High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.

Leukemic Involvement in the Thorax.

Leukemias are malignancies in which abnormal white blood cells are produced in the bone marrow, resulting in compromise of normal bone marrow hematopoiesis and subsequent cytopenias. Leukemias are classified as myeloid or lymphoid depending on the type of abnormal cells produced and as acute or chronic according to cellular maturity. The four major types of leukemia are acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Clinical manifestations are due to either bone marrow suppression (anemia, thrombocytopenia, or neutropenia) or leukemic organ infiltration. Imaging manifestations of leukemia in the thorax are myriad. While lymphadenopathy is the most common manifestation of intrathoracic leukemia, leukemia may also involve the lungs, pleura, heart, and bones and soft tissues. Myeloid sarcomas occur in 5%-7% of patients with acute myeloid leukemia and represent masses of myeloid blast cells in an extramedullary location. ©RSNA, 2019.

Diagnostic Potential of Imaging Flow Cytometry.

Imaging flow cytometry (IFC) captures multichannel images of hundreds of thousands of single cells within minutes. IFC is seeing a paradigm shift from low- to high-information-content analysis, driven partly by deep learning algorithms. We predict a wealth of applications with potential translation into clinical practice.

Generation and Quantitative Analysis of Pulsed Low Frequency Ultrasound to Determine the Sonic Sensitivity of Untreated and Treated Neoplastic Cells.

Low frequency ultrasound in the 20 to 60 kHz range is a novel physical modality by which to induce selective cell lysis and death in neoplastic cells. In addition, this method can be used in combination with specialized agents known as sonosensitizers to increase the extent of preferential damage exerted by ultrasound against neoplastic cells, an approach referred to as sonodynamic therapy (SDT). The methodology for generating and applying low frequency ultrasound in a preclinical in vitro setting is presented to demonstrate that reproducible cell destruction can be attained in order to examine and compare the effects of sonication on neoplastic and normal cells. This offers a means by which to reliably sonicate neoplastic cells at a level of consistency required for preclinical therapeutic assessment. In addition, the effects of cholesterol-depleting and cytoskeletal-directed agents on potentiating ultrasonic sensitivity in neoplastic cells are discussed in order to elaborate on mechanisms of action conducive to sonochemotherapeutic approaches.

Myeloid leukemia in a urine specimen: a case report and review of the literature.

Urinary tract cytology has a long history of utilization for the diagnosis and follow-up of tumors involving the urothelial tract. As expected, the most common tumor encountered in exfoliative urine cytology is urothelial carcinoma. While the sensitivity of urinary tract cytology for the diagnosis of low-grade urothelial carcinomas is low, its sensitivity and accuracy for high grade urothelial carcinomas is much higher. However, nonurothelial malignancies, such as hematopoietic malignancies, can also be encountered in urine specimens. Leukemic cells in urine can be diagnosed readily by cytological examination in cases where more invasive procedures are difficult to perform. Additionally, cell block sections can be utilized to determine the immunocytochemical profile of the tumor cells to confirm the diagnosis. Herein we report a case of a 75-year-old man with a past medical history of acute myeloid leukemia (AML), who presented with congested heart failure and painless macroscopic hematuria. AML relapse was diagnosed. Cytological examination of the urine using a ThinPrep® smear, cytospin preparation, and immunohistochemical stains performed on the cell block sections were examined. Findings were consistent with leukemic cells of myeloid origin in the bladder washing specimen.

Outbreak of invasive pulmonary aspergillosis among patients hospitalized in a bone marrow transplant ward: tomographic findings.

OBJECTIVE: To evaluate the main aspects on CT scans of six patients hospitalized in a bone marrow transplant ward, diagnosed with invasive pulmonary aspergillosis (IPA), during an in-hospital outbreak of the disease. METHODS: We reviewed 10 chest CT scans of six neutropenic or immunocompromised patients hospitalized in the hematology and bone marrow transplant ward of the Hospital São Paulo, in the city of São Paulo, Brazil, who were diagnosed with IPA between April of 2007 and October of 2007. The diagnosis of IPA was confirmed by anatomopathological findings (in 2 cases), culture (in 3 cases) or appropriate treatment response (in 1 case). RESULTS: We evaluated the CT scans of three male and three female patients, ranging from 22 to 58 years of age. The most common tomographic findings were nodules (5/6 cases) and areas of consolidation (2/6 cases). The nodules were more often multiple (3/5 cases), with irregular contours (4/5 cases) and accompanied by the halo sign (3/5 cases). One case presented multiple, centrally distributed areas of consolidation, and another presented an isolated, peripheral area of consolidation. Areas of ground-glass attenuation and septal thickening were found in three and two patients, respectively. Bilateral pleural effusion occurred in three cases. CONCLUSIONS: Consolidation, nodules, septal thickening, pleural effusion and ground-glass opacities were the principal tomographic findings in the six patients hospitalized in the above mentioned ward during the IPA outbreak. The nodules were often (in 67% of the cases) accompanied by the halo sign, a classically described finding in patients with IPA.

