarray (TMA) technique with antibodies to e-cadherin, β-catenin, PAX8, bcl-2, EMA, and MIB-1. Keratin AE1/AE3 and p63 were used for quality control. A significant finding was strong and consistent positivity for bcl-2 in type A (90%) and type AB (88.8%) thymoma, while 100% of B1, B2, and B3 were negative. The distribution of e-cadherin and β-catenin was not useful for differential diagnosis. E-cadherin and β-catenin were expressed in a high proportion of all the tumors (92-100%), except for B2 thymoma which showed only 45% expression. A significant increase in the expression of the MIB-1 proliferation marker (mean: 12.8% nuclear positivity) was also observed in B3 thymoma compared with the other histologic types. Statistical significance was confirmed using Kruskal's non-parameterized test for distribution. EMA was generally negative except for spindle cells in the fibrous septa in types A and AB thymoma. PAX8 showed less consistent nuclear staining than p63 and was only widely expressed in 55.7% of cases. Bcl-2 may serve as a useful marker to separate spindle cell thymomas (Type A and AB) from the other types, and the MIB1 proliferation index may be of use to differentiate type B2 from type B3 thymoma., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Primary CNS lymphomas (PCNSLs) are aggressive diffuse large B-cell lymphomas (DLBCLs) limited to the CNS that generally have a poor prognosis. Classification of DLBCL into germinal center B-cell (GCB) and activated B-cell (non-GCB) subtypes has prognostic value in systemic DLBCL, with GCB-type having a better prognosis. The aim of this study was to determine whether GCB versus non-GCB classification in PCNSLs has similar prognostic value. We analyzed clinical, radiological and histologic data from 24 patients with biopsy confirmed DLBCL of the CNS with classification into GCB versus non-GCB subtypes. We found that after a median follow-up of 15 months, only 39% of patients with non-GCB-type PCNS DLBCL were alive, whereas all patients with GCB-type were alive. Non-GCB-type had a median survival of 11 months, whereas all GCB-type patients were alive after a median follow-up of 22 months. As previously reported, we also found that patients younger than 70 years had longer survival (median 29 months) compared to older patients (median 8.8 months). There was no statistically significant difference between the ages, gender, focality, size or location of lesions, or treatment of non-GCB and GCB-type patients. Our findings suggest that classifying PCNSLs into GCB versus non-GCB subtype using the Hans algorithm may help stratify patients into two groups with different prognosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease., (© 2020 by The American Society of Hematology.)

Spatial mapping of proteins in tissues is hindered by limitations in multiplexing, sensitivity and throughput. Here we report immunostaining with signal amplification by exchange reaction (Immuno-SABER), which achieves highly multiplexed signal amplification via DNA-barcoded antibodies and orthogonal DNA concatemers generated by primer exchange reaction (PER). SABER offers independently programmable signal amplification without in situ enzymatic reactions, and intrinsic scalability to rapidly amplify and visualize a large number of targets when combined with fast exchange cycles of fluorescent imager strands. We demonstrate 5- to 180-fold signal amplification in diverse samples (cultured cells, cryosections, formalin-fixed paraffin-embedded sections and whole-mount tissues), as well as simultaneous signal amplification for ten different proteins using standard equipment and workflows. We also combined SABER with expansion microscopy to enable rapid, multiplexed super-resolution tissue imaging. Immuno-SABER presents an effective and accessible platform for multiplexed and amplified imaging of proteins with high sensitivity and throughput.

Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL, and CALR genes; however, 10%-15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in primary myelofibrosis patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, types 1- and 2-like CALR mutations were identified by Sanger Sequencing and real time polymerase chain reaction. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher's exact test and Wilcoxon's rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile vs unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P = .0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P = .0056), higher rate of TN cases (27.8% vs 16.2%, P = .0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P = .0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71 M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study., (© 2018 Wiley Periodicals, Inc.)

