Maria A Proytcheva

Interests

Research

Pediatric hematopathology; Standardization of laboratory hematology; Leadership development for physicians

Teaching

Hematopholoty; Coagulation; Blood bank and transfusion medicine; Leadership and laboratory management

Courses

Scholarly Contributions

Books

• Proytcheva, M. (2011). Diagnostic Pediatric Hematopathology. Cambridge University Press. doi:10.1017/CBO9780511781292
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  Diagnostic pediatric hematopathology textbook focuses on the diagnostic aspects of benign and neoplastic hematologic diseases in chilren and discusses a wide range of key problems and issues that must be addressed in reaching a proper diagnosis.  The text is intended as a helpful instrument in the everyday practice of pathologists, pediatric pathologists, and hematopathologists 

Chapters

• Mcghan, L. J., & Proytcheva, M. (2018). Myeloid Proliferations of Down Syndrome. In Atlas of Bone Marrow Pathology(pp 193-198). Springer, New York, NY. doi:10.1007/978-1-4939-7469-6_12
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  Individuals with Down syndrome (DS) have a markedly increased risk of developing unique myeloid proliferations such as transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome (ML-DS) [1, 2]. These proliferations occur in the first 3 years of life and are a result of several transforming genetic events that arise during the fetal and newborn period. The initial event, an additional chromosome 21, leads to increased megakaryocytic proliferation in the fetal liver. Subsequent mutation of GATA-binding protein 1 (GATA1) results in the development of TAM. Further acquisition of additional mutations of epigenetic regulators and common signaling pathways such as JAK family kinases, MPL, and multiple RAS pathway genes leads to the transformation to MS-DS [3].

