Incidence, risk factors, and outcome of asymptomatic central nervous system involvement in adult patients with acute myeloid leukemia.

Examination of central nervous system (CNS) involvement is not routine diagnostic practice in adult patients with acute myeloid leukemia (AML). Therefore, many asymptomatic patients with CNS involvement might go undetected. The effect of CNS involvement on the AML disease course is not well defined, with conflicting results regarding clinical outcome. This study aimed to determine the incidence of asymptomatic CNS involvement in AML estimated by multiparametric flow cytometry of cerebrospinal fluid (MFC-CSF) at diagnosis, the related potential risk factors, and prognosis. In total, 645 patients with de novo AML were screened; 183 (28.4%) of them fulfilled institutional practice for MFC-CSF analysis based on presence of CNS symptoms and/or clinical features. CNS symptoms and signs were observed in 8/183 (4.4%) patients, but most patients (175/183, 95.6%) were asymptomatic. In the asymptomatic group, 73/175 (41.7%) patients had positive or suspicious cerebrospinal fluid (CSF) findings categorized as CNS positive (CNSpos) and 102/175 (58.3%) had normal CNS findings categorized as CNS negative (CNSneg). The presence of leukemic blasts was confirmed in 81/183 (44.3%) patients; the total incidence of CNS involvement in the whole AML group was 12.6% (81/645). Compared with asymptomatic patients with CNSneg, those with CNSpos had a significantly higher frequency of lymphadenopathy, white blood cell count ≥30 × 109/L, presence of the monocytic phenotype, and a high percentage of bone marrow (BM) blasts. The multivariate logistic regression model identified monocytic phenotype (p = 0.047) and high percentage of BM blasts (p = 0.042) as predictors for CNSpos. CNSpos did not affect overall survival in patients with AML. There was a higher incidence of CNS involvement in asymptomatic adult patients with de novo AML, emphasizing possible undervalued rates of CNS disease at diagnosis. Prospective studies should determine whether diagnostic lumbar puncture for MFC-CSF analysis and CNS prophylaxis could contribute to better selection and prognosis in this patient population.

Arterial Thrombosis in Patients with Acute Myeloid Leukemia: Incidence and Risk Factors.

BACKGROUND: Patients with hematological malignancies have an increased risk of arterial thrombotic events (ATEs) after diagnosis, compared to matched controls without cancer. However, data about incidence and risk factors for ATE development in patients with acute myeloid leukemia (AML) are missing. AIM: The objectives of this study were to determine the incidence of ATE in non-promyelocytic-AML patients and to define the potential risk factors for ATE development. METHODS: We conducted a retrospective cohort study of adult patients with newly diagnosed AML. The primary outcome was the occurrence of confirmed ATE, defined as myocardial infarction, stroke or critical limb ischemia. RESULTS: Out of 626 eligible AML patients, 18 (2.9%) patients developed ATE in the median time of 3 (range: 0.23-6) months. Half of these patients died due to ATE complications. Five parameters were predictors of ATE: BMI > 30 (p = 0.000, odds ratio [OR] 20.488, 95% CI: 6.581-63.780), prior history of TE (p = 0.041, OR 4.233, 95% CI: 1.329-13.486), presence of comorbidities (p = 0.027, OR 5.318, 95% CI: 1.212-23.342), presence of cardiovascular comorbidities (p < 0.0001, OR 8.0168, 95% CI: 2.948-21.800) and cytogenetic risk score (p = 0.002, OR 2.113, 95% CI: 1.092-5.007). CONCLUSIONS: Our study showed that patients with AML are at increased risk of ATE. The risk was increased in patients with cardiovascular comorbidities, previous thrombosis, adverse cytogenetic risk as well as BMI > 30.

COVID-19-Associated Pulmonary Aspergillosis in Patients with Acute Leukemia: A Single-Center Study.

Patients with coronavirus disease 19 (COVID-19) have increased susceptibility to secondary respiratory infections including invasive pulmonary aspergillosis (IPA). COVID-19-associated pulmonary aspergillosis (CAPA) is difficult to diagnose and can be associated with increased mortality especially in severe immunodeficiency such as hematological malignancies. Our study evaluates IPA in COVID-19 patients defined as COVID-19-CAPA among patients with acute leukemia (AL). A retrospective single-center study analyzed 46 patients with COVID-19 infection and acute leukemia, admitted to the Clinic for Haematology, Clinical Center of Serbia, Belgrade between the 2 April 2020 and 15 May 2021. During hospitalization, all participants were diagnosed with probable IPA according to the previous consensus definitions. Positive serology and galactomannan (GM) detection values in bronchoalveolar lavage (BAL) and serum were used as microbiological criteria. COVID-19 associated probable IPA was found in 22% (9/41) tested patients, where serum GM and IgM anti-Aspergillus antibodies were positive in 12% (5/41) and 10% (4/41) had positive serology for aspergillosis. One patient died while eight recovered during follow-up. Our study showed that COVID-19 might be a risk factor for IPA development in patients with AL. Early diagnosis and prompt treatment are required as reported mortality rates are high.

