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Whether the diagnosis and treatment of coronavirus disease 2019 (COVID-19) affect the clinical course of patients with hematologic malignancies has been of interest during the COVID-19 pandemic.We describe a 47-year-old female who was concurrently diagnosed with COVID-19 and acute myeloid leukemia (AML).She developed COVID-19 pneumonia which required treatment with remdesivir and dexamethasone, and induction therapy for t-AML was delayed. After her COVID-19 was resolved and isolation ended, follow-up bone marrow examination showed decreased leukemic burden.This case describes possible effects of COVID-19 treatment on the clinical course of patients with AML from a laboratory perspective.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation. It occurs because of severe inflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes, characterized by the production of excessive levels of cytokines. Virus-associated HLH is a well-known entity, and parvovirus B19 is one of the common causes. Parvovirus B19 can also affect blood cell lineages. Therefore, HLH may be accompanied by several diseases such as cytopenia, aplastic anemia, and myelodysplastic syndrome. Herein, we report the case of a patient with hereditary spherocytosis who was diagnosed with parvovirus B19-induced HLH and aplastic crisis. A 7-year-old girl presented to our hospital with fever, pleural effusion, pancytopenia, hepatosplenomegaly, and hypotension. A bone marrow biopsy was performed under the suspicion of HLH, which revealed hemophagocytes. The diagnostic criteria for HLH were met, and prompt chemoimmunotherapy was initiated considering the clinically unstable situation. Her health improved rapidly after initiating treatment. Further study revealed that she had hereditary spherocytosis, and parvovirus B19 had caused aplastic crisis and HLH. The patient's clinical progress was excellent, and chemoimmunotherapy was reduced and discontinued at an early stage. This case shows that aplastic crisis and HLH can coexist with parvovirus B19 infection in patients with hereditary spherocytosis. Although the prognosis was good in this case of HLH caused by parvovirus B19, early detection and active treatment are essential.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by ineffective hematopoiesis, morphologic dysplasia, and cytopenia. MDS overlap syndromes include various disorders, such as myelodysplastic/myeloproliferative neoplasms and hypoplastic MDS with aplastic anemia characteristics. MDS overlap syndromes share the characteristics of other diseases, which make differential diagnoses challenging. Advances in genomic studies have led to the discovery of frequent mutations in MDS and overlap syndromes; however, most of the mutations are not specific for the diagnosis of these diseases. The molecular characteristics of the overlap syndromes usually do not show a just "in-between" form but rather heterogeneous features. Established diagnostic criteria for these diseases based on clinical, morphologic, and laboratory features are still useful when combined with genomic data. It is expected that further studies for MDS and overlap syndromes will place emphasis on the roles of mutations as therapeutic targets and prognostic indicators.

Posttransplant anemia is a common complication after kidney transplantation. Parvovi rus B19 (PVB19) infection can induce pure red cell aplasia (PRCA) in immunosuppressed transplant patients. We herein report a case of recurrent PVB19-associated PRCA in a kidney transplant patient. A 49-year-old woman presented with anemia and normal renal function 1 year after a deceased-donor kidney transplantation for immunoglobulin A ne phropathy-related end-stage renal disease. She received desensitization therapy, and 2 years later, she underwent transplantation with thymoglobulin induction. Despite repeat ed red cell transfusion and erythropoietin therapy, her anemia aggravated progressively. Bone marrow biopsy revealed normocytic normochromic PRCA. Real-time polymerase chain reaction detected a high plasma load of PVB19. Administration of intravenous im munoglobulin (IVIG) at 2 g/kg with adjuvant reduction of tacrolimus and discontinuation of myfortic acid effectively treated the anemia. However, the PVB19 load remained high, and PRCA recurred 7 months after the initial IVIG treatment. Tacrolimus was switched to cyclosporine in the second IVIG treatment, which successfully improved PRCA and reduced the PVB19 load. Our case suggested that PVB19-associated PRCA should be suspected when persistent anemia is observed in kidney transplant patients with heavy immunosuppression and that PVB19-associated PRCA can recur in the presence of per sistent PVB19 viremia.

Precision medicine has received increased attention as an effective approach for the treatment of cancer patients. Because of challenges associated with the availability of archived tissue, liquid biopsies are often performed to detect cancer-specific mutations. One of the major advantages of the liquid biopsy is that the treatment can be monitored longitudinally, even after the tumor tissue is no longer available. In a clinical setting, one component of precision medicine is the detection of cancer-specific mutations using archived samples. In this study, we evaluated the epidermal growth factor receptor (EGFR) mutation status of samples of lung cancer patients stored before introduction of the plasma EGFR test at our institution. The aim of this study was to validate the utility of archived plasma samples for detection of the EGFR mutation in nonsmall cell lung cancer (NSCLC) patients. The Cobas® EGFR Mutation Test v2 was the first liquid biopsy test approved as a companion diagnostic test for patients with NSCLC treated with tyrosine kinase inhibitors. We tested for the EGFR mutation in 116 plasma samples archived in the biobank, and the results were compared with those obtained in the tissue or cytology EGFR mutation test. The EGFR mutation-positive rate from archived plasma was lower than that determined from tissue or cytology at 19.0% and 53.4%, respectively, and the concordance rate between the two tests was 58.6%. Of interest, five (4.3%) samples showed the T790M mutation in the plasma test, whereas this mutation was only detected in two (1.7%) tissue/cytology samples. Five (4.3%) samples were additionally positive in the plasma test. Overall, these results indicate that archived plasma samples can serve as an alternative source for the plasma EGFR mutation test when tissue samples are not available, and can improve precision medicine and long-term follow-up in a noninvasive manner.