Ultrasonic characterization of whole cells and isolated nuclei.

High frequency ultrasound imaging (20 to 60 MHz) is increasingly being used in small animal imaging, molecular imaging and for the detection of structural changes during cell and tissue death. Ultrasonic tissue characterization techniques were used to measure the speed of sound, attenuation coefficient and integrated backscatter coefficient for (a) acute myeloid leukemia cells and corresponding isolated nuclei, (b) human epithelial kidney cells and corresponding isolated nuclei, (c) multinucleated human epithelial kidney cells and d) human breast cancer cells. The speed of sound for cells varied from 1522 to 1535 m/s, while values for nuclei were lower, ranging from 1493 to 1514 m/s. The attenuation coefficient slopes ranged from 0.0798 to 0.1073 dB mm(-1) MHz(-1) for cells and 0.0408 to 0.0530 dB mm(-1) MHz(-1) for nuclei. Integrated backscatter coefficient values for cells and isolated nuclei showed much greater variation and increased from 1.71 x 10(-4) Sr(-1) mm(-1) for the smallest nuclei to 26.47 x 10(-4) Sr(-1) mm(-1) for the cells with the largest nuclei. The findings suggest that integrated backscatter coefficient values, but not attenuation or speed of sound, are correlated with the size of the nuclei.

Nuclear localizing sequences promote nuclear translocation and enhance the radiotoxicity of the anti-CD33 monoclonal antibody HuM195 labeled with 111In in human myeloid leukemia cells.

UNLABELLED: Our objective was to evaluate the toxicity of the anti-CD33 monoclonal antibody HuM195 modified with peptides (CGYGPKKKRKVGG) harboring the nuclear localizing sequence (NLS; underlined) of simian virus 40 large T antigen and labeled with (111)In against acute myeloid leukemia (AML) cells. METHODS: HuM195 was derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (sulfo-SMCC) to introduce maleimide groups for reaction with NLS-peptides and then conjugated with diethylenetriaminepentaacetic acid for labeling with (111)In. The immunoreactivity of NLS-HuM195 was evaluated by its ability to displace the binding of (111)In-HuM195 to HL-60 leukemia cells. Nuclear localization was measured in HL-60 cells by subcellular fractionation. The antiproliferative effects of (111)In-NLS-HuM195 and (111)In-HuM195 on HL-60, U937, or K562 cells with high, intermediate, or minimal CD33 expression, respectively, were studied. The survival of HL-60 cells or patient AML specimens treated with (111)In-NLS-HuM195 or (111)In-HuM195 was studied. Normal tissue toxicity was evaluated in BALB/c mice injected intravenously with of 3.7 MBq (22 microg) of (111)In-NLS-HuM195 or (111)In-HuM195. RESULTS: NLS-HuM195 exhibited relatively preserved CD33 binding affinity (dissociation constant [K(d)] = 4.3 +/- 1.7 x 10(-9) mol/L to 6.9 +/- 1.3 x 10(-9) mol/L). Nuclear uptake increased from 10.5% +/- 0.5% for (111)In-HuM195 to 28.5% +/- 4.1% or 65.9% +/- 1.5% for (111)In-HuM195 substituted with 4 or 8 NLS-peptides, respectively. The inhibitory concentrations of 50% (IC(50)) and 90% (IC(90)) for HL-60 cells treated with (111)In-NLS-HuM195 were 37 kBq per 10(3) cells and 77-81 kBq per 10(3) cells, respectively. The IC(50) and IC(90) values for (111)In-HuM195 were 92 kBq per 10(3) cells and 203 kBq per 10(3) cells. Growth inhibition was correlated with the level of CD33 expression. The survival of HL-60 cells was reduced from 232 +/- 22 colonies (control) to 7 +/- 1 colonies with 1.48 mBq per cell of (111)In-NLS-HuM195; no colonies were found at 3.33 mBq per cell. The surviving fraction decreased >2-fold in 7 of 9 AML specimens treated with an excess of (111)In-NLS-HuM195 and >10-fold in 2 of these specimens. There were no decreases in body weight or hematologic parameters or increases in alanine aminotransferase or creatinine in mice administered 3.7 MBq (22 microg) of (111)In-NLS-HuM195 or (111)In-HuM195. There was no morphologic damage to the liver or kidneys. CONCLUSION: We conclude that NLS-peptides routed (111)In-HuM195 to the nucleus of AML cells, where the emitted Auger electrons were lethal. (111)In-NLS-HuM195 is a promising targeted radiotherapeutic agent for AML.

Extramedullary myeloid leukemia: the value of cytogenetic analysis in pediatric orbital tumors.

