Tixagevimab/cilgavimab (AZD7442/Evusheld) prevent from COVID19 in patients with hematologic malignancies under active chemotherapy.

Despite the efficacy of COVID-19 vaccines, patients with hematologic malignancy may still be fatal from COVID19. Therefore, we prospectively performed the analysis of administration of tixagevimab/cilgavimab in the real-world. In August 2022, 94 patients under active chemotherapy for lymphoma, multiple myeloma, or acute leukemia received a single dose AZD7442/Evusheld (two consecutive intramuscular injections of tixagevimab and cilgavimab, 300 mg each). Quantitative measurement of anti-SARS-CoV-2 spike protein (anti-S) and viral nucleocapsid (anti-N) titers were conducted before administration of tixagevimab/cilgavimab and at 1, 3, and 6 months after administration. Twenty-five patients (26.6%) had previously confirmed COVID-19 infection. Fifty-eight patients (61.7%) had previously received COVID-19 vaccinations, with a median of two doses (range, 1-5). The median anti-S Ab level increased from baseline (997.05 AU/mL) to 1 month (20,967.25 AU/mL), then decreased at 3 months (13,145.0 AU/mL), and 6 months (7123.0 AU/mL) (p < 0.001). There was no significant safety issue with tixagevimab/cilgavimab. With a median follow-up time of 6 months, thirteen patients (13.8%) had documented SARS-Cov-2 infection. A 20.2% rate of anti-N positivity was observed six months after the administration of tixagevimab/cilgavimab. The results of this study support the potential role of tixagevimab/cilgavimab for the prevention of symptomatic and severe COVID-19.Trial registration: KCT0007617; August 16, 2022.

T-large granular lymphocytic leukemia.

T-cell large granular lymphocyte (T-LGL) leukemia is characterized by clonal expansion of cytotoxic T cells resulting in cytopenia. The proliferation of clonal LGLs is caused by prolonged antigenic stimulation, which leads to apoptotic dysregulation owing mainly to the constitutive activation of survival pathways, notably the JAK/STAT pathway. Understanding how leukemic T-LGL persists can aid in the development of future immunosuppressive therapies. In this review, we summarize the diagnosis and current standard of therapy for T-LGL leukemia, as well as recent advances in clinical trials.

Research use only and cell population data items obtained from the Beckman Coulter DxH800 automated hematology analyzer are useful in discriminating MDS patients from those with cytopenia without MDS.

We investigated the performance of research use only/cell population data (RUO/CPD) items obtained from the Beckman Coulter DxH800 automated hematologic analyzer in discriminating MDS patients from cytopenic patients without MDS.Total of 14 routine CBC, 18 research use only (RUO) items, and 70 CPD items were obtained retrospectively at diagnosis. The results were then compared between 94 MDS patients and 100 cytopenic patients without MDS. In items with statistically significant differences, receiver operating characteristic (ROC) analysis was performed and the results were compared.Four CBC/RUO items [red cell distribution width-standard deviation (RDW-SD), immature reticulocyte fraction (IRF), mean sphered cell volume (MSCV), high light scatter reticulocytes (HLR)], and two CPD items [mean volume of neutrophils (NE-V-Mean) and mean volume of early granulated cells (EGC-V-Mean)] showed area-under the curve (AUC) scores > 0.750. Notably, four RUO/CPD items (MSCV > 81.4/HLR > 0.15%/NE-V-Mean > 145/EGC-V-Mean > 156) showed high sensitivity (91.9%/93.6%/88.1%/90.2%, respectively) in discriminating MDS patients from cytopenic patients without MDS. With these six items, scores ≥ 4 (defined as ≥ 4 items exceeding cutoff values out of six items) showed AUC scores/sensitivity/specificity/accuracy (0.891/87.3%/79.0%/83.0%, respectively).Six CBC/RUO/CPD items showed satisfactory AUC scores of > 0.750, and four RUO/CPD items showed high sensitivity in discriminating MDS patients from cytopenic patients without MDS. Scoring system with six items showed high sensitivity, specificity, and accuracy with decision criteria of ≥ 4 scores. Therefore, DxH800 RUO/CPD items would be useful in discriminating MDS patients from cytopenic patients without MDS.