A revised WHO classification of hematopoietic neoplasm introduced the new category 'Myeloid Neoplasms with Germline Predisposition', reflecting the growing importance of genetic testing for myeloid neoplasms. Here, we investigated monozygotic twins with the same de novo mutation in GATA2 but different phenotypes. The patient suffering a bleeding tendency was diagnosed with myelodysplastic syndrome (MDS), and her monozygotic twin showed dysmegakaryopoietic features in the bone marrow. Targeted sequencing revealed the same germline mutation in GATA2, c.1192C T, in both sisters and different somatic mutations in 14 genes between the sisters. The GATA2 mutation was absent in both parents, and their hemograms were normal. The methylation profile of the GATA2 promoter region was different between the twins, showing denser promoter methylation in the patient, correlated with MDS. Thus, we concluded that the twins had acquired a de novo GATA2 mutation but showed different phenotypes, possibly due to the critical role of epigenetic changes.

Objectives Diagnosis of central nervous system involvement in acute lymphoblastic leukemia (ALL) requires morphologic expertise; therefore, we evaluated interphase fluorescence in situ hybridization (iFISH) of cerebrospinal fluid (CSF) cytospin preparations as a potential complementary test. Methods Twenty-three CSF cytospin specimens from 13 pediatric patients with ALL were included. iFISH probes detecting BCR-ABL1, ETV6-RUNX1, and KMT2A rearrangement and CDKN2A deletion, which were present at initial diagnosis, were used on follow-up CSF cytospin specimens and were compared with cytology. Results Seventeen (73.9%) follow-up specimens showed concordant results between iFISH and cytology. Two (8.7%) samples with discordant results were positive by iFISH but not by cytology; one (4.3%) was positive only by cytology. In the remaining three (13.0%) specimens, too few cells were available for cytology, whereas iFISH interpretation was possible. Conclusions iFISH of CSF cytospin preparations improves malignant cell detection in pediatric ALL.

We hypothesized that a subset of idiopathic cytopenia of undetermined significance (ICUS) is associated with an increased autonomous proliferation with exhaustion of hematopoiesis. The aim of this study was to investigate the cell turnover rate and replicative history of the bone marrow cells of ICUS patients. To this end, we examined telomere length (TL), proliferation, and apoptosis of the bone marrow cells of ICUS patients and healthy controls (HCs) using telomere quantitative fluorescence in situ hybridization and immunohistochemical staining for Ki-67 and cleaved caspase-3. We also performed targeted sequencing of 88 myeloid-associated genes. A total of 37 patients with ICUS were enrolled in this study, with a median age of 66 years (range: 31-83). TLs were significantly shorter in patients with ICUS than in the HCs (8.8, interquartile range [IQR] 6.8-12.1 vs 18.4, IQR 14.4-22.0, p 0.0001). Proliferation (Ki-67-positive) and apoptosis (cleaved caspase-3-positive) were significantly increased in patients with ICUS compared to HCs (median = 20.0% vs 5.0%, p = 0.0003; 45.0% vs 22.5%, p = 0.0005, respectively). The shortening of TL and the increased proliferation and apoptotic activity was also prominent in patients with ICUS without mutation and dysplasia than in HCs (p 0.0001, p 0.0001, and p = 0.0093, respectively). TL was not associated with mutational profile and clinical characteristics as well in patients with ICUS. To our knowledge, this is the first study to show that ICUS is associated with premature replicative senescence with increased proliferation and apoptosis of bone marrow cells. Further study is needed to address the cause of replicative exhaustion in ICUS patients.

Redd1 is a stress response protein that functions as a repressor of mTORC1, a central regulator of protein translation, resulting in the inhibition of cell growth and metabolism. However, paradoxically, high Redd1 expression favors cancer progression and generates resistance to cancer therapy. Herein, we revealed that constitutive overexpression of Redd1 induced HSP27 and HSP70 expression in lung cancer cells. The expression of Redd1, HSP27 and HSP70 was highly increased in lung cancer tissues compared with that in normal lung tissues. Inhibition of HSP27 or HSP70 suppressed AKT phosphorylation, which was induced by constitutive overexpression of Redd1 and enhanced the inhibitory effects on viability of Redd1‑overexpressing cells. Inhibition of AKT phosphorylation resulted in a decrease of HSP27 and HSP70 expression in Redd1‑overexpressing cells. These data indicated that HSPs and AKT in Redd1‑overexpressing cells positively regulated the function and expression of each other and were involved in lung cancer cell survival. Knockdown of HSP27, HSP70 or AKT enhanced ionizing radiation (IR) sensitivity, particularly in lung cancer cells in which Redd1 was stably overexpressed. Collectively, constitutive overexpression of Redd1 led to HSP27 and HSP70 induction and AKT activation, which were involved in lung cancer cell survival and resistance to IR, suggesting that Redd1 may be used as a therapeutic target for lung cancer.

Breast cancer cells possess a deregulated apoptotic pathway with increased expression levels of anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins and ribosomal S6 kinase 1 (S6K1) protein activity. Therefore, combined interference of anti-apoptotic Bcl-2 family and S6K1 protein expression may be a reasonable therapeutic strategy for the treatment of patients with breast cancer. In the present study, it was identified that the administration of a combination of ABT263 [navitoclax; a Bcl-2/Bcl-extra large (Bcl-xL) inhibitor] and PF4708671 (an S6K1 inhibitor) markedly increased apoptotic cell death in the BT474 breast cancer cells compared with the administration of either agent alone. Furthermore, the downregulation of Bcl-2/Bcl-xL and S6K1 with small interfering RNA induced a significant increase in cell death compared with RNA interference of either agent alone. Notably, combination treatment with ABT263 and PF4708671 decreased the expression level of survivin protein, with this ectopic expression of survivin attenuating cell death. Thus, the present study determined that the combined inhibition of Bcl-2/Bcl-xL and S6K1 may be a good strategy for treating patients with breast cancer.