Prediction of optimal cytogenetic responses at 6 and 12 months in patients with chronic myeloid leukemia in chronic phase treated with imatinib.

PURPOSE: Imatinib mesylate transformed the treatment and paradigms of chronic myeloid leukemia. European LeukemiaNet (ELN) group has defined specific treatment milestones with an optimal outcome to be achieved in patients. METHODS: In a retrospective cohort study, we evaluated the impact of clinical and biological variables on achieving an optimal response at 6 and 12 months according to ELN recommendations. We included 106 patients with chronic phase chronic myeloid leukemia (CML) with appropriate bone marrow aspirate and biopsy for immunohistochemistry. RESULTS: The number of white blood cells (WBC), the percentage of peripheral blast, the values of Sokal and ELTS scores and the percentage of Ki-67+ cells in the bone marrow predicted a complete cytogenetic response (CCyR) at 6 months, but only WBC and EUTOS score predicts CCyR at 12 months. We found that Sokal score below 0.775 was very sensitive to achieve of CCyR at 6 months (m) and that all patients with a value <0.550 achieved CCyR-6m. Patients with a low percentage of blast in the peripheral blood (≤1.5%) or in the bone marrow (≤5%) together with lower WBC (≤100×109/L) were likely to have significantly higher CCyR rates at 6 and 12 months respectively. Also, patients with a higher number of Ki67+ cells in the leukemic areas of the bone marrow had a significantly better outcome. Unfortunately, our investigation did not reveal that bone marrow fibrosis (MF grade), microvascular density, percentage of CD34+, CD61+ or PTCH1+ cells could have any effect on achievement of CCyR at 6 or 12 months. CONCLUSION: Our investigation has shown that only a few biological characteristics in patients with CML can predict the optimal treatment outcome after imatinib.

Predictive parameters for imatinib failure in patients with chronic myeloid leukemia.

OBJECTIVE: Until recently, imatinib was the standard first-line treatment in chronic myeloid leukemia (CML). The inclusion of nilotinib and dasatinib as first-line options in CML raised a debate on treatment selection. The aim of our study was to analyze predictive parameters for imatinib response as the first-line treatment of CML patients. METHODS: The study included 168 consecutive patients with chronic phase Philadelphia-positive CML who were diagnosed and treated with Imatinib 400 mg once daily at a single university hospital. Numerous parameters were analyzed in terms of imatinib response including comorbidities as well as occurrence of second malignancies. RESULTS: After the median follow-up of 87 months in 61 patients (36.3%), the imatinib failure was verified. Cox regression analysis identified hepatomegaly (p = 0.001), leukocytosis ≥ 100 × 109/l (p = 0.001), blood blasts ≥ 1% (p = 0.002), and the presence of additional cytogenetic aberrations (p = 0.002) as predictors of Imatinib failure. Based on these findings, a new prognostic model was developed according to which imatinib failure had 17% (8/47) of patients in low risk, 34.9% (30/86) of patients in intermediate risk, and 76.7% (23/30) of patients in high-risk group (HR = 3.973, 95% CI for HR 2.237-7.053, p < 0.001). CONCLUSION: The new score allows better selection of patients who are suitable for treatment with imatinib and may guideline the clinical decision for front-line treatment of CML.

Imaging the Bonds of Dehalogenated Benzene Radicals on Cu(111) and Au(111).

Dissociative adsorption of doubly substituted benzene molecules leads to formation of benzyne radicals. In this study, co-adsorbed hydrogen molecules are used in scanning tunneling hydrogen microscopy to enhance the contrast of the meta- and the para-isomers of these radicals on Cu(111) and Au(111). Up to three hydrogen molecules are attached to one radical. One hydrogen molecule reveals the orientation of the carbon ring and its adsorption site, allowing discrimination between the two radicals. Two hydrogen molecules reflect the bond picture of the carbon skeleton and reveals that adsorption on Cu(111) distorts the meta- isomer differently from its gas-phase distortion. Three hydrogen molecules allow us to determine the bond picture of a minor species.

Gene expression profile of circulating CD34(+) cells and granulocytes in chronic myeloid leukemia.

PURPOSE: We compared the gene expression profile of peripheral blood CD34(+) cells and granulocytes in subjects with chronic myeloid leukemia (CML), with the accent on signaling pathways affected by BCR-ABL oncogene. METHODS: The microarray analyses have been performed in circulating CD34(+) cells and granulocytes from peripheral blood of 7 subjects with CML and 7 healthy donors. All studied BCR-ABL positive CML patients were in chronic phase, with a mean value of 2012±SD of CD34(+)cells/µl in peripheral blood. RESULTS: The gene expression profile was more prominent in CML CD34(+) cells (3553 genes) compared to granulocytes (2701 genes). The 41 and 39 genes were significantly upregulated in CML CD34(+) cells (HINT1, TXN, SERBP1) and granulocytes, respectively. BCR-ABL oncogene activated PI3K/AKT and MAPK signaling through significant upregulation of PTPN11, CDK4/6, and MYC and reduction of E2F1, KRAS, and NFKBIA gene expression in CD34(+) cells. Among genes linked to the inhibition of cellular proliferation by BCR-ABL inhibitor Imatinib, the FOS and STAT1 demonstrated significantly decreased expression in CML. CONCLUSION: The presence of BCR-ABL fusion gene doubled the expression quantity of genes involved in the regulation of cell cycle, proliferation and apoptosis of CD34(+) cells. These results determined the modified genes in PI3K/AKT and MAPK signaling of CML subjects.