Orbital extramedullary myeloid tumor, or granulocytic sarcoma, can be difficult to diagnose even with the use immunohistochemical stains, especially if it precedes the development of systemic leukemia. We describe a 6-year-old boy with a rapidly progressive orbital tumor. This patient underwent an orbital biopsy, which was consistent with extramedullary myeloid tumor but not conclusive. Cytogenetic studies on a bone marrow biopsy revealed a translocation consistent with acute myelogenous leukemia.

Long-term transfusion of polymerized bovine hemoglobin in a Jehovah's Witness following chemotherapy for myeloid leukemia: a case report.

A 52-year-old female Jehovah's Witness presented with relapsed secondary acute myeloid leukemia. Because of chemotherapy-induced anemia, she was infused with the bovine hemoglobin (Hb)-based oxygen carrier HBOC-201 (Biopure) as the sole means of transfusion support. HBOC-201 has only been used for management of acute hemorrhage, and its utility in providing longer term transfusion support is unknown. Over a period of 18 days, a total dose of 1230 g of HBOC-201 was delivered. Although the patient succumbed to the disease after 18 days of treatment, this case documents our experience with the highest dose and duration of HBOC-201 ever used. Although possible renal toxicity could not be definitively excluded, the homogeneous extraction of oxygen by the brain in the presence of and perhaps from HBOC-201 was demonstrated.

Myeloid leukemias and lung involvement.

Myeloid leukemias are clonal malignancies characterized by the presence of increased numbers of immature myeloid cells in the marrow and peripheral blood. Pulmonary involvement by myeloid leukemia is relatively uncommon and seen mainly in patients with severe disease. The most common form of pulmonary involvement consists of leukemic infiltration along the lymphatics in the peribronchovascular, septal, and pleural interstitial tissue. Less common manifestations include myeloid sarcoma, leukostasis, leukemic cell lysis pneumopathy, and hyperleukocytic reaction. The radiological manifestations of pulmonary leukemic cell infiltration and leukostasis consist mainly of bilateral thickening of the peribronchovascular interstitium and interlobular septa, a pattern that resembles that of interstitial pulmonary edema. The radiological manifestations of leukemic cell lysis pneumopathy and hyperleukocytic reaction consist of symmetric bilateral areas of consolidation. This manuscript reviews the histological and radiological intrathoracic manifestations of myelogenous leukemias.

Imaging of diffuse metastatic and dystrophic pulmonary calcification in children after haematopoietic stem cell transplantation.

The authors describe three cases of diffuse pulmonary calcification; two metastatic in children with acute transitory renal failure and the other dystrophic in a child with leukaemia. All three patients underwent haematopoietic stem cell transplantation (HSCT). Chest radiographs disclosed diffuse calcification within the lungs. The distribution of this calcification was bilateral but asymmetric. Diagnosis was made in two cases by high resolution computed tomography (HRCT) and in one case by HRCT and bone scan. Radiological characteristics, scintigraphic features, pathological mechanism and clinical outcome of such pulmonary calcification are discussed.

Acute myeloid leukemia presenting as bilateral proptosis from diffuse extraocular muscle infiltration.

PURPOSE: To report a case of acute myeloid leukemia with bilateral proptosis as the sole presenting sign. DESIGN: Observational case report. METHODS: A patient with bilateral proptosis was seen in consultation by pediatric ophthalmology. RESULTS: Complete blood count, computerized tomography, and bone marrow biopsy confirmed the diagnosis of acute myeloid leukemia, with the proptosis due to diffuse infiltration of all extraocular muscles. CONCLUSION: In a child with the sudden onset of proptosis without any other systemic findings, the diagnosis of acute leukemia must be considered.

Haematological malignancies in childhood in Croatia: investigating the theories of depleted uranium, chemical plant damage and 'population mixing'.

Some of potential causes proposed to explain the reported increase of haematological malignancies in childhood during or after the war period in several countries include depleted uranium, chemical pollution and population mixing theory. The aim of this study was to define the population of Croatian children aged 0-14 years who were potentially exposed to each of those risks during the war and to investigate any possible association between the exposure and the incidence of haematological malignancies. The authors analyzed the data reported by the Cancer Registry of Croatia during the pre-war period (1986-1990), war period (1991-1995) and post-war period (1996-1999). In the group of 10 counties potentially exposed to depleted uranium and two counties where chemical war damage occurred, no significant difference in incidence of the studied haematological malignancies was noted in comparison to pre-war period. The incidence of lymphatic leukaemia significantly increased in four counties where population mixing had occurred during the war period, supporting the 'mixing theory'. In those counties, the incidence of Hodgkin's lymphoma decreased during and after the war. In Croatia as a whole, decreases in incidence of myeloid leukaemias during war and non-Hodgkin lymphoma after the war were noted.