Poorly differentiated non-keratinizing squamous cell carcinoma of the thymus, also known as lymphoepithelioma-like carcinoma, is a rare primary malignant neoplasm of thymic origin. The mainstay of treatment for these tumors is surgical and they tend to respond poorly to chemotherapy. The checkpoint programmed cell death ligand-1 protein (PD-L1) bound to its receptor (PD-1) has been demonstrated to be an important therapeutic target for many different tumors. Expression of PD-L1/PD-1 in lymphoepithelioma-like carcinoma of the thymus may indicate that these tumors are potential targets for inhibitor therapy. Twenty-one cases of lymphoepithelioma-like carcinoma of the thymus were collected and reviewed. Tissue microarrays were created using triplicate 2 mm cores for each case. PD-L1/PD-1 staining pattern (neoplastic cells versus tumor infiltrating lymphocytes) was documented for each case. Out of 21 cases, 15 (71.4%) showed various degrees of membranous PD-L1 staining. Of the positive cases, 48% showed high expression of PD-L1 (>50% of tumor cells) and 24% showed low expression (<50%). PD-1 staining showed focal positivity in 12/20 (60%) cases among tumor infiltrating lymphocytes. PD-L1/PD-1 inhibitor therapy has been applied successfully in other solid malignant tumors with high expression of PD-L1/PD-1. The high level of PD-L1 expression in our cases indicates that PD-L1 may play a role in the pathogenesis of these tumors and that PD-L1/PD-1 blockade may be a viable therapeutic option for patients with lymphoepithelioma-like carcinoma of the thymus who have failed other first-line therapies.

Thymic carcinoma represents a rare and poorly understood type of thymic epithelial neoplasm that has been the subject of much controversy. Poorly differentiated nonkeratinizing squamous cell carcinoma, also known as lymphoepithelioma-like thymic carcinoma, is a rare variant of thymic carcinoma that has not been adequately characterized in the literature. The clinicopathologic, immunohistochemical, ultrastructural, and molecular features of 25 cases are reported. The patients were 19 men and 6 women, ranging in age from 20 to 85 years (mean: 60 y). The tumors presented clinically as anterior mediastinal masses with chest pain and shortness of breath or were found incidentally on imaging studies. Tumor size ranged from 2.0 to 13.5 cm in greatest diameter. Most of the tumors were small, well-circumscribed and confined to the mediastinum. Five cases presented with large, bulky, and infiltrative masses. Histologically, the hallmark of these tumors was a neoplastic proliferation of large, round to oval cells with vesicular nuclei, prominent eosinophilic nucleoli, and scant cytoplasm. Two histologic growth patterns were identified: tumors with a heavy lymphoplasmacytic stroma (lymphoepithelioma-like pattern), and tumors showing abundant desmoplastic stroma (desmoplastic pattern). Immunohistochemical stains showed strong positivity of the tumor cells for cytokeratin AE1/AE3, CK5/6, CK18, MOC31, p16, p40, and p63. MIB-1 showed on average 35% nuclear positivity. CD117 was positive in 21/25 cases and CD5 in 20/25 cases. Epstein-Barr encoded RNA in situ hybridization was positive in only 1 case. Electron microscopy in 4 cases showed primitive round to oval cells with prominent nucleoli, scant cytoplasm and immature cell junctions. Molecular features were studied by next-generation sequencing using high quality sequence data obtained from 18 patients. Variants with allele frequency between 5% and 45% and quality scores >50 were classified as somatic. A total of 16/18 cases had one or more somatic variants of unknown significance. One case showed an IDH1 p. R132C mutation, also of unknown significance. No "actionable" genes amenable to currently available targeted therapies were identified in this cohort. Clinical follow-up was obtained in 20 patients; 14 patients were alive and well with no evidence of disease between 1.5 and 16 years after diagnosis (median survival: 4 y; mean: 5.5 y). Most survivors had relatively small tumors (<5 cm. diameter), were in stage I and II at diagnosis and showed clear surgical margins. Five patients died of their tumors with metastases to bone, brain, chest wall, lungs and lymph nodes; all were in advanced stages and showed positive margins. Prognosis for these tumors appears to be correlated with the staging and status of the margins at the time of initial surgery.