Distinct Clinical Features of Plasma Cell Myeloma Patients Exhibiting Dysmorphic Plasma Cells: Association with More Plasma Cells at Diagnosis.

Dysmorphic plasma cells are occasionally found in bone marrow (BM) aspirates of plasma cell myeloma (PCM) patients. We retrospectively analyzed the incidences of significant dysmorphic plasma cells (SDPC) presentations and their associations with clinical features in PCM patients. Total 91 PCM patients diagnosed from January 2013 to December 2017 at author's institution were enrolled. SDPC presentation was determined as ≥ 5% (SDPC5) or ≥ 10% (SDPC10) among total PC and clinical features of PCM patients were compared with respect to SDPC presentation status. Incidence of SDPC5/SDPC10 presentation was 39.6%/18.7%. Patients with SDPC5/SDPC10 showed significantly more BM PC (P = 0.004/0.020) and higher incidences of CKS1B gains (P = 0.022/0.001) and RB1 loss (P = 0.032 for SDPC10 only) at diagnosis than those without SDPC5/SDPC10. Patients with SDPC5/SDPC10 also showed significantly greater absolute BM PC (P = 0.007/0.034 and 0.047/0.049 for 1st and 2nd follow-up, respectively) and serum M-protein (P = 0.041/0.044 and 0.039/0.049 for 1st and 2nd follow-up, respectively) reductions after chemotherapy than those without SDPC5/SDPC10. SDPC5/SDPC10 presentation was confirmed as an independent predictor of BM PC ≥ 37.7% [hazard ratio (HR) 4.649/2.613, P = 0.005/0.039]. Our present study demonstrated that SDPC presentation would be an independent predictor of more BM PC at diagnosis in PCM patients. Associations between SDPC presentation and higher incidence of CKS1B gains and RB1 loss, greater PC/serum monoclonal protein reductions after chemotherapy were also identified. Association between SDPC presentation and favorable treatment response should be evaluated in more comprehensive study.

Clinical Utility of 18F-Florbetaben PET for Detecting Amyloidosis Associated With Multiple Myeloma: A Prospective Case-Control Study.

PURPOSE: The aims of this study were to evaluate the diagnostic performance of F-florbetaben PET/CT for detecting amyloid deposits in patients with multiple myeloma (MM) and to identify the optimal PET analysis method. METHODS: Fourteen patients with MM were prospectively enrolled (6 with amyloidosis, 8 control subjects). Dynamic imaging of the kidneys was performed for 20 minutes, and the retention ratio was obtained. At 90 minutes after injection, PET was performed. All images were assessed qualitatively and quantitatively, and the SUVmax, SUVmean, and SUVratio were obtained. Variables were compared between the amyloidosis group and the control group. Amyloid deposition was confirmed according to international consensus guidelines. RESULTS: Tracer uptake was abnormal in all patients with amyloidosis. The visual detection rate was excellent (100%) in the heart, stomach, and tongue but limited in the kidneys (50%) and poor (0%) in the esophagus, liver, and colon. F-florbetaben PET/CT identified 13 unexpected cases of abnormal uptake, confirming further amyloid deposition. Both spherical and manual volumes of interest showed similar diagnostic performance when evaluating amyloidosis in target organs. There was no significant difference in diagnostic performance between the SUVmax, SUVmean, and SUVratio. CONCLUSIONS: F-florbetaben PET/CT can accurately detect systemic amyloid deposits in patients with MM. F-florbetaben PET/CT was particularly useful in the heart, stomach, and tongue but of limited value in the esophagus, liver, and colon. F-florbetaben PET/CT can provide clinical information on organ involvement and could replace pathologic examination for diagnosis of amyloidosis in the future.

Comparison of High Sensitivity and Conventional Flow Cytometry for Diagnosing Overt Paroxysmal Nocturnal Hemoglobinuria and Detecting Minor Paroxysmal Nocturnal Hemoglobinuria Clones.