Dear Editor, T lymphoblastic leukemia (T-ALL) comprises 10-15% of pediatric ALL cases and is known to be a clinically and genetically heterogeneous disease [1]. Recent studies have presented various cytogenetic abnormalities in T-ALL. The alterations often present as reciprocal translocations implicated in several transcriptional factor genes and lead to arrest during T-cell differentiation [1,2]. Although cytogenetic aberrations are known to be critical in leukemogenesis of many hematologic malignancies, the relationships between these aberrations and the prognosis are not well understood in T-ALL except for t(11;19), a mixed-lineage leukemia gene (MLL)-ENL fusion related to favorable prognosis [3]. Here, we report a very rare case of pediatric T-ALL with t(11;17)(q23;q21) involving MLL rearrangement, which has not been previously reported in Korea. A 16-month-old boy was admitted to our hospital because of fever, cough, rhinorrhea, and poor oral intake. Physical examination revealed anemic conjunctiva, cervical lymph node enlargement, and splenomegaly. Chest radiography showed no abnormal findings. The complete blood count (CBC) results were as follows: hemoglobin, 8.2 g/dL; leukocytes, 41.3×109/L; platelets, 177×109/L; and reticulocyte count, 3.4%. The blood smear showed increased blasts (66%). The bone marrow (BM) specimen contained 65% blasts and showed a hypercellular pattern. Small-to-medium sized blasts were observed with condensed nuclear chromatin and an irregular nuclei margin. Immunophenotyping using the BM aspirate was brightly positive for CD2 (86%), cCD3 (91%), CD5 (91%), CD7 (92%), and CD34 (76%). Serum lactate dehydrogenase was increased to 638 IU/L. Cytogenetic studies on the BM revealed the karyotype of 46,XY,t(11;17)(q23;q21)[17]/46,XY[3] (Fig. 1A). The patient was diagnosed with T-ALL according to the 2008 WHO classification [4]. Fig. 1 Bone marrow karyogram at diagnosis and interphase FISH analysis after induction chemotherapy. (A) G-banded karyogram showing t(11;17)(q23;q21). The arrows denote the rearranged chromosomes. (B) FISH analysis using 11q23 break-apart probe revealed MLL ... The patient began receiving induction chemotherapy comprised of prednisolone, vincristine, L-asparaginase, intrathecal cytosine arabinoside, and methotrexate. He seemed to respond to chemotherapy, with decreasing leukocyte counts and spleen size. However, the BM aspirate performed on the 7th day showed increased blasts to 69%. Moreover, interphase FISH analysis using an 11q23 break-apart probe revealed MLL rearrangement (158 of 200, 79%) (Fig. 1B). He was switched to more intensive induction chemotherapy including doxorubicin and cyclophosphamide. The patient achieved complete remission after 28 days of re-induction chemotherapy. Because of his high-risk features, the patient received cord blood stem cell transplantation. At the time of writing, he is alive and has been in a continuous complete remission state for 26 months. MLL/11q23 rearrangement is intricate in many hematologic malignancies such as ALL, AML, and MDS. The 11q23 translocation, which is rarely identified in T-ALL, is a distinct subtype characterized by differentiation arrest at an early stage of thymocyte differentiation [5]. Since MLL fusion partners are also known to have an important role in leukemogenesis, recent efforts to unravel MLL fusion partners using long-distance inverse-PCR (LDI-PCR) as compensatory diagnostic method have been implemented by using current molecular diagnostic tools [6,7]. Not only scarce MLL rearrangement but also few fusion genes are involved in T-ALL, despite that 79 different MLL fusion partner genes have been identified in other hematologic malignancies [6,8]. When balanced t(11;17)(q23;q21) involving MLL rearrangement was searched on the molecular level, three different fusions with MLL at 11q23 were generated by proximally clustered genes at the same chromosomal loci: MLLT6/AF17, ACACA, and LASP1 at 17q21 [8]. Thus far, MLL with each of the other three fusion partner genes at 17q21 has been identified mainly in AML and rarely in ALL [8]. Unfortunately, the fusion partner gene in this case could not be confirmed by using LDI-PCR because of specimen problems. A literature search revealed only two cases regarding t(11;17)(q23;q21) in adults with T-ALL [9,10] (Table 1). Table 1 Reported cases of T-ALL with t(11;17)(q23;q21) Prior studies have suggested that immunophenotypic markers are correlated with genetic alterations in pediatric acute leukemia [2]. The immunophenotype of leukemic cells in our patient could be classified into the pre-T stage and immature stage according to the European Group for the Immunological Characterization of Leukaemias and T-cell receptor classification system [2]. The immature stage of T-ALL was reported with respect to poor outcome and the lack of a common genetic lesion [1,2]. In several studies, MLL-rearranged T-ALL overexpressed multiple HOX, which are transcription factors that initiate T-cell differentiation [5]. Additional cases involving genetic profiling of t(11;17)(q23; q21) involving MLL rearrangement will help assess whether this rare fusion impacts the disease progression and reveals prognostic information.