Journals/Publications

• Truscott, L., Pariury, H., Hanmod, S., Davini, M., de la Maza, M., Sapp, L. N., Staples, K., Proytcheva, M., & Katsanis, E. (2023). Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation. Pediatric blood & cancer, 70(2), e30102.
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  Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies.
• Katsanis, E., Proytcheva, M., de la Maza, M., Davini, M., Hanmod, S., Pariury, H., Truscott, L., Sapp, L. N., & Staples, K. (2022). Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation. Pediatric Blood & Cancer, 70(2). doi:10.1002/pbc.30102
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  Abstract: Background Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. Procedure We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose—busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies. Results With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II–IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). Conclusions Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.
• Alswied, A., Rehman, A., Lai, L. W., Duran, J., Sardar, M., & Proytcheva, M. A. (2021). Rare monosomy 7 and deletion 7p at diagnosis of chronic myeloid leukemia in accelerated phase. Cancer genetics, 252-253, 111-114.
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  Clonal cytogenic evolution with the development of additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is a marker for disease progression and is known to impact therapy and survival. The presence of ACAs has been shown to affect the responses to tyrosine kinase inhibitors (TKI) in patients with newly diagnosed CML in accelerated phase (CML-AP). We report a rare case of a CML patient who presented in CML-AP and was found to have multiple ACAs including monosomy 7, deletion 7p, trisomy 8, and an extra Philadelphia chromosome (Ph) in separate Ph-positive cell line, respectively. Six months after combined chemotherapy with TKI, the patient achieved a major cytogenetic response with disappearance of monosomy 7/deletion 7p with no major molecular response.
• Macaraeg, M., Proytcheva, M., & Katsanis, E. (2019). Transfusion independence after repeated haploidentical hematopoietic cell transplants in a patient with congenital dyserythropoietic anemia type II and hemosiderosis. Pediatric transplantation, 23(8), e13587.
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  Matched related or unrelated donor allogeneic HCT has occasionally been applied in patients with severe CDA type II and proven to be curative. We report on the first patient with CDA to undergo haploidentical bone marrow transplantation with PT-CY. A 12-year-old boy with severe hemosiderosis, and a, consequently, disturbed BM microenvironment, developed recurrent graft failures and required salvage with two additional haploidentical HCTs. He achieved complete donor chimerism and transfusion independence after the third HCT. Our case underscores the risks associated with performing haploidentical HCT in older pediatric patients with CDA and severe chronic iron overload.
• Proytcheva, M., Macaraeg, M., & Katsanis, E. (2019). Transfusion independence after repeated haploidentical hematopoietic cell transplants in a patient with congenital dyserythropoietic anemia type II and hemosiderosis. Pediatric Transplantation, 23(8). doi:10.1111/petr.13587
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  Matched related or unrelated donor allogeneic HCT has occasionally been applied in patients with severe CDA type II and proven to be curative. We report on the first patient with CDA to undergo haploidentical bone marrow transplantation with PT-CY. A 12-year-old boy with severe hemosiderosis, and a, consequently, disturbed BM microenvironment, developed recurrent graft failures and required salvage with two additional haploidentical HCTs. He achieved complete donor chimerism and transfusion independence after the third HCT. Our case underscores the risks associated with performing haploidentical HCT in older pediatric patients with CDA and severe chronic iron overload.
• Katsanis, E., Proytcheva, M., Zeng, Y., Hahn, S., Stokes, J., Hoffman, E. A., Schmelz, M., & Chernoff, J. (2017). Pak2 regulates myeloid-derived suppressor cell development in mice. Blood Advances, 1(22), 1923-1933. doi:10.1182/bloodadvances.2017007435
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  Myeloid-derived suppressor cells (MDSCs) are CD11b+Gr1+ cells that induce T-cell hyporesponsiveness, thus impairing antitumor immunity. We have previously reported that disruption of Pak2, a member of the p21-activated kinases (Paks), in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and expansion of CD11bhighGr1high cells in mice. In this study, we confirmed that Pak2-KO CD11bhighGr1high cells suppressed T-cell proliferation, consistent with an MDSC phenotype. Loss of Pak2 function in HSPCs led to (1) increased hematopoietic progenitor cell sensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, (2) increased MDSC proliferation, (3) decreased MDSC sensitivity to both intrinsic and Fas-Fas ligand-mediated apoptosis, and (4) promotion of MDSCs by Pak2-deficient CD4+ T cells that produced more interferon γ, tumor necrosis factor α, and GM-CSF. Pak2 disruption activated STAT5 while downregulating the expression of IRF8, a well-described myeloid transcription factor. Together, our data reveal a previously unrecognized role of Pak2 in regulating MDSC development via both cell-intrinsic and extrinsic mechanisms. Our findings have potential translational implications, as the efficacy of targeting Paks in cancer therapeutics may be undermined by tumor escape from immune control and/or acceleration of tumorigenesis through MDSC expansion.
• Zeng, Y., Hahn, S., Stokes, J., Hoffman, E. A., Schmelz, M., Proytcheva, M., Chernoff, J., & Katsanis, E. (2017). Pak2 regulates myeloid-derived suppressor cell development in mice. Blood advances, 1(22), 1923-1933.
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  Myeloid-derived suppressor cells (MDSCs) are CD11bGr1 cells that induce T-cell hyporesponsiveness, thus impairing antitumor immunity. We have previously reported that disruption of Pak2, a member of the p21-activated kinases (Paks), in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and expansion of CD11bGr1 cells in mice. In this study, we confirmed that CD11bGr1 cells suppressed T-cell proliferation, consistent with an MDSC phenotype. Loss of Pak2 function in HSPCs led to (1) increased hematopoietic progenitor cell sensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, (2) increased MDSC proliferation, (3) decreased MDSC sensitivity to both intrinsic and Fas-Fas ligand-mediated apoptosis, and (4) promotion of MDSCs by Pak2-deficient CD4 T cells that produced more interferon γ, tumor necrosis factor α, and GM-CSF. Pak2 disruption activated STAT5 while downregulating the expression of , a well-described myeloid transcription factor. Together, our data reveal a previously unrecognized role of Pak2 in regulating MDSC development via both cell-intrinsic and extrinsic mechanisms. Our findings have potential translational implications, as the efficacy of targeting Paks in cancer therapeutics may be undermined by tumor escape from immune control and/or acceleration of tumorigenesis through MDSC expansion.