BACKGROUND: High sensitivity flow cytometry (HS-FCM) was recently developed for diagnosing paroxysmal nocturnal hemoglobinuria (PNH). We compared its performance with conventional flow cytometry (C-FCM) for diagnosing overt PNH and detecting minor (0.1-1%) PNH clones in aplastic anemia (AA)/low-grade myelodysplastic syndrome (MDS) patients. METHODS: C-FCM and HS-FCM were performed simultaneously on 41 samples from healthy controls and 23 peripheral blood samples from 15 AA/low-grade MDS and eight PNH patients, using a Navios flow cytometer (Beckman Coulter, Miami, FL, USA). Results were compared. RESULTS: No healthy control samples had PNH clone size >0.01%. For granulocytes, C-FCM detected a smaller PNH clone size than HS-FCM (mean difference: 0.7-1.7%). In AA/low-grade MDS patients, three samples showed >1% PNH clones with C-FCM but not with HS-FCM. Seven samples showed minor PNH clones by C-FCM, but HS-FCM showed negative results for all these samples. In PNH patients, C-FCM detected a smaller PNH clone size than HS-FCM (mean difference: 1.9-5.0%). For red blood cells, C-FCM detected a greater PNH clone size than HS-FCM (mean difference: 1.5%). In AA/low-grade MDS patients, C-FCM showed >1% PNH clones in six samples, but HS-FCM showed >1% PNH clones in none of the samples. C-FCM detected minor PNH clones in nine samples, but six of them were negative by HS-FCM. In PNH patients, C-FCM detected a greater PNH clone size than HS-FCM (mean difference: 2.5%). CONCLUSIONS: HS-FCM can sensitively detect minor PNH clones and reduce false-positive C-FCM minor PNH clone cases in AA/low-grade MDS patients.

Description of Mycobacterium chelonae subsp. bovis subsp. nov., isolated from cattle (Bos taurus coreanae), emended description of Mycobacterium chelonae and creation of Mycobacterium chelonae subsp. chelonae subsp. nov.

Three rapidly growing mycobacterial strains, QIA-37T, QIA-40 and QIA-41, were isolated from the lymph nodes of three separate Korean native cattle, Hanwoo (Bos taurus coreanae). These strains were previously shown to be phylogenetically distinct but closely related to Mycobacterium chelonae ATCC 35752T by taxonomic approaches targeting three genes (16S rRNA, hsp6 and rpoB) and were further characterized using a polyphasic approach in this study. The 16S rRNA gene sequences of all three strains showed 99.7 % sequence similarity with that of the M. chelonae type strain. A multilocus sequence typing analysis targeting 10 housekeeping genes, including hsp65 and rpoB, revealed a phylogenetic cluster of these strains with M. chelonae. DNA-DNA hybridization values of 78.2 % between QIA-37T and M. chelonae indicated that it belongs to M. chelonae but is a novel subspecies distinct from M. chelonae. Phylogenetic analysis based on whole-genome sequences revealed a 95.44±0.06 % average nucleotide identity (ANI) value with M. chelonae, slightly higher than the 95.0 % ANI criterion for determining a novel species. In addition, distinct phenotypic characteristics such as positive growth at 37 °C, at which temperature M. chelonae does not grow, further support the taxonomic status of these strains as representatives of a novel subspecies of M. chelonae. Therefore, we propose an emended description of Mycobacterium chelonae, and descriptions of M. chelonae subsp. chelonae subsp. nov. and M. chelonae subsp. bovis subsp. nov. are presented; strains ATCC 35752T(=CCUG 47445T=CIP 104535T=DSM 43804T=JCM 6388T=NCTC 946T) and QIA-37T (=KCTC 39630T=JCM 30986T) are the type strains of the two novel subspecies.

Angioimmunoblastic T-Cell Lymphoma in a Patient with Klinefelter Syndrome.