Piperlongumine (PL) has been shown to selectively induce apoptotic cell death in cancer cells via reactive oxygen species (ROS) accumulation. In this study, we characterized a molecular mechanism for PL-induced cell death.Cell viability and cell death were assessed by MTT assay and Annexin V-FITC/PI staining, respectively. ROS generation was measured using the H2DCFDA. Small interfering RNA (siRNA) was used for suppressing gene expression. The mRNA and protein expression were analyzed by RT-PCR and Western blot analysis, respectively.We found that PL promotes C/EBP homologous protein (CHOP) induction, which leads to the up-regulation of its targets Bim and DR5. Pretreatment with the ROS scavenger N-acetyl-cysteine abolishes the PL-induced up-regulation of CHOP and its target genes, suggesting an essential role for ROS in PL-induced CHOP activation. The down-regulation of CHOP or Bim with siRNA efficiently attenuates PL-induced cell death, suggesting a critical role for CHOP in this cell death. Furthermore, PL potentiates TRAIL-induced cytotoxicity in breast cancer cells by upregulating DR5, as DR5 knockdown abolished the sensitizing effect of PL on TRAIL responses.Overall, our data suggest a new mechanism for the PL-induced cell death in which ROS mediates CHOP activation, and combination treatment with PL and TRAIL could be a potential strategy for breast cancer therapy.

Resistance of estrogen receptor-positive breast cancer cells to tamoxifen represents a major barrier to the successful treatment of breast cancer. In the present study, we found that vacuolar H+ ATPase (vATPase) inhibitors, bafilomycin A1 and concanamycin A, sensitize tamoxifen-induced cell death. siRNA targeting ATP6V0C, a 16-kDa hydrophobic proteolipid subunit of vATPase that plays a central role in H+ transport, markedly increased cell death induced by tamoxifen. Interestingly, bafilomycin A1 induced up-regulation of DR4/DR5 and CHOP. Knock-down of CHOP by siRNA suppressed the cell death induced by bafilomycin A1 and tamoxifen, suggesting that bafilomycin A1-mediated CHOP activation sensitizes to tamoxifen. In addition, we found that bafilomycin A1 enhances TRAIL-induced cell death in breast cancer cells. Furthermore, we showed that combination of vATPase inhibitors with tamoxifen also effectively induced cell death in HER2- and ERα-overexpressing breast cancer cells. Overall, our results demonstrate that inhibition of vATPase can potentiate the apoptotic effects of tamoxifen through up-regulation of CHOP.

Background: Chromosome 22q11.2 microduplications are extremely rarely detected; in comparison, the deletion of same region, known as the DiGeorge/velocardiofacial syndrome, occurs more frequently. Thyroid anomalies commonly occur in patients with 22q11.2 deletion syndrome, however few reports of thyroid anomalies associated with 22q11.2 microduplication have been published thus far. Case Report: We present a case of a male infant who was prenatally diagnosed with 22q11.2 microduplication and was found to have congenital hypothyroidism due to thyroid hemiagenesis after birth. Moreover, the baby had bilateral hearing impairment, bilateral cryptorchidism, and a rotated penis. At the age of 2 years, the infant was euthyroid with levothyroxine replacement, but he showed significant developmental delay. Conclusions: To our knowledge, this is the first case of congenital hypothyroidism with thyroid hemiagenesis in a patient showing 22q11.2 microduplication. Thyroid dysgenesis could be an additional clinical feature shared by the 22q11.2 microduplication and deletion syndrome, suggesting that the duplication and deletion of a gene may result in a common phenotype. Thyroid dysgenesis should be considered in the evaluation and management of patients with this genomic disorder.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for many nosocomial and community-acquired infections, resulting in significant morbidity and mortality. A practical way to limit the spread of MRSA is early detection and proper treatment. However, screening culture for MRSA typically requires 2–3 days. The Xpert MRSA assay (Cepheid, Sunnyvale, CA, USA) is a real-time polymerase chain reaction-based assay developed for screening an MRSA-specific DNA sequence within the staphylococcal cassette chromosome in 2 h. Lower respiratory tract specimens, such as transtracheal aspirates (TTAs) and bronchoalveolar lavage fluid (BALF), are commonly obtained from intubated patients. Therefore, using the lower respiratory tract specimens with the Xpert MRSA assay may be a practical tool for patient care. We performed the Xpert MRSA assay on 108 TTA and 21 BALF specimens from 92 patients and compared the results to those obtained by culture. The two assays showed concordant results in 120 (93.0%) cases and discordant results in 9 (7.0%) cases, which were culture-negative and Xpert MRSA-positive. Among the discordant cases, 5 patients developed culture-positive samples 2–15 days after the Xpert MRSA detected MRSA. We conclude that the Xpert MRSA assay is a rapid, sensitive and clinically useful test, particularly for the early detection of MRSA.

Background: Insufficiency of the pulmonary surfactant system is the primary cause of respiratory distress syndrome (RDS) in preterm infants. Genetic factors, including specific single-nucleotide polymorphisms in the genetic components of surfactant protein A (SP-A1 and SP-A2), affect protein structure and function, as well as risk of RDS. Objective: We investigated the association between variations in SP-A genotypes and RDS within the genetically homogeneous Korean population. Methods: We used TaqMan® real-time polymerase chain reaction technology to assess nine single-nucleotide polymorphisms of SP-A in 261 full-term and 152 preterm infants. Among the preterm infants, 76 infants with RDS were matched with 76 control infants with respect to gestation, use of antenatal steroids and gender. Results: The SP-A2 1A⁰ variant and the homozygous 1A⁰/1A⁰ genotype were associated with protection from RDS (OR 0.31, 95% CI 0.13–0.78). In addition, the 1A1 carrier genotype (containing one copy of the 1A1 variant) was associated with increased risk of RDS (OR 2.42, 95% CI 1.06–5.52). The significance of these results is that the association of patterns with RDS was opposite to the findings of previous research with Finnish and North American study populations. Conclusions: We have identified associations between specific variants of the SP-A genes and RDS risk in the Korean preterm study population. Our data strongly support SP-A as a candidate gene for susceptibility to RDS, and reveal the dissimilarity of the associated risk/protective genetic variants between different ethnic study populations.