Whether the human tumor virus, Epstein-Barr Virus (EBV), promotes breast cancer remains controversial and a potential mechanism has remained elusive. Here we show that EBV can infect primary mammary epithelial cells (MECs) that express the receptor CD21. EBV infection leads to the expansion of early MEC progenitor cells with a stem cell phenotype, activates MET signaling and enforces a differentiation block. When MECs were implanted as xenografts, EBV infection cooperated with activated Ras and accelerated the formation of breast cancer. Infection in EBV-related tumors was of a latency type II pattern, similar to nasopharyngeal carcinoma (NPC). A human gene expression signature for MECs infected with EBV, termed EBVness, was associated with high grade, estrogen-receptor-negative status, p53 mutation and poor survival. In 11/33 EBVness-positive tumors, EBV-DNA was detected by fluorescent in situ hybridization for the viral LMP1 and BXLF2 genes. In an analysis of the TCGA breast cancer data EBVness correlated with the presence of the APOBEC mutational signature. We conclude that a contribution of EBV to breast cancer etiology is plausible, through a mechanism in which EBV infection predisposes mammary epithelial cells to malignant transformation, but is no longer required once malignant transformation has occurred., (Copyright © 2016. Published by Elsevier B.V.)

Cutaneous T-cell lymphoma is a type of non-Hodgkin's lymphoma, which is a neoplasm affecting the lymphatic system. Mycosis fungoides is the most common subset of cutaneous T-cell lymphoma and is often treated conservatively. This neoplasm is most common in adults older than 60 years and does not regularly manifest in the toes. A case is reported of a 70-year-old man seen for a nonhealing hallux ulceration leading to amputation. Histopathologic examination revealed a rare transformed CD30(+) high-grade cutaneous T-cell lymphoma. The morbidity of lymphomas is highly dependent on type and grade. Pharmaceutical precision therapies exist that target specific molecular defects or abnormally expressed genes, such as high expression of CD30. This article focuses on treatment protocol and emphasizes the importance of early diagnosis, determination of cell type, and proper referral of atypical dermatologic lesions.

We report a large B-cell lymphoma of follicular origin with extreme signet ring cell differentiation. Initially classified as follicular lymphoma on a fine needle core biopsy, the presence of cohesive sheets of extrafollicular signet ring cells triggered an excisional biopsy for further characterization. The excised lymph node revealed focal follicular hyperplasia, follicular lymphoma, and a neoplasm composed of vague nodules and sheets of large atypical cells, all of which virtually exhibited large clear intracytoplasmic vacuoles with peripheral displacement of nuclei. The tumor cells were negative for mucin and lacked immunoreactivity with pancytokeratin, but were strongly immunoreactive with CD20, BCL-2, BCL-6, and CD10 antibodies. Electron microscopy studies revealed electron-lucent vacuoles with no particular internal structure. This case is unique in that extreme signet ring cell differentiation somewhat obscured the true cytological identity of the interfollicular lymphoma and suggested alternative diagnoses.

Cell cycle re-entry of quiescent T lymphocytes regulated by cdk2 is required for antigen-specific clonal expansion and generation of productive T cell responses. Recently, we determined that induction of antigen-specific T cell tolerance results in impaired cdk2 activity leading to enhanced Smad3 transactivation, upregulation of p15 and blockade of cell cycle progression. Here we report that pharmacologic inhibition of cdk2 with (R)-roscovitine blocked expansion of alloreactive T cells in vitro and in vivo and protected from lethal acute GvHD. In addition to inhibiting alloreactive T cell responses, (R)-roscovitine prevented TNF-alpha-mediated activation of NF-kappa B pathway, which is involved in the inflammatory process leading to the development of GvHD. The combined anti-proliferative and anti-inflammatory properties of (R)-roscovitine make it an attractive treatment modality toward control of GvHD.