BACKGROUND Although patients with Klinefelter syndrome have elevated risk and incidence rates for several solid cancers, reports on the incidence of hematological malignancies have been equivocal. CASE REPORT We report a patient diagnosed with angioimmunoblastic T-cell lymphoma in whom Klinefelter syndrome was newly detected. Moreover, we discuss the development of a variety of lymphomas in patients with Klinefelter syndrome. CONCLUSIONS This is the first case describing angioimmunoblastic T-cell lymphoma in a patient with Klinefelter syndrome who was treated with chemotherapy.

Mycobacterium paraintracellulare sp. nov., for the genotype INT-1 of Mycobacterium intracellulare.

Three mycobacterial strains, isolated from independent Korean patients with pulmonary infections, belonging to the Mycobacterium intracellulare genotype 1 (INT-1) were characterized using a polyphasic approach. The sequences of the 16S rRNA gene and internal transcribed spacer 1 (ITS1) of the INT-1 strains were identical to those of Mycobacterium intracellulare ATCC 13950T. However, multilocus sequence typing (MLST) analysis targeting five housekeeping genes (hsp65, rpoB, argG, gnd and pgm) revealed the phylogenetic separation of these strains from M. intracellulare ATCC 13950T. DNA-DNA hybridization values of >70 % confirmed that the three isolates belong to the same species, while the values of <70 % between one of them and the type strains of M. intracellulare and Mycobacterium chimaera confirmed their belonging to a distinct species. In addition, phenotypic characteristics such as positive growth on MacConkey agar and in acidic broth culture, unique matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS profiles of lipids, and unique mycolic acids profiles further supported the taxonomic status of these strains as representatives of a novel species of the Mycobacterium avium complex named Mycobacterium paraintracellulare. The type strain is MOTT64T (=KCTC 29084T=JCM 30622T).

Coexistence of follicular lymphoma and an unclassifiable myeloproliferative neoplasm in a treatment-naïve patient: A case report.

Myeloproliferative neoplasms are associated with lymphoproliferative diseases following the administration of cytotoxic drugs or exposure to radiation, but are rare prior to therapy. The present study reports the case of a 61-year-old female with a history of transient ischemic attack. The patient, who presented with a palpable mass in the epitrochlear area of the left arm, was simultaneously diagnosed with follicular lymphoma and an unclassifiable myeloproliferative neoplasm. Excisional lymph node biopsy revealed stage I follicular lymphoma (grade 1). Laboratory findings demonstrated leukocytosis, erythrocytosis, thrombocytosis and decreased erythropoietin. Biopsy of the bone marrow revealed hypercellularity, with predominance of erythroid cells, and large polylobated megakaryocytes with increased mitotic figures, but no evidence of lymphomatous infiltration. The janus kinase 2 V617F mutation was also detected in the cells derived from the bone marrow specimen. Following local excision of the lymph node in the left epitrochlear area, radiation was delivered to the involved field, at a dose of 24 Gy in 12 fractions. The patient was started on hydroxyurea (1 g twice per day, orally) 2 weeks subsequent to radiotherapy, and was administered 500 mg twice per day as maintenance therapy. At the six-month follow-up, the white blood cell count, hemoglobin levels and platelet count had reduced, and the patient was in a healthy condition. A computed tomography scan of the neck, chest and abdomen indicated no abnormalities. To the best of our knowledge, the present study is the first case report of follicular lymphoma coexisting with an unclassifiable myeloproliferative neoplasm in a previously healthy patient. Molecular and genetic studies are required to further evaluate this infrequent disease association.

Mass-forming extramedullary hematopoiesis in multiple myeloma: 18F-FDG PET/CT is useful in excluding extramedullary myeloma involvement.

AIMS AND BACKGROUND: Extramedullary hematopoiesis (EMH), a benign condition, is usually observed in patients with hematologic disorders. We report the first case of mass-forming EMH detected on a 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scan in a patient with multiple myeloma (MM). METHODS: A 58-year-old woman underwent workup for bicytopenia, and was diagnosed with MM based on the results of bone marrow aspiration and serum protein electrophoresis. An 18F-FDG PET/CT scan revealed a paravertebral mass with mild FDG avidity, suggesting a tumorous condition. RESULTS: Biopsy was performed to exclude malignancy and the mass was eventually confirmed as EMH. CONCLUSIONS: Differential diagnosis of a mildly FDG-avid paravertebral mass in MM should include EMH.

VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia.

Very late antigen-4 (VLA-4) and CXC chemokine receptor 4 (CXCR4) perform critical roles in the adhesion of hematopoietic and leukemic stem cells to marrow stromal cells. This mechanism is associated with chemoresistance in patients with acute myeloid leukemia (AML). Here, we measured VLA-4 and CXCR4 expressions in leukemic myeloblasts to determine their prognostic implications. Using multicolor flow cytometry, positive VLA-4 and CXCR4 expressions were measured in leukemic myeloblasts in bone marrow aspirates that were obtained from newly diagnosed adult AML patients (n = 98). VLA-4 expression was higher in patients at favorable or intermediate cytogenetic risk than in patients at poor risk (p < 0.001 and p = 0.002, respectively), but CXCR4 expression was not significantly different. Among the 72 non-promyelocytic leukemia patients analyzed who received cytarabine + anthracycline-based induction chemotherapy, high VLA-4 expression was independently associated with a high probability of complete remission (p = 0.019) and superior relapse-free survival (RFS) (p < 0.001). However, high CXCR4 expression independently increased the probability of relapse (p = 0.002) and was associated with a shorter RFS (p = 0.006). When categorizing patients into three groups according to VLA-4 and CXCR4 expression levels, the group of high VLA-4 and low CXCR4 showed longer RFS (p = 0.001) and overall survival (OS) (p = 0.011) than the group of low VLA-4 or high CXCR4.

A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.

KBG syndrome is a very rare genetic disorder characterized by macrodontia of upper central incisors, global developmental delay, distinctive craniofacial features, short stature, and skeletal anomalies. Ankyrin repeat domain 11 gene (ANKRD11) has recently been identified as a causal factor of this syndrome. We describe a 6-yr-old Korean boy with features of KBG syndrome. The patient had a short stature, macrodontia, dysmorphic facial features, speech and motor delay with intellectual disability, and partial seizures as indicated by the electroencephalogram, but he was neither autistic nor had autism spectrum disorders. Using high-resolution oligonucleotide array comparative genomic hybridization, we identified a heterozygous 240-kb deletion at 16q24.3 corresponding to ANKRD11. This patient provided additional evidence on the influence of ANKRD11 in KBG syndrome and suggested that deletion limited to ANKRD11 is unlikely to cause autism.

RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.

Anaplastic lymphoma receptor tyrosine kinase (ALK) is located on chromosome 2p23; the chromosomal rearrangements of this gene are common genetic alterations, resulting in the creation of multiple fusion genes involved in tumorigenesis. However, the presence of an ALK fusion in myeloid malignancies is extremely rare. We report a case of acute myelomonocytic leukemia in a 31-year-old woman with an unusual rearrangement between RAN-binding protein 2 (RANBP2) and ALK and a karyotype of 45,XX,inv(2)(p23q21),-7[20]. We detected an ALK rearrangement using fluorescence in situ hybridization, identified the ALK fusion partner by using RNA transcriptome sequencing, and demonstrated the RANBP2-ALK fusion transcript by reverse transcriptase--PCR and Sanger sequencing. Immunohistochemistry for ALK showed strong staining of the nuclear membrane in leukemic cells. The patient had an unfavorable clinical course. Our results, together with a literature review, suggest the RANBP2-ALK fusion combined with monosomy 7 may be related to a unique clonal hematologic disorder of childhood and adolescence, characterized by myelomonocytic leukemia and a poor prognosis.

Cytogenetic classification in Korean multiple myeloma patients: prognostic significance of hyperdiploidy with 47-50 chromosomes and the number of structural abnormalities.