As the activation of autophagy contributes to the efficacy of many anticancer therapies, deciphering the precise role of autophagy in cancer therapy is critical. Here, we report that the dual mTORC1/2 inhibitors PP242 and OSI-027 decreased cell viability but did not induce apoptosis in the non-small cell lung cancer (NSCLC) cell lines H460 and A549. PP242 induced autophagy in NSCLC cells as demonstrated by the formation of massive vacuoles and acidic vesicular organelles and the accumulation of LC3-II. JNK was activated by PP242, and PP242-induced autophagy was blocked by inhibiting JNK pathway with SP600125 or JNK siRNA, suggesting that JNK activation is required for the mTORC1/2 inhibitor-mediated induction of autophagy in NSCLC cells. Inhibiting JNK or autophagy increased the sensitivity of H460 cells to mTORC1/2 inhibitors, indicating that JNK or autophagy promoted survival in NSCLC cells treated with mTORC1/2 inhibitors. Together, these data suggest that combining mTORC1/2 inhibitors with inhibitors of JNK or autophagy might be an effective approach for improving therapeutic outcomes in NSCLC.

Background : One of the major concerns with biobanking is the absence of standard operating procedures to eliminate pre-analytical variation arising from sample collection, preparation, and storage. Currently, there is a lack of tools to carry out quality control procedures for stored blood samples. The aim of this study is to assess the quality of stored blood samples in our biobank and to suggest appropriate indicators for their quality control. Methods : The stored blood samples that we tested have been registered into our biobank since 2003. These were transferred to our biobank after carrying out routine requested tests, because the samples would have otherwise been discarded. For the purpose of quality control, we analyzed the concentrations and the integrity of DNA and RNA extracted from the stored samples and tested the levels of several serum proteins; the results were compared with the corresponding pre-storage levels. Results : A total of 19 samples were stored from 2006 to 2009. Of the 22 samples stored between 2003 and 2005, 50% showed complete DNA integrity. However, sufficient RNA integrity was noted in only 1 sample stored as recently as 2009. High blood urea nitrogen levels were also noted in the stored sera, but the increase did not correlate to the duration of storage. Conclusions : The amount and integrity of nucleic acids extracted from stored blood samples are potential indicators that can be used for quality control. A guideline for the quality assessment of stored blood samples in a biobank is urgently needed.

Inversion of chromosome 16 [inv(16)(p13.1q22)] and t(16;16)(p13.1;q22) are associated with acute myelomonocytic leukemia (AMML) with eosinophilia and a favorable prognosis. On the other hand, patients with del(16)(q22) usually present with MDS or chronic myelomonocytic leukemia (CMML), which can evolve to AMML without eosinophilia, and this chromosomal aberration is associated with older age, a complex karyotype, and a poor prognosis. We report a case of AML with del(16)(q22) which showed a complex karyotype, absence of eosinophilia in bone marrow study and a poor response to chemotherapy.

The incidence of multiple myeloma suggests an ethnic difference. Compared to Caucasians, who have an incidence rate of 3–5/100,000, Asians show much lower incidence rate compared to them, in the range of 0.5–3/100,000. In Korea, The very first case report of multiple myeloma was published in 1959 [1], and was followed by a few case reports until the 1970s. Since that time, the number of cases of multiple myeloma in Korea increased steadily, reaching 100 cases/year in 1990 [2] and 500 cases/year in 2000 [3], and it is still going up. Currently in Korea, 1,000 patients are estimated to be diagnosed with multiple myeloma, and 700 patients are assumed to die of this disease every year, and 4,000–5,000 patients are suffering from this disease [4]. The most updated, age-standardized, incidence rate of multiple myeloma in Korea is 1.4/100,000, and ranked as the third most common among the hematologic malignancies, only surpassed by non-Hodgkin’s lymphoma and acute myeloid leukemia [5]. Besides, the mortality from multiple myeloma

Tetraploidy or near-tetraploidy is a rare cytogenetic abnormality found in AML, and is divided into primary and secondary forms. The secondary tetraploidy or near-tetraploidy found in AML is known to be specifically associated with t(8;21). In this case report, FISH analysis detected RUNX1-RUNX1T1 gene rearrangement in the absence of cytogenetic abnormality of t(8;21), which suggests the presence of unvailed t(8;21). This is the first case report of tetraploidy or near-tetraploidy AML with cryptic RUNX1/RUNX1T1 in Korea. Although the prognosis of tetraploidy or near- tetraploidy with t(8;21) is known to be poor, this patient shows a relatively good clinical course compared to other reported cases.

이지원∙이진경∙홍영준∙홍석일∙장윤환 원자력병원 진단검사의학과 Background : Immunoglobulin heavy chain (IGH ) gene rearrangement, 13q14 deletion and trisomy 1q are frequently observed in Korean patients with multiple myeloma. The purpose of our study was to analyze the statistical correlation between chromosomal aberrations and routine laboratory test results as prognostic markers and to evaluate the potential of chromosomal aberrations for the indirect assessment of prognosis in multiple myeloma patients. Methods : We investigated the prevalence of cytogenetic aberrations in 41 patients with newly diagnosed multiple myeloma. Cytogenetic analysis was conducted by conventional karyotyping and FISH for the presence of IGH/CCND1 translocation, 13q14 deletion, and trisomy 1q using bone marrow aspirates. The records of routine laboratory tests were reviewed and their correlation with cytogenetic abnormalities was investigated. Results : Sixteen (39.0%) of 41 patients had at least one cytogenetic abnormalities in conventional karyotyping or FISH. In FISH analysis of 37 patients, 8 (21.6%) showed positive result for IGH/CCND1 translocation, 8 (21.6%) for trisomy 1q, and 5 (13.5%) for 13q14 deletion. Cytogenetic abnormalities, especially trisomy 1q, were associated with significantly lower hemoglobin level and significantly higher bone marrow plasma cell percentage and β 2-microglobulin level. Conclusions : Statistical correlation between the presence of trisomy 1q and prognostic markers suggests that the evaluation of trisomy 1q in multiple myeloma patients may be used for the indirect assessment of prognosis in these patients. (Korean J Lab Med 2008;28:413-8)