• Hayward, C. P., Moffat, K. A., George, T. I., Proytcheva, M., & Iorio, A. (2016). Report on the International Society for Laboratory Hematology Survey on guidelines to support clinical hematology laboratory practice. International journal of laboratory hematology, 38 Suppl 1, 133-8.
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  Given the importance of evidence-based guidelines in health care, we surveyed the laboratory hematology community to determine their opinions on guideline development and their experience and interest in developing clinical hematology laboratory practice guidelines.
• Nolte, D. A., & Proytcheva, M. A. (2016). Flowers blossoming in the desert heat. Blood, 128(24), 2868.
• Proytcheva, M., Hayward, C. P., Moffat, K. A., George, T. I., & Iorio, A. (2016). Report on the International Society for Laboratory Hematology Survey on guidelines to support clinical hematology laboratory practice. International Journal of Laboratory Hematology, 38, 133-138. doi:10.1111/ijlh.12501
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  Introduction: Given the importance of evidence-based guidelines in health care, we surveyed the laboratory hematology community to determine their opinions on guideline development and their experience and interest in developing clinical hematology laboratory practice guidelines. Methods: The study was conducted using an online survey, distributed to members of the International Society for Laboratory Hematology (ISLH) in 2015, with analysis of collected, anonymized responses. Results: A total of 245 individuals participated. Most worked in clinical and/or research laboratories (83%) or industry (11%). 42% felt there were gaps in current guidelines. The majority (58%) recommended that ISLH engages its membership in guideline development. Participants differed in their familiarity with, and use of, different organizations' guidelines. Participants felt it was important to follow best practice recommendations on guideline development, including engagement of experts, statement about conflict of interests and how they were managed, systematic review and grading evidence for recommendations, identifying recommendations lacking evidence or consensus, and public input and peer review of the guideline. Moreover, it was considered important to provide guidelines free of charge. Industry involvement in guidelines was considered less important. Conclusions: The clinical laboratory hematology community has high expectations of laboratory practice guidelines that are consistent with recent recommendations on evidence-based guideline development.
• Canto, C., & Proytcheva, M. A. (2015). Bone marrow failure syndromes, a practical approach to diagnosis. Journal of Hematopathology, 8(2), 101-112. doi:10.1007/s12308-015-0252-5
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  The inherited bone marrow failure (IBMF) syndromes are a heterogeneous group of disorders with characteristic quantitative or qualitative abnormalities affecting one or more hematopoietic lineages. IBMF syndromes are due to germline mutations affecting structural proteins or key cellular pathways such as DNA repair, telomerase biology, and ribosomal biosynthesis. These mutations lead to single or multiple peripheral blood cytopenias that either result from an absence of one or more lineages of hematopoietic progenitors in the marrow or to an increase cell death of one or more marrow progenitor lineages. Most IBMF syndromes manifest in childhood, but some are recognized later in life depending on the severity of symptoms. This review we will summarize the clinical presentation, diagnostic findings, and genetic findings of the most frequent and best studied IBMF syndromes with a special focus on the diagnostic dilemmas which can occur during the work up of a child with suspected a IBMF syndrome.
• Hayward, C. P., Moffat, K. A., George, T. I., & Proytcheva, M. (2015). Assembly and evaluation of an inventory of guidelines that are available to support clinical hematology laboratory practice. International journal of laboratory hematology, 37 Suppl 1, 36-45.
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  Practice guidelines provide helpful support for clinical laboratories. Our goal was to assemble an inventory of publically listed guidelines on hematology laboratory topics, to create a resource for laboratories and for assessing gaps in practice-focused guidelines.
• Lukefahr, A. L., & Proytcheva, M. (2018). Alder-Reilly Anomaly in the Cerebrospinal Fluid of a Child With Hurler Syndrome. Journal of pediatric hematology/oncology, 40(1), 74-75. doi:10.1097/MPH.0000000000001041
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  Hurler syndrome is an autosomal recessive mucopolysaccharidosis characterized by intralysosomal accumulation of glycosaminoglycan fragments, with cellular accumulation of distended lysosomes resulting in interference with normal cell function. One of the peripheral blood features of mucopolysaccharidoses is the presence of numerous, dark lilac granules within lymphocytes, monocytes, and neutrophils, also known at Alder-Reilly anomaly. Here we describe intracytoplasmic granules with haloes in mononuclear cells present in the cerebrospinal fluid of a 2-year-old boy with the diagnosis of Hurler syndrome, undergoing pretransplant evaluation for an unrelated donor cord blood stem cell transplant.
• Palmer, L., Briggs, C., McFadden, S., Zini, G., Burthem, J., Rozenberg, G., Proytcheva, M., & Machin, S. J. (2015). ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. International journal of laboratory hematology, 37(3), 287-303.
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  These guidelines provide information on how to reliably and consistently report abnormal red blood cells, white blood cells and platelets using manual microscopy. Grading of abnormal cells, nomenclature and a brief description of the cells are provided. It is important that all countries in the world use consistent reporting of blood cells. An international group of morphology experts have decided on these guidelines using consensus opinion. For some red blood cell abnormalities, it was decided that parameters produced by the automated haematology analyser might be more accurate and less subjective than grading using microscopy or automated image analysis and laboratories might like to investigate this further. A link is provided to show examples of many of the cells discussed in this guideline.
• Proytcheva, M., Hayward, C. P., Moffat, K. A., & George, T. I. (2015). Assembly and evaluation of an inventory of guidelines that are available to support clinical hematology laboratory practice. International Journal of Laboratory Hematology, 37(3), 36-45. doi:10.1111/ijlh.12348
• Babiker, H. M., & Proytcheva, M. (2014). Basophilic blast phase of chronic myelogenous leukemia. Blood, 124(15), 2464.
• Proytcheva, M., & Babiker, H. M. (2014). Basophilic blast phase of chronic myelogenous leukemia. Blood, 124(15), 2464-2464. doi:10.1182/blood-2014-08-593194