[Extranodal marginal zone non Hodgkin's lymphoma of the lung: a ten-year experience].

BACKGROUND/AIM: Bronchus-associated lymphoid tissue (BALT) lymphoma is a rare subtype of low grade marginal zone B cell lymphoma representing 10% of all MALT lymphomas. The purpose of this study was to analyze the outcome of this group of patients comparing prognostic parameters and therapy modalities. METHODS: A total of eight patients with BALT lymphoma had diagnosed between January 1998-April 2008 at the Institute of Hematology, Clinical Center of Serbia, Belgrade, and they were included in this retrospective analysis. RESULTS: Male/female ratio was 2/6, the median age was 64 years (range 37-67 years). Six patients had nonspecific respiratory symptoms and all of them had B symptoms. The patients were seronegative for HIV, HCV and HBsAg. Three patients had Sjogren's syndrome, rheumatoid arthritis and pulmonary tuberculosis, respectively. Seven patients were diagnosed by transbronchial biopsy and an open lung biopsy was done in one patient. Patohistological findings revealed lymphoma of marginal zone B cell lymphoma: CD20+/CD10-/CD5-/CyclinD1/CD23-/IgM- with Ki-67+< 20% of all cells. According to the Ferraro staging system, five patients had localized disease (CS I-IIE) and three had stage IVE; bulky tumor mass had 3 patients. All patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Five patients received monochemotherapy with chlorambucil and 3 were treated with CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone). A complete response (CR) was achieved in 5 patients and a partial response (PR) in 3 of them, treated with chlorambucil monotherapy and CHOP regimen. All patients were alive during a median follow-up period of 49 months (range 6-110 months). Three patients relapsed after monochemotherapy into the other extranodal localization. They were treated with CHOP regimen and remained in stable PR. CONCLUSION. BALT lymphoma tends to be localised disease at the time of diagnosis, responds well to monochemotherapy with chlorambucil and has a favourable prognosis.

Chirality change of chloronitrobenzene on Au(111) induced by inelastic electron tunneling.

Chirality chameleon: Inelastic electron tunneling manipulation can be used to change a single chloronitrobenzene (ClNB) molecule, randomly adsorbed on Au(111), into its desired enantiomeric form (r or l, see STM images and ball-and-stick representation) and to vary its rotational orientation. The different threshold voltages for chirality change (260 mV) and rotation (380 mV) allow these processes to be induced separately.

Bending a bond within an individual adsorbed molecule.

Inelastic electron tunneling manipulation of a bond within chloronitrobenzene molecules on Cu(111) shows that the energy costs for bond bending within a molecule might be partially gained through better adsorption sites of the involved atoms. The chlorine either keeps its gas phase angle and is adsorbed near an on-top site or gets distorted to be adsorbed near a hollow site. Noise analysis reveals that the excitation of several vibrational modes may initiate this bond bending.

Electron-induced isomerisation of dichlorobenzene on Cu(111) and Ag(111).

The constitutional isomerisation of single dichlorobenzene molecules adsorbed on the surfaces of Ag(111) and Cu(111) between their meta- and para-isomers is induced and investigated by means of a low temperature scanning tunneling microscope. On both substrates similar isomerisation thresholds are found indicating that the excitation mechanism of this reaction does not depend significantly on the underlying substrate. The isomerisation threshold voltage of (170 +/- 7) meV most likely corresponds to excitation of a C-C stretch mode whose gas-phase energies we calculated ab initio to lie at 174 and 172 meV for meta- and para-isomers respectively. Though the reaction is found to be localized on the submolecular scale, it depends heavily on the second substituent both in terms of excitation energy and reaction outcome.

Submolecular imaging of chloronitrobenzene isomers on Cu(111).

We compare computer simulations to experimental scanning tunneling microscopy (STM) images of chloronitrobenzene molecules on a Cu(111) surface. The experiments show that adsorption induced isomerization of the molecules takes place on the surface. Furthermore, not only the submolecular features can be seen in the STM images, but different isomers can also be recognized. The Todorov-Pendry approach to tunneling produces simulated STM images which are in good accordance with the experiments. Alongside with STM simulations in a tight-binding basis, ab initio calculations are performed in order to analyze the symmetry of relevant molecular orbitals and to consider the nature of tunneling channels. Our calculations show that while the orbitals delocalized to the phenyl ring create a relatively transparent tunneling channel, they also almost isolate the orbitals of the substitute groups at energies which are relevant in STM experiments. These features of the electronic structure are the key ingredients of the accurate submolecular observations.