Ionizing radiation including I(131) might produce chromosomal translocation, causing hematologic malignancy. The incidence of leukemia following radioactive iodine treatment for thyroid cancer has been reported to be approximately 0.1 to 2.0% in Western countries, whereas fewer cases have been reported in Korea. We hereby report four cases of secondary hematologic malignancy, who received iodine therapy for thyroid cancer after thyroidectomy: two cases of acute lymphoblastic leukemia with t(9;22)(q34;q11.2), a case of MDS with 5q deletion, and a case of MDS with normal karyotype. Three cases of hematologic malignancy have developed after cumulative dosage of less than 800 mCi. The treatment intervals in two cases were less than 12 months, and the other two cases had I(131) therapy only once. Assessment of causality using the Naranjo probability scale for adverse drug reactions showed that a 'possible' relationship existed between the use of I(131) and secondary hematologic malignancy in all of the four cases in this report.

Background : Working Formulation and Revised European American Classification of Lymphoid Neoplasms (REAL) have mainly been used in the studies for bone marrow involvement of malignant lymphoma in Korea. We investigated the incidence and histologic patterns of malignant lymphoma according to the WHO classification. Methods : This study included 507 cases of malignant lymphoma that were requested for bone marrow study for the staging during the period January 1999-December 2005 in Korea Cancer Cen- ter Hospital. Medical records, peripheral blood smears, bone marrow aspiration smears, biopsy sections, and histopathologic findings were analyzed retrospectively. Results : Of the 507 cases of malignant lymphoma, 473 (93.3%) were non-Hodgkin lymphoma (NHL) and 34 (6.7%) were Hodgkin lymphoma (HL). The overall incidence of bone marrow involve- ment by NHL and HL was 12.5% (59/473) and 11.8% (4/34), respectively. Among NHL cases, the incidence of bone marrow involvement by B-cell and T-cell neoplasms was 11.4% (43/377) and 16.7% (16/96), respectively. Although the incidences of bone marrow involvement by several B-cell neoplasms were more than 30%, diffuse large B cell lymphoma showed a relatively low incidence of bone marrow involvement (4.6%). Of bone marrow involvement patterns, diffuse infiltration pat- tern was the most common (40.0%). Peripheral blood involvement by lymphoma was observed in 35.6% of cases with bone marrow involvement. Conclusions : We used WHO classification in the study for the bone marrow involvement of malig- nant lymphoma, and this single-institution study should give a useful, up-to-date histopathologic information. (Korean J Lab Med 2007;27:383-7)

We report three cases of plasma cell myeloma with obscure and discordant data for a monoclonal component. In this study, the results of serum heavy/light chain (sHLC) were retrospectively compared with those of conventional methods during disease monitoring. All three patients achieved a complete response and experienced a relapse during follow-up, and the sHLC ratio allowed early prediction of disease relapse and correlated well with other electrophoretic methods compared with the free light chain ratio. Therefore, we suggest that the sHLC assay may be useful as a complementary tool; it has a good correlation with conventional methods and sensitivity in assessing disease status and treatment response in patients with plasma cell myeloma.

Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H+ ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC.

Chronic lymphocytic leukemia (CLL) is frequent in the West, but rare in Korea. In this study, the frequency of chromosome aberration in Korean CLL patients was examined by applying interphase fluorescence in situ hybridization (FISH). Conventional cytogenetic test and FISH were performed on bone marrow aspirates obtained from 16 CLL patients. By applying DNA probes (Vysis, Downers Grove, IL, USA), the deletion in 11q22–23, 13q14, 13q34, and 17p13, and trisomy 12 were examined. With FISH, molecular cytogenetic aberration was detected in 10 of 16 patients [63%, 95% confidence interval (CI) 39–86], whereas with conventional cytogenetic test, chromosomal aberration was detected only in 2 out of 13 cases (15%, 95% CI 0–35). In total, the cases with one or more chromosomal aberrations were 11 out of 16 cases (69%, 95% CI 46–92). The most frequently detected aberration was the 13q14 deletion (69%, 95% CI 44–94), followed by trisomy 12 (19%, 95% CI 0–38) and 11q22 deletion (14%, 95% CI 0–33). No deletion in 17p13 was observed. In conclusion, CLL in Korean is a heterogeneous genetic disorder, showing similar genetic changes in Europe and North America.