• Andolina, J. R., Morrison, C. B., Thompson, A. A., Chaudhury, S., Mack, A. K., Proytcheva, M., & Corey, S. J. (2013). Shwachman-Diamond syndrome: diarrhea, no longer required?. Journal of pediatric hematology/oncology, 35(6), 486-9.
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  Exocrine pancreatic insufficiency and diarrhea have been hallmarks in the diagnosis of Shwachman-Diamond syndrome (SDS). We report 2 cases of genetically confirmed SDS in patients who presented with an unusual phenotype. Patient #1 presented with pancytopenia without other system involvement, while patient #2 presented with severe neutropenia, anemia, and a bifid thumb. Neither patient had diarrhea or malabsorption. Both patients had the classic heterozygous mutations c183_184 TA>CT and c.258+2 T>C in the Shwachman-Bodian-Diamond syndrome gene. Incomplete phenotypes may be more common than previously recognized in bone marrow failure syndromes; gastrointestinal symptoms should not be considered a prerequisite for SDS.
• Bass, L. M., Barsness, K., Benya, E., Proytcheva, M., & Kagalwalla, A. (2013). Mesenteric Castleman disease detected by capsule endoscopy. Journal of pediatric gastroenterology and nutrition, 57(1), e3-5.
• Proytcheva, M. (2013). Bone marrow evaluation for pediatric patients. International Journal of Laboratory Hematology, 35(3), 283-289. doi:10.1111/ijlh.12073
• Proytcheva, M. (2013). Bone marrow evaluation for pediatric patients. International journal of laboratory hematology, 35(3), 283-9.
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  Due to the immaturity of the hematopoietic system at birth and different oxygenation and immune response needs of the growing organism, the bone marrow composition at birth and early infancy differs as compared to older children and adults. These age-related differences, while generally recognized, are not well known to the world of hematopathology. The purpose of this article is to address the current limitation of the literature by reviewing the bone marrow ontology, its composition at birth, and the changes occurring during early infancy, and to compare these findings to adults. The review also provides a useful framework for bone marrow examination in children.
• Yoon, J. W., Gallant, M., Lamm, M. L., Iannaccone, S., Vieux, K. F., Proytcheva, M., Hyjek, E., Iannaccone, P., & Walterhouse, D. (2013). Noncanonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma. Molecular cancer research : MCR, 11(6), 604-15.
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  Although Hedgehog signaling plays a major role in GLI1 transcription, there is now evidence suggesting that other pathways/genes, such as c-MYC, may also regulate GLI1 expression. We initiated studies in Burkitt lymphoma cells, which constitutively express c-MYC due to a chromosomal translocation, to determine whether Hedgehog or c-MYC regulates GLI1 expression. We show that all Burkitt lymphoma cell lines tested express GLI1, PTCH1, and SMO and that five of six Burkitt lymphomas express GLI1. Exposure to Sonic or Indian Hedgehog or cyclopamine (SMO inhibitor) does not modulate GLI1 expression, cell proliferation, or apoptosis in most Burkitt lymphoma cell lines. Sequence analysis of PTCH1, SMO, and SuFu failed to show mutations that might explain the lack of Hedgehog responsiveness, and we did not detect primary cilia, which may contribute to it. We show that c-MYC interacts with the 5'-regulatory region of GLI1, using chromatin immunoprecipitation (ChIP) assay, and E-box-dependent transcriptional activation of GLI1 by c-MYC in NIH3T3 and HeLa cells. The c-MYC small-molecule inhibitor 10058-F4 downregulates GLI1 mRNA and protein and reduces the viability of Burkitt lymphoma cells. Inhibition of GLI1 by GANT61 increases apoptosis and reduces viability of some Burkitt lymphoma cells. Collectively, our data provide evidence that c-MYC directly regulates GLI1 and support an antiapoptotic role for GLI1 in Burkitt lymphoma. Burkitt lymphoma cells do not seem to be Hedgehog responsive. These findings suggest a mechanism for resistance to SMO inhibitors and have implications for using SMO inhibitors to treat human cancers.
• Cooper, D. L., Proytcheva, M., Medoff, E., Seropian, S. E., Snyder, E. L., Krause, D. S., & Wu, Y. (2012). Successful collection and engraftment of autologous peripheral blood progenitor cells in poorly mobilized patients receiving high-dose granulocyte colony-stimulating factor. Journal of clinical apheresis, 27(5), 235-41.
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  Granulocyte Colony-Stimulating Factor (G-CSF) alone or in conjunction with chemotherapy is commonly used to mobilize hematopoietic progenitor cells (HPC) into peripheral blood for progenitor cell harvest for autologous HPC transplantation. However, in up to 30% of patients, HPC are not effectively mobilized. In this study, we report the efficacy and safety profiles of a mobilization strategy using high-dose (up to 36 μg/kg) G-CSF in poorly mobilized patients.
• Nelson, B. P., Wolniak, K. L., Evens, A., Chenn, A., Maddalozzo, J., & Proytcheva, M. (2012). Early posttransplant lymphoproliferative disease: clinicopathologic features and correlation with mTOR signaling pathway activation. American journal of clinical pathology, 138(4), 568-78.
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  Early posttransplant lymphoproliferative disorders (EPTLDs) represent the first changes in posttransplant lymphoproliferative disorders (PTLDs) morphologic spectrum. EPTLD data are available mostly from case reports and series that include other types of PTLD. Fifteen EPTLDs were reviewed retrospectively. Clinical data, histopathology, clonality, and Epstein- Barr virus (EBV) status were correlated with staining intensity to an antibody for phosphorylated S6 (pS6) ribosomal protein, a downstream effector of mammalian target of rapamycin (mTOR). Median time from transplantation to EPTLD was 50 months (range, 7-135 mo). EPTLDs involved tonsil and/or adenoids (n = 11) and lymph nodes (n = 4), all of which were nonclonal and EBV-encoded RNA-positive. Most (n = 11) were plasmacytic hyperplasia and florid follicular hyperplasia (n = 4). All regressed with reduced immunosuppression, and had increased pS6 staining compared with normal tonsil (P = .002, F test). EPTLDs developed later than previously reported, involved mostly tonsils/adenoids, were EBV-encoded RNA (EBER) positive, showed increased pS6, and had excellent clinical outcome with reduction of immunosuppression.
• Ibarra, M. F., Klein-Gitelman, M., Morgan, E., Proytcheva, M., Sullivan, C., Morgan, G., Pachman, L. M., & O'Gorman, M. R. (2011). Serum neopterin levels as a diagnostic marker of hemophagocytic lymphohistiocytosis syndrome. Clinical and vaccine immunology : CVI, 18(4), 609-14.
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  The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.
• Proytcheva, M. (2011). Juvenile myelomonocytic leukemia. Seminars in diagnostic pathology, 28(4), 298-303.