Chromosomal abnormalities are important prognostic factors for patients diagnosed with multiple myeloma (MM). We retrospectively reviewed the clinical and laboratory data of 525 MM patients to assess the abnormalities frequently found by conventional cytogenetic analysis and to determine their relationship to prognosis and clinical parameters. Samples from 222 (42.3%) patients had abnormal karyotypes. Hyperdiploidy-1 (>50 chromosomes), hyperdiploidy-2 (47-50 chromosomes), pseudodiploidy (46 with abnormalities), and hypodiploidy (<46 chromosomes) were found in 55, 44, 42, and 81 patients, respectively. The median overall survival (OS) was significantly shorter in patients with hyperdiploidy-2 (20.9 months), pseudodiploidy (19.9 months), and hypodiploidy (18.3 months) compared with patients with normal karyotype (66 months) and hyperdiploidy-1 (55.4 months) (P < 0.001). Among patients with chromosomal abnormalities, those with 1q amplification had a shorter median OS (17 vs. 25.1 months, P = 0.018). Patients with a chromosome 13 deletion in the pseudodiploidy group also had a shorter OS. A karyotype with more than six structural abnormalities was found to have the most significant independent prognostic value by multivariate analysis. These data show that hyperdiploidy with 47-50 chromosomes should be recategorized as an unfavorable risk group, and the number of structural abnormalities needs to be considered as an important factor for prognosis. In conclusion, our findings imply that subclassification of chromosomal abnormalities by conventional cytogenetics could be applied to the prognostic assessment of MM.

Generation of lymphocytes potentiated against leukemic lymphoblasts by stimulation using leukemic cell lysate-pulsed dendritic cells in patients with acute lymphoblastic leukemia and measurement of in vitro anti-leukemic cytotoxicity.

Using granulocyte-macrophage colony stimulating factor, interleukin4 and tumor necrosis factor α, we generated dendritic cells (DCs) from mononuclear cells isolated from the peripheral blood (PB) of eight patients with acute lymphoblastic leukemia (ALL), who were in complete remission (CR), and pulsed these DCs with leukemic cell lysates. Specific cytotoxicity assays were performed by incubation of effector cells (lymphocytes generated from cryopreserved mononuclear cells isolated in CR state of ALL) and targets (cryopreserved leukemic cells at diagnosis). Patients showing decreased cytotoxicity had poorer clinical courses. When we measured lymphocyte subsets, we found positive correlations between cytotoxicity levels and the proportions of T lymphocytes and CD8+ T lymphocytes, but negative correlations between cytotoxicity levels and the proportions of NK cells and regulatory T lymphocytes. In conclusion, we show here that leukemia-specific autologous DCs can be generated from the PB of ALL patients in CR, that the incubation of these DCs with leukemic cell lysates can generate lymphocytes potentiated against leukemic cells, and that relationships are evident among all of cytotoxicity, lymphocyte subsets, and patient prognosis.

The incidence of cough induced by remifentanil during anesthetic induction was decreased by graded escalation of the remifentanil concentration.

BACKGROUND: It is well known that opioids induce coughing. Many drugs such as lidocaine and ketamine are used to effectively prevent the coughing induced by opioids and this has been revealed to be effective. In this study, we evaluated the preventive effect of a graded escalation of the remifentanil concentration using a target controlled infusion pump and we compared this with the effect of lidocaine. METHODS: One hundred fifty ASA I and II patients who were scheduled for elective surgery were randomly divided into 3 groups. The patients were pretreated with 2% lidocaine 1 mg/kg (Group L) or saline (Group S) and remifentanil infusion (an effect site concentration of 4.0 ng/ml) was followed 1 minute later by using a target controlled infusion pump. Group R was pretreated with saline and this was followed by remifentanil infusion (effect site concentration of 2.0 ng/ml at first and then it was reset to 4.0 ng/ml). We evaluated the incidence, severity and onset time of cough after remifentanil infusion. RESULTS: The incidence of coughing was significantly decreased in Group R (6 cases, 12%) and Group L (7 cases, 14%), as compared to that of Group S (17 cases, 34%) (P < 0.05), but there was no significant difference between Group R and Group L. The groups showed no significant difference in the severity and the onset time of coughing. CONCLUSIONS: This study demonstrated that administering graded escalation of the remifentanil concentration suppresses remifentanil-induced coughing as effectively as lidocaine 1 mg/kg pretreatment.