This unit describes a method for the rapid and simultaneous detection of hybrid mRNAs (hRNA; also known as gene fusions, RNA fusions, or chimeric RNA), resulting from recurrent chromosome translocations or inversions in acute leukemia. The principal components of the assay are a multiplex RT-PCR, which simultaneously amplifies any of a number of possible hRNA targets, and a liquid bead microarray (LBMA), which is capable of unambiguously identifying the amplified hRNA. The entire procedure from RNA extraction to display of results can be broken into four steps: (1) conjugated-microsphere and LBMA manufacture and quality control, (2) cDNA synthesis, (3) multiplex PCR, and (4) hybridization of multiplex PCR products to the hRNA-detecting LBMA and assay read-out on a flow cytometer. The assay is designed to detect the most common risk-stratifying translocation in pediatric acute lymphoblastic leukemia, satisfying the demand for inclusion of genetic data in the diagnosis of acute leukemia as predicated by the current WHO classification of hematopoietic and lymphoid neoplasms.

We report a case of an extracavitary primary effusion lymphoma occurring in the anorectum of a patient with advanced acquired immune deficiency syndrome. The morphology, null cell immunophenotype, and acquisition of plasma cell markers in this case are typical of the so-called solid variant of primary effusion lymphoma. Lymphoma cells in this case were shown to be co-infected with human herpesvirus-8 and Epstein-Barr virus. Following combination chemotherapy and highly active antiretroviral therapy, this patient has remained in clinical remission for > 3.5 years. The purpose of this report is to add another case to the emerging literature regarding the heterogeneous category of extraserous human herpesvirus-8-associated lymphomas.

Human papillomavirus (HPV) is the worldwide cause of carcinoma of the uterine cervix, a cancer that is the second most common neoplasm in women, resulting in nearly 250,000 deaths a year. The magnitude of the risk of cancer after HPV infection, however, is virus type-specific. Over 40 HPV types can infect the genital tract. Comprehensive, high-throughput typing assays for HPV, however, are not currently available. Blending multiplex PCR and multiplex hybridization using spectrally addressable liquid bead microarrays we have developed a high-throughput, fast, single-tube-typing assay capable of simultaneously typing 45 HPV. The overall incidence of HPV in 429 women tested using this new assay was 72.2% for those with squamous intraepithelial lesions, 51.5% for those with atypical squamous cells of undetermined significance and 15.4% for women with normal cytology, respectively. This compared well with the incidence of HPV detected by a parallel non-typing generic high-risk assay. The new assay detected a wide spectrum of HPV types and a high incidence of mixed infections. We believe our assay may find widespread applications in areas requiring virus type-specific information, such as in epidemiological studies, cancer screening programs, monitoring therapeutic interventions, and evaluating the efficacy of HPV vaccine trials.

The Mdm2 gene is amplified in approximately one-third of human sarcomas and overexpressed in a variety of other human cancers. Mdm2 functions as an oncoprotein, in part, by acting as a negative regulator of the p53 tumor suppressor protein. Multiple spliced forms of Mdm2 transcripts have been observed in human tumors; however, the contribution of these variant transcripts to tumorigenesis is unknown. In this report, we isolate alternative splice forms of Mdm2 transcripts from sarcomas that spontaneously arise in Mdm2-overexpressing mice, including Mdm2-b, the splice form most commonly observed in human cancers. Transduction of Mdm2-b into a variety of cell types reveals that Mdm2-b promotes p53-independent cell growth, inhibits apoptosis, and up-regulates the RelA subunit of NFkappaB. Furthermore, expression of Mdm2-b induces tumor formation in transgenic mice. These results identify a p53-independent role for Mdm2 and determine that an alternate spliced form of Mdm2 can contribute to formation of cancer via a p53-independent mechanism. These findings also provide a rationale for the poorer prognosis of those patients presenting with tumors harboring multiple Mdm2 transcripts.