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  Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with features characteristic of both myelodysplastic and myeloproliferative disorders. Children with JMML typically present with marked splenomegaly and hepatomegaly and varying degrees of lymphadenopathy, pallor, and skin rash. The peripheral blood usually show leukocytosis, absolute monocytosis, often with dysplastic features, anemia, and thrombocytopenia. While the bone marrow findings are less specific, hypercellularity due to myelomonocytic proliferation, mild dysplasia, and a reduced number of megakaryocytes are usually present. The hallmark of JMML is hypersensitivity of marrow progenitors to granulocyte-monocyte colony stimulating factor (GM-CSF) in vitro. Recent studies have shown that this abnormal proliferation is due to an aberrant signal transduction resulting from mutations in components of the RAS-signaling pathway. JMML is an aggressive neoplasm and, while hematopoietic stem cell transplantation is currently the only curative option, there is an unacceptably high relapse rate after transplant.
• Castro, E. C., Blazquez, C., Boyd, J., Correa, H., de Chadarevian, J. P., Felgar, R. E., Graf, N., Levy, N., Lowe, E. J., Manning, J. T., Proytcheva, M. A., Senger, C., Shayan, K., Sterba, J., Werner, A., Surti, U., & Jaffe, R. (2010). Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society, 13(3), 225-37.
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  We describe the clinicopathologic features of 15 patients who had histiocytic lesions that followed acute lymphoblastic leukemia (ALL). Twenty-one separate histiocytic lesions were evaluated that covered a wide spectrum, some conforming to the usual categories of juvenile xanthogranulomas (5), Langerhans' cell histiocytosis (1), Langerhans' cell sarcoma (4), Rosai-Dorfman disease (1), and histiocytic sarcoma (4). Most were atypical for the category by histology, phenotype, or abnormally high turnover rate. Seven low-grade lesions defied easy categorization and were characterized only as "atypical histiocytic lesion" following ALL. For those evaluated, the molecular signature of the prior leukemia was present in the histiocytic lesion. In 3 of 15 patients, the leukemia and histiocytic lesion shared immunoglobulin H or monoclonal TCR gene rearrangements and, in 4 of 15 patients, clonal identity was documented by fluorescence in situ hybridization. Four patients died of progressive disease, 3 of whom had histiocytic sarcoma and 1 who had an atypical lesion. One patient died of recurrent ALL. The other 10 patients are alive, 7 after recurrences and treatment with surgery and/or chemotherapy. The post-ALL lesions are more aggressive than their native counterparts, but despite the demonstration of the presence of the leukemia signature in 7 of 15 patients, the prognosis is generally favorable, except for patients with histiocytic sarcoma. It remains unclear whether the histiocytic lesions arise as a line from the original ALL or whether transdifferentiation is involved.
• Laposata, M., Proytcheva, M. A., Rutledge, J. C., & Stratton, C. W. (2010). Professional quality assurance in laboratory medicine: what about the competency of laboratory directors?. American journal of clinical pathology, 134(5), 706-8.
• Sullivan, C., Proytcheva, M., Pachman, L. M., O'gorman, M. R., Morgan, G. A., Morgan, E. R., Klein-gitelman, M. S., & Ibarra, M. (2010). Serum Neopterin Levels as a Diagnostic Marker of Hemophagocytic Lymphohistiocytosis Syndrome. Clinical Immunology, 135, S50. doi:10.1016/j.clim.2010.03.153
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  The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.
• Proytcheva, M. A. (2009). Issues in neonatal cellular analysis. American journal of clinical pathology, 131(4), 560-73.
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  Hematologic values in neonates differ significantly from those in older children and adults. Quantitative and qualitative differences are present as a reflection of the developmental changes during fetal hematopoiesis and, so, correlate with gestational age. At birth, the hemoglobin, mean corpuscular volume, and WBC counts of term newborns are significantly higher than those of older children and adults, and in preterm neonates the differences are even more pronounced. This review explores these differences and the major factors that account for them from the hematology laboratory standpoint. After a discussion of the developmental hematopoiesis and normal hematologic values in term and preterm neonates, important preanalytic factors, such as limited blood availability, effect of sampling site, and violent crying, and analytic interferences are examined. Finally, the review addresses resulting challenges in interpretation of hematologic test results in term and preterm neonates, especially issues surrounding neonatal reference intervals and critical value reporting, and suggests possible solutions.
• Katz, B. Z., Pahl, E., Crawford, S. E., Kostyk, M. C., Rodgers, S., Seshadri, R., Proytcheva, M., & Pophal, S. (2007). Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort. Pediatric transplantation, 11(1), 58-65.
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  PTLD is an important complication following heart transplantation. To better define the risk factors of PTLD in children, we performed a case-control study. All pediatric cardiac transplant recipients who developed their first episode of PTLD were matched by age (+/-1 yr) and time since transplant (+/-1 yr) with those who did not. PTLD occurred in nine of 95 cardiac transplant recipients (9%), 0.3-7.8 yr following cardiac transplantation (median = 2.5 yr). Patients were 0.1-16.4 yr (median = 3.7) at transplantation. Biopsies revealed polymorphic B cell hyperplasia (three), polymorphic B cell lymphoma (one), monomorphic diffuse large cell B cell lymphoma (three) and monomorphic Burkitt's-like lymphoma (two). Patients who developed PTLD were at no greater risk of death (p = 0.31). Recipient EBV seronegativity at time of transplant (p = 0.08), EBV seroconversion (p = 0.013) and recipient CMV seronegativity (p = 0.015) were associated with the development of PTLD by conditional logistic regression; sex, race, donor age, recipient diagnosis, donor CMV seropositivity, recipient treatment for CMV infection, EBV seropositivity at the time of PTLD diagnosis, and number of rejection episodes, treated rejection episodes, and lympholytics used were not. There was no significant association between PTLD and death in our recipients. EBV seroconversion and recipient CMV seronegativity were associated with the development of PTLD.
• Seshadri, R., Rodgers, S., Proytcheva, M., Pophal, S., Pahl, E., Kostyk, M. C., Katz, B. Z., & Crawford, S. E. (2007). Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort.. Pediatric transplantation, 11(1), 58-65. doi:10.1111/j.1399-3046.2006.00609.x
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  PTLD is an important complication following heart transplantation. To better define the risk factors of PTLD in children, we performed a case-control study. All pediatric cardiac transplant recipients who developed their first episode of PTLD were matched by age (+/-1 yr) and time since transplant (+/-1 yr) with those who did not. PTLD occurred in nine of 95 cardiac transplant recipients (9%), 0.3-7.8 yr following cardiac transplantation (median = 2.5 yr). Patients were 0.1-16.4 yr (median = 3.7) at transplantation. Biopsies revealed polymorphic B cell hyperplasia (three), polymorphic B cell lymphoma (one), monomorphic diffuse large cell B cell lymphoma (three) and monomorphic Burkitt's-like lymphoma (two). Patients who developed PTLD were at no greater risk of death (p = 0.31). Recipient EBV seronegativity at time of transplant (p = 0.08), EBV seroconversion (p = 0.013) and recipient CMV seronegativity (p = 0.015) were associated with the development of PTLD by conditional logistic regression; sex, race, donor age, recipient diagnosis, donor CMV seropositivity, recipient treatment for CMV infection, EBV seropositivity at the time of PTLD diagnosis, and number of rejection episodes, treated rejection episodes, and lympholytics used were not. There was no significant association between PTLD and death in our recipients. EBV seroconversion and recipient CMV seronegativity were associated with the development of PTLD.
• Trobaugh-Lotrario, A. D., Kletzel, M., Quinones, R. R., McGavran, L., Proytcheva, M. A., Hunger, S. P., Malcolm, J., Schissel, D., Hild, E., & Giller, R. H. (2005). Monosomy 7 associated with pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): successful management by allogeneic hematopoietic stem cell transplant (HSCT). Bone marrow transplantation, 35(2), 143-9.
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  Pediatric acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with monosomy 7 is associated with poor disease-free survival when treated by conventional chemotherapy, immunosuppression or supportive measures. Hematopoietic stem cell transplant (HSCT) may improve outcomes; however, data to support this are limited. To better understand the curative potential of HSCT in these patients, all cases of AML and MDS with monosomy 7 treated by two transplant programs (1992 to present) were reviewed. A total of 16 patients were treated, all by allogeneic HSCT. Primary diagnoses were MDS (N = 5), therapy-related MDS (N = 3), AML (N = 5) and therapy-related AML (N = 3). In all, 11 patients (69%) survive event-free at 2 years with median follow-up of 986 days (range 330-2011 days). Toxicity caused deaths of the five nonsurviving patients, four of whom were transplanted with active leukemia. Allogeneic HSCT is effective therapy for childhood AML and MDS associated with monosomy 7, particularly for patients with AML in complete remission and MDS.
• Trobaugh-lotrario, A. D., Kletzel, M., Quinones, R. R., Mcgavran, L., Proytcheva, M. A., Hunger, S. P., Malcolm, J., Schissel, D., Hild, E., & Giller, R. H. (2005). Monosomy 7 associated with pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): successful management by allogeneic hematopoietic stem cell transplant (HSCT).. Bone marrow transplantation, 35(2), 143-9. doi:10.1038/sj.bmt.1704753
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  Pediatric acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with monosomy 7 is associated with poor disease-free survival when treated by conventional chemotherapy, immunosuppression or supportive measures. Hematopoietic stem cell transplant (HSCT) may improve outcomes; however, data to support this are limited. To better understand the curative potential of HSCT in these patients, all cases of AML and MDS with monosomy 7 treated by two transplant programs (1992 to present) were reviewed. A total of 16 patients were treated, all by allogeneic HSCT. Primary diagnoses were MDS (N = 5), therapy-related MDS (N = 3), AML (N = 5) and therapy-related AML (N = 3). In all, 11 patients (69%) survive event-free at 2 years with median follow-up of 986 days (range 330-2011 days). Toxicity caused deaths of the five nonsurviving patients, four of whom were transplanted with active leukemia. Allogeneic HSCT is effective therapy for childhood AML and MDS associated with monosomy 7, particularly for patients with AML in complete remission and MDS.
• Wu, Y., Snyder, E. L., Seropian, S., Proytcheva, M. A., Medoff, E., Krause, D. S., & Cooper, D. L. (2005). Successful Engraftment of Autologous Peripheral Blood Progenitor Cells Derived from Multiple Collections in Poor Mobilizers by Hyperstimulation with G-CSF.. Blood, 106(11), 5508-5508. doi:10.1182/blood.v106.11.5508.5508
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  G-CSF alone or in conjunction with chemotherapy is the most commonly used regimen to mobilize hematopoietic progenitor cells into peripheral blood (PB) for stem cell harvest. However, in about 10–30 % of patients when mobilized with this regimen, their hematopoietic progenitor cells are not effectively mobilized. We have adopted an approach of using higher doses of G-CSF from 16 to 36 ug/kg patient body weight to mobilize hematopoietic progenitor cells in patients that are poorly mobilized. Poor mobilization (PM) is defined as peak pre-apheresis PBCD34 count of 500/uL, and platelet engraftment as a platelet count >20,000/uL without platelet transfusions for 2 consecutive days, respectively, as well as day 15 lymphocyte count. Safety of stem cell mobilization, apheresis collection, and stem cell infusion were also evaluated. The results are shown in the tables below. | Groups | I (GM + L) | II (GM + H) | III (PM + L) | IV (PM + H) | |:----------------------------------------------------------------------------------------- | -------------- | -------------- | ------------- | --------------- | | L: low dose G-CSF (5-12 ug/kg); H: high dose G-CSF (15-36 ug/kg). Median (Range); No. (%) | | No. (patients/collections) | 232/485 | 62/273 | 10/40 | 56/290 | | Peak PBCD34 (/uL) | 85 (21-1320) | 30 (21-99) | 17 (11-20) | 13.5 (5-20) | | CD34 yield (10^6) per recipient Kg wt/apheresis | 3.7 (0.4-37.8) | 1.2 (0.2-11.1) | 1 (0.4-2.7) | 0.7 (0.1-2.89) | | Total CD34 yield (10^6) per recipient kg wt | 9.5 (3.2-37.8) | 6.1 (3.2-17.9) | 4.6 (2.2-7.2) | 4.4 (1.08-6.66) | | GCSF toxicity (Pain, headache, etc) | | | | | | None | 230 (47.4%) | 161 (59%) | 18 (45%) | 158 (54.5%) | | Mild, no pain meds | 155 (32%) | 80 (29.3%) | 18 (45%) | 77 (26.6%) | | Moderate, requiring NSAIDS | 49 (10.1%) | 23 (8.4%) | 1 (2.5%) | 31 (10.7%) | | Severe, requiring Narcotics | 51 (10.5%) | 9 (3.3 %) | 3 (7.5%) | 24 (8.3%) | | Apheresis Toxicity (none) | 87.8% | 89.4% | 85% | 89% | | Apheresis Toxicity (mild to moderate) | 12.2% | 10.6% | 15% | 11% | Efficacy and safety of stem cell mobilization and collection | Groups | I | II | III | IV | |:------------------------------------------- | -------------- | ---------------- | ---------------- | ---------------- | | Median (Range) | | No. (Patients /Infusions) | 232/249 | 48/54 | 8/8 | 32/32 | | Total CD34 (10^6)/recipient kg wt infused | 5.8 (2.5-18.9) | 4.7 (2.0-8.8) | 4.1 (2.1-5.9) | 3.5 (2.4-5.8) | | Days to ANC of 500 | 10 (7-16) | 10 (7-12) | 10 (9-12) | 10 (6-12) | | Days to platelet of 20,000/uL | 10 (6-33) | 10 (8-30) | 13 (8-34) | 10 (8-24) | | Day 15 (+/− 3) lymphocyte count (x 1000/uL) | 0.53 (0-2.96) | 0.38 (0.01-1.25) | 0.43 (0.24-0.75) | 0.74 (0.22-3.69) | | DMSO toxicity (none) | 93.6% | 77.8% | 75% | 90.6% | | DMSO toxicity (yes) | 6.4% | 22.2% | 25% | 9.4% | Efficacy and safety of stem cell infusion and engraftment In summary, multiple collections of autologous peripheral blood progenitor cells through hyperstimulation by G-CSF in poor mobilizers is an effective alternative approach for stem cell harvest. This approach results in successful engraftment, and is safe and well tolerated by patients.
• Tabaee, A., Zadeh, M. H., Proytcheva, M., & LaBruna, A. (2003). Eosinophilic angiocentric fibrosis. The Journal of laryngology and otology, 117(5), 410-3.
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  Eosinophilic angiocentric fibrosis of the upper respiratory tract is a rare disorder of unknown aetiology. Despite characteristic histological findings, the aetiology and management of this lesion remain unclear. We describe a case of nasal eosinophilic angiocentric fibrosis and discuss possible demographic and aetiological patterns.
• Tabaee, A., Zadeh, M. H., Proytcheva, M., & Labruna, A. (2003). Eosinophilic angiocentric fibrosis.. The Journal of laryngology and otology, 117(5), 410-3. doi:10.1258/002221503321626500
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  Eosinophilic angiocentric fibrosis of the upper respiratory tract is a rare disorder of unknown aetiology. Despite characteristic histological findings, the aetiology and management of this lesion remain unclear. We describe a case of nasal eosinophilic angiocentric fibrosis and discuss possible demographic and aetiological patterns.
• Sanz, M. M., Proytcheva, M., Ellis, N. A., Holloman, W. K., & German, J. (2000). BLM, the Bloom's syndrome protein, varies during the cell cycle in its amount, distribution, and co-localization with other nuclear proteins. Cytogenetics and cell genetics, 91(1-4), 217-23.
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  BLM, the protein encoded by the gene mutated in Bloom's syndrome (BS), is a phylogenetically highly conserved DNA helicase that varies in amount and distribution in the nucleus during the cell-division cycle. It is undetectable in many cells as they emerge from mitosis but becomes abundant during G(1) and remains so throughout S, G(2), and mitosis. BLM is widely distributed throughout the nucleus but at certain times also becomes concentrated in foci that vary in number and size. It co-localizes transitorily with replication protein A (RPA) and promyelocytic leukemia protein (PML) nuclear bodies, and at times it enters the nucleolus. The observations support the hypothesis that BLM is distributed variously about the nucleus to manipulate DNA in some, very possibly several, nucleic acid transactions, when and where they take place. The specific transaction(s) remain to be identified. Although absence from the nucleus of functional BLM - the situation in BS - obviously is not lethal in the human, other helicases would appear to be unable to substitute for it completely, witness the hypermutability and hyperrecombinability of BS cells.
• Ellis, N. A., Proytcheva, M., Sanz, M. M., Ye, T. Z., & German, J. (1999). Transfection of BLM into cultured Bloom syndrome cells reduces the sister-chromatid exchange rate toward normal.. American journal of human genetics, 65(5), 1368-74. doi:10.1086/302616
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  The gene BLM, mutated in Bloom syndrome (BS), encodes the nuclear protein BLM, which when absent, as it is from most BS cells, results in genomic instability. A manifestation of this instability is an excessive rate of sister-chromatid exchange (SCE). Here we describe the effects on this abnormal cellular phenotype of stable transfection of normal BLM cDNAs into two types of BS cells, SV40-transformed fibroblasts and Epstein-Barr virus (EBV)-transformed lymphoblastoid cells. Clones of BLM-transfected fibroblasts produced normal amounts of BLM by western blot analysis and displayed a normal nuclear localization of the protein by immunofluorescence microscopy. They had a mean of 24 SCEs/46 chromosomes, in contrast to the mean of 69 SCEs in controls transfected only with the vector. BLM-transfected fibroblast clones that expressed highest levels of the BLM protein had lowest levels of SCE. The lymphoblastoid cells transfected with BLM had SCE frequencies of 22 and 42 in two separate experiments in which two different selectable markers were used, in contrast to 57 and 58 in vector-transfected cells; in this type cell, however, the BLM protein was below the level detectable by western blot analysis. These experiments prove that BLM cDNA encodes a functional protein capable of restoring to or toward normal the uniquely characteristic high-SCE phenotype of BS cells.
• Neff, N. F., Ellis, N. A., Ye, T. Z., Huang, K., Proytcheva, M., Sanz, M. M., & Noonan, J. P. (1999). The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells.. Molecular biology of the cell, 10(3), 665-76. doi:10.1091/mbc.10.3.665
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  Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by growth deficiency, immunodeficiency, genomic instability, and the early development of cancers of many types. BLM, the protein encoded by BLM, the gene mutated in BS, is localized in nuclear foci and absent from BS cells. BLM encodes a DNA helicase, and proteins from three missense alleles lack displacement activity. BLM transfected into BS cells reduces the frequency of sister chromatid exchanges and restores BLM in the nucleus. Missense alleles fail to reduce the sister chromatid exchanges in transfected BS cells or restore the normal nuclear pattern. BLM complements a phenotype of a Saccharomyces cerevisiae sgs1 top3 strain, and the missense alleles do not. This work demonstrates the importance of the enzymatic activity of BLM for its function and nuclear localization pattern.
• Ciocci, S., Ye, T. Z., Lennon, D. N., Proytcheva, M., Alhadeff, B., German, J., Ellis, N. A., Groden, J., Straughen, J. E., & Goodfellow, P. N. (1996). Physical mapping of the bloom syndrome region by the identification of YAC and P1 clones from human chromosome 15 band q26.1.. Genomics, 35(1), 118-28. doi:10.1006/geno.1996.0330
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  The gene for Bloom syndrome (BLM) has been mapped to human chromosome 15 band q26.1 by homozygosity mapping. Further refinement of the location of BLM has relied upon linkage-disequilibrium mapping and somatic intragenic recombination. In combination with these mapping approaches and to identify novel DNA markers and probes for the BLM candidate region, a contiguous representation of the 2-Mb region that contains the BLM gene was generated and is presented here. YAC and P1 clones from the region have been identified and ordered by using previously available genetic markers in the region along with newly developed sequence-tagged sites from radiation-reduced hybrids, polymorphic dinucleotide repeat loci, and end sequences of YACs and P1s. A long-range restriction map of the 2-Mb region that allowed estimation of the distance between polymorphic microsatellite loci is also reported. This map and the DNA markers derived from it were instrumental in the recent identification of the BLM gene.

Proceedings Publications

• Proytcheva, M. A., & Hofmann, I. (2015, September). Guess Editor: Special Issue on Pediatric Hematopathology. In Journal of Hematopathology, 8, Springer Berlin Heidelberg.
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  The Journal of Hematology decided to publish a Special Issue on Pediatric Hematopathology and I was invited to be a co-Editor of the special issue
• Proytcheva, M. A., & Marlar, R. (2015, May). Guess Editor: Special Issue: International Society for Laboratory Haematology 2015 Education Issue. In 2015 Society for Laboratory Haematology Annual Meeting, 37, 1–143.
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  Guess editor of the Special Education Issue: International Society for Laboratory Haematology 2015.

Presentations

• Proytcheva, M. A. (2016, 04/04/2016). Pediatric Hematopathology Workshop. Hematology Society of Australia and New Zealand Branch Meeting. Christchurch, New Zealand: Hematology Society of Australia and New Zealand.
• Proytcheva, M. A. (2015, 05/18/2015). ISLH Guidelines on Peripheral Blood Cell Morphology, Grading, and Review and Reporting by Physicians. ISLH Educational. Chicago, IL: International Society of Laboratory Hematology.
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  Worldwide there is marked variation in the hematology laboratories practices in reporting of complete blood counts and peripheral blood film evaluation. With the advances of automated hematology analyzers, there is a need to standardize of these practices and to develop standard nomenclature of the morphologic abnormalities of the red and white blood cells and platelets as well as on the grading, reviewing and reporting of the of peripheral blood findings. the International Council for Standardization of Hematology has developed various guidelines to address such issues. The session will focus on help of technology and focus on the patient care. There is great variability in the regional and national practices of the hematology laboratories reporting on the morphologic nomenclature, grading, review and reporting peripheral blood findings. Reliable and consistent reporting of abnormal red and white blood cells and platelets using light microscopy requires is an important to improve the quality of patient care, reduce medical error and potentially lower healthcare costs1. This educational session will focus on the need for standardization and review the International Council for Standardization in Hematology (ICSH) guidelines for peripheral blood morphology nomenclature, grading, review, and reporting. Using such guidelines by the hematology laboratories assures high quality laboratory testing2,3. It is intended for hematology laboratory technologists, laboratory scientists, hematologists, and clinical pathologists in training and posttraining.1. Marques MB, Anastasi J, Ashwood E, et al. The Clinical Pathologist as Consultant. Am J Clin Pathol 2011;135:11-2.2. Palmer L, Briggs C, McFadden S, et al. ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. Int J Lab Hematol 2015:n/a-n/a.3. Barnes PW, McFadden SL, Machin SJ, Simson E, international consensus group for h. The international consensus group for hematology review: suggested criteria for action following automated CBC and WBC differential analysis. Lab Hematol 2005;11:83-90.
• Proytcheva, M. A. (2015, November 19). ICSH Guidelines on Peripheral Blood Cell Morphology Grading, Review & Reporting. Webinar. N/A: International Sociaety of Laboratory Hematology.
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  Review of the latest guidelines of the International Council for Standardization of Hematology (ICSH) to provide a framework for reliable and consistent review, grading, and reporting of abnormal red and white blood cells and platelets by laboratory scientists. In addition, challenges in peripheral blood film review and reporting by physicians and provide a framework to standardize this area are discussed.

Poster Presentations

• Duran, J., Otsuji, J., Proytcheva, M., & Fuchs, D. (2021, September). Chronic Myeloid Leukemia With Cutaneous Manifestation in an Adolescent Patient.. College of American Pathologists 2021 (CAP21) Annual MeetingCollege of American Pathologist.
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  Abstract: Chronic myeloid leukemia (CML) is rare among children, accounting for 2% of leukemias in patients younger than 15 years and 9% between 15–19 years of age, with an annual incidence of 0.6–1.0 and 2.1 per million, respectively. Its clinical presentation is usually more aggressive than that in adults. Lymphadenopathy and cutaneous or other tissue infiltration is uncommon; when present, accelerated or blast phases are suspected. We present a case of a 16-year-old male diagnosed with CML with cutaneous manifestations. The patient presented with a palpable abdominal mass. Initial workup revealed WBC count >428 K/mm3 with 2% blasts, Hb of 8.6 g/dL, elevated uric acid and lactate dehydrogenase, hepatomegaly, and massive splenomegaly. Fluorescence in situ hybridization (FISH) on peripheral blood demonstrated BCR/ABL1 rearrangement in 195/200 scored cells (97.5%). Bone marrow biopsy showed 100% cellularity with absolute myeloid hyperplasia, absolute erythroid hypoplasia, and an increased number of small megakaryocytes (Figure 2.101, A and B). Altogether, these findings were consistent with a diagnosis of CML. Furthermore, a 1.3-cm nodule on the right lateral hip was noted. Core needle biopsy showed fibroadipose tissue infiltrated by mature neutrophils forming microabscesses, eosinophils, and infrequent immature forms (
• Proytcheva, M. A. (2016, 04/07/2016). Blood film and bone marrow features in neonates and young children. Hemalogy Grand Rounds, Lab PLUS, Auckland, New Zealand. Auckland, New Zealand: Lab PLUS.

Case Studies

• Shponka, V., & Proytcheva, M. (2017. Megaloblastic anemia caused by severe B12 deficiency in a breastfed infant(pp On line).
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  An 8-month-old female, exclusively breastfed, presented with pallor and a two-month history of vomiting, diarrhea, and failure to thrive. CBC showed absolute neutropenia in the setting of normal white blood cell count (WBC 5.3x103/µL; ANC 0.42x103/µL, ALC 4.67 x103/µL), marked macrocytic anemia (Hgb 6.5 g/dl, MCV 96.2 fl, MCH 34.4 pg, MCHC 35.8 g/dL), mild thrombocytopenia (147x103/µL). The peripheral blood was remarkable for presence of macroovalocytes, microcytes, basophilic stippling, and rare hypersegmented neutrophils (panel A). The differential diagnosis included nutritional deficiency, congenital bone marrow failure syndrome, infection- or drug-induced bone marrow suppression, and acute leukemia. The marrow was hypercellular with absolute erythroid hyperplasia, megaloblastic erythroid and myeloid maturation, dyserythropoiesis and dysgranulopoiesis (panels B-D). There was no morphologic or immunophenotypic evidence of acute leukemia, and normal cytogenetics. Additional studies: vitamin B12< 30 pg/mL, LDH 2274 IU/L and normal iron studies and folate. The diagnosis of B12 deficiency was made and the patient was treated with B12 injection with subsequent marked increase in reticulocytes (from 3.18% to 9.88%) and clinical improvement.While rare, vitamin B12 deficiency is seen in young children and should be included in the differential diagnosis of macrocytic anemia with pancytopenia, gastrointestinal symptoms, failure to thrive, and neurologic dysfunction.

Other Teaching Materials

• Hayword, C., Proytcheva, M., & Huisman, A. (2018. Developed and implement ISLH Mentorship Program. International Society of Laboratory Hematology.
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  Three year program that aligns mentees from resource-poor areas including Eastern Europe, Asia, Africa, and South America to be paired with an established mentor. The program started last year and supports 5 mentees from Africa, Nepal, and Pakistan. The mentees will present their experience on the next ISLH meeting in 2018.
• Proytcheva, M. A. (2015. CPIP G Case 7: T-Lymphoblastic Leukemia/Lymphoma (SAM eligible). © 2015 College of American Pathologists.
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  Online CME Self Assessment Module