TO THE EDITOR: Prolongation of activated partial thromboplastin time (aPTT) is one of the common problems in the field of consultative hematology. When considering a patient with aPTT prolongation, other combined coagulation abnormalities should be identified first. If prolongation of prothrombin time (PT) or thrombocytopenia is also observed, possible causes such as liver disease or disseminated intravascular coagulation may be considered as one of the differential diagnoses. If a patient has no other coagulation abnormalities, including PT prolongation, thrombocytopenia, or decreased fibrinogen level, the patient can be considered to exhibit isolated aPTT prolongation. Isolated aPTT prolongation should be carefully examined, because hemophilia may also be present in this population [1]. In addition, confirmation through repeated tests is also needed, because various laboratory errors, including inadequate venous puncture, delayed analysis, incorrect preparation of plasma, and use of heparin, may cause isolated and transient aPTT prolongation. The plasma mixing test is the cornerstone test for the initial differential diagnosis of persistent and isolated aPTT prolongation; corrected cases suggest factor deficiency, while uncorrected cases suggest the presence of an inhibitor, such as lupus anticoagulant [2]. We examined the cause of isolated aPTT prolongation in cancer patients before cancer surgery. We found that most patients with isolated aPTT prolongation who were scheduled for cancer surgery had factor deficiency (88.8%), primarily factor XII (75.0%). Intrinsic factors of the coagulation pathway were measured in 44 patients (Fig. 1). Clinical data, including the history of bleeding tendency, type of surgery, and post-operative bleeding or thromboembolic outcomes, as well as laboratory results, including aPTT, change in hemoglobin level, activities of factors VIII, IX, XI, XII, von Willebrand factor antigen (vWF:Ag), and vWF ristocetin cofactor (vWF:RCo), were retrospectively reviewed. Bleeding risk associated with surgery was stratified as previously reported [3]. Surgeries associated with a high bleeding risk were as follows: coronary artery bypass, heart valve replacement surgery, intracranial or spinal surgery, aortic aneurysmal repair, peripheral artery bypass, other major vascular surgery, major orthopedic surgery (e.g., hip or knee replacement), reconstructive plastic surgery, major cancer surgery, prostate surgery, and bladder surgery. The median age was 53 years (range, 24-81 years), and 29 patients (65.9%) were female. Twenty-two patients (50.0%) were scheduled for surgery due to thyroid cancer, and 13 patients (29.5%) were scheduled to undergo an operation with a high risk of bleeding (Table 1). Fig. 1 Flowchart of patient selection. Abbreviation: aPTT, activated partial thromboplastin time. Table 1 Baseline characteristics. Among 44 patients, 75.0% had factor XII deficiency. Factor VIII and XI deficiency was detected in 25.0% and 20.5% of patients, respectively. In contrast, there was no patient with factor IX deficiency. Only a small percentage of patients showed vWF:Ag and vWF:RCo deficiency (7.5% and 2.5%, respectively; Table 2). The decrease in peripheral blood hemoglobin and hematocrit after surgery was -1.1±0.9 g/dL and -3.8±3.4% (mean±standard deviation), respectively. Post-operative events, including emergency operation and red blood cell (RBC) transfusion due to bleeding during or after surgery, occurred in only three patients. There was no thromboembolic event in 44 patients. Table 2 Results of coagulation factors of the intrinsic pathway. The first patient was a 53-year-old woman who had mild coagulation factor VIII deficiency (FVIII:C 41%) and who underwent left lobectomy of the thyroid and neck dissection due to thyroid cancer. She had experienced hematoma at the surgical site and underwent an emergency operation for hematoma evacuation on post-operative day 26. Unfortunately, we could not confirm the causal relationship between factor deficiency and the post-operative bleeding event in this case. The second patient was a 66-year-old woman with gynecological cancer. She had undergone major operations, including total colectomy, omentectomy, and peritonectomy and experienced post-operative disseminated intravascular coagulation. Accordingly, transfusion was needed in this patient. She had mild factor XII deficiency (FXII:C 39%) before surgery. The last patient was a 52-year-old man. He received bilateral T8-L3 posterior fixation due to spinal cord compression. He needed RBC transfusion due to intra-operative bleeding, although coagulation factor deficiency was not found. We could not detect a significant association between coagulation factor deficiency and post-operative bleeding in patients with cancer and isolated aPTT prolongation. Our findings demonstrated that the main cause of isolated aPTT prolongation in patients with cancer might be a factor deficiency rather than the presence of an inhibitor such as lupus anticoagulant. In addition, the most commonly deficient factor was coagulation factor XII. In contrast, a previous study investigating the cause of isolated aPTT prolongation in general patients in an acute care setting demonstrated that the prevalent cause of aPTT prolongation was the presence of lupus anticoagulant [4]. When considered with our results, this suggests that the etiology of isolated aPTT prolongation might differ according to the disease subgroup. To our knowledge, the current study is the first to examine and report the cause of isolated aPTT prolongation and the frequency of factor deficiency of the intrinsic coagulation pathway in patients with cancer. Factor XII deficiency, a rare congenital disorder, has sporadically been reported in case reports worldwide. Moreover, until the current report, there was only one report of three cases with genetically confirmed severe congenital factor XII deficiency in Korean patients [5]. Except for sporadic case reports, there have been only a few studies investigating factor XII deficiency in the clinical context. Factor XII deficiency is also known to be associated with thromboembolism as well as bleeding risk [6]. One Greek report showed that factor XII activity was significantly lower in women who experienced recurrent spontaneous abortion, while all normal controls had normal factor XII activity [7]. However, there was no peri-operative thromboembolic event in our study population. Furthermore, factor XII deficiency was not associated with post-operative bleeding events, though one female patient with mild factor XII deficiency received RBC transfusion after a major operation. Although the degree of factor XII deficiency in our patients with cancer was mild and the definition of the lower limit of normal for factor XII is somewhat variable (54% to 70%) [8,9], we consider it valuable to report an unexpected high incidence of factor XII deficiency in patients with cancer and isolated aPTT prolongation.

Granulocytosis occurs in 40% of patients with lung and gastrointestinal cancers, 20% of patients with breast cancer, 30% of patients with brain tumor and ovarian cancer and 10% of patients with renal cell carcinoma. Granulocytosis occurs because of production of G-CSF, GM-CSF and IL-6. Uterine cervical carcinoma with granulocytosis as a paraneoplastic syndrome, however, has been rarely reported. We recently witnessed a case of invasive squamous cell carcinoma of the uterine cervix with granulocytosis. Leukocytosis developed up to 69,000/microL, and then normalized after chemo-radiotherapy. There was no evidence of infection, tumor necrosis, glucocorticoid administration, or myeloproliferative disease by examination of a bone marrow aspirate when granulocytosis appeared. This phenomenon was probably associated with the secretion of hematopoietic growth factors such as G-CSF, GM-CSF and IL-6 by the tumor. We suggest that, like some other solid tumors, cervical cancer can present with granulocytosis as a paraneoplastic syndrome.

Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease (CLD). A newer form of ventilation called high-frequency oscillatory ventilation (HFOV) has been shown to result in less lung injury in experimental studies.The objective of this review is to determine the effect of the elective use of HFOV as compared to conventional ventilation (CV) on the incidence of CLD, mortality and other complications associated with prematurity and assisted ventilation in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS).Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross-references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in January 2009.Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomization and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 h of life.The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta-analysis was performed using a fixed effect model. Where heterogeneity was over 50%, the random effects RR is also given.Seventeen eligible studies of 3,652 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28-30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. The effect was similar in trials with a high lung volume strategy for HFOV targeting at very low FiO(2) and trials with a high lung volume strategy with somewhat higher or unspecified target FiO(2). Subgroups of trials showed a significant reduction in CLD with HFOV when no surfactant was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomization occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group. In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high-volume strategy with HFOV found increased rates of grade 3 or 4 intraventricular hemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group.

Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic α,β-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine.

Lung cancer is one of the main causes of cancer-related mortality. The identification of early diagnostic biomarkers improved outcomes for lung cancer patients. Serum fibrin-fibrinogen degradation products (FDP) levels are elevated in numerous malignancies due to hemostatic alterations. The serum FDP levels were compared to the levels of cytokeratin 19 fragment antigen (CYFRA 21-1), another well-established biomarker. The serum samples from 193 lung cancer patients, 84 healthy controls and 106 patients with benign respiratory diseases were obtained. The serum FDP level was measured using the DR-70 immunoassay and the CYFRA 21-1 level was measured by electrochemiluminescence using the Roche Analytics E170. Receiver operating characteristics curves were used to assess the predictive sensitivity and specificity. The mean serum FDP level in lung cancer patients (35.01±229.02 μg/ml) was significantly higher compared to the 190 non-cancerous subjects (0.60±0.75 μg/ml; P=0.039). The mean serum CYFRA 21-1 level in lung cancer patients (4.50±6.67 ng/ml) was also significantly higher compared to the non-cancerous subjects (1.40±0.83 ng/ml; P

Extraction of high-quality RNA is a crucial step in gene expression profiling. To achieve optimal RNA extraction from frozen blood, the performance of three RNA extraction kits- TRI reagent, PAXgene blood RNA system (PAXgene) and NucleoSpin RNA blood kit (NucleoSpin)- was evaluated. Fifteen blood specimens collected in tubes containing potassium ethylenediaminetetraacetic acid (EDTA) and stored at −80°C for approximately 5 years were randomly selected. The yield and purity of RNA, RIN (RNA integrity number) values and cycle threshold (Ct) values were assessed. Mean RNA yields with TRI reagent, PAXgene and NucleoSpin were 15.6 ± 8.7 μg/ml, 3.1 ± 1.7 μg/ml and 9.0 ± 5.5 μg/ml, respectively. Mean A260/280 ratios of RNA for the three kits were 1.7 ± 0.1, 2.0 ± 0.1, and 2.0 ± 0.0, and mean RIN values recorded as 3.2 ± 0.8, 6.0 ± 1.1, and 6.4 ± 0.9, respectively. The Ct values of housekeeping genes, 18S rRNA, β-actin, RPLP0 and HPRT1, were as follows: TRI reagent (19.2 ± 1.6, 30.6 ± 1.8, 29.9 ± 1.4 and 36.3 ± 1.3), PAXgene 16.6 ± 1.4, 26.4 ± 1.3, 28.2 ± 1.8 and 33.8 ± 1.1), and NucleoSpin (16.3 ± 1.5, 27.2 ± 1.3, 27.0 ± 1.6 and 32.9 ± 1.6). RNA yield using TRI reagent was 1.7 times higher than that with NucleoSpin and 5 times higher than that with PAXgene. However, the purity and integrity of TRI-extracted RNA was lower than that extracted with PAXgene and NucleoSpin. Moreover, the Ct values of housekeeping genes after extraction with TRI reagent were approximately 1.7-3.8 times higher than those obtained with PAXgene and NucleoSpin. The PAXgene and NucleoSpin kits produced similar results in terms of RNA purity and integrity and subsequent gene amplification. However, RNA yields from NucleoSpin were 2.9-fold higher, compared to PAXgene. Based on these findings, we conclude that NucleoSpin is the most effective kit for extraction of abundant and high-quality RNA from frozen blood.

The PI3K/Akt/mTOR axis in lung cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for lung cancer. However, non-small cell lung cancer cells are resistant to BEZ235, a dual inhibitor of PI3K and mTOR. Interestingly, blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA dramatically sensitized the BEZ235-induced cell death, as evident from increased PARP cleavage. Furthermore, inhibition of Stat3 led to enhancement of cell death induced by LY294002, a PI3K inhibitor. Treatment of cells with a combination of BEZ235 and S3I-201 significantly induced the proapoptotic transcription factor, CHOP, and its targets, Bim and DR4. Knockdown of CHOP or Bim suppressed cell death stimulated by the combination treatment, implicating the involvement of these BEZ235/S3I-201-induced factors in pronounced cell death. Moreover, the BEZ235/S3I-201 combination enhanced TRAIL-induced cell death. Our results collectively suggest that blockage of Stat3 presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition.

r To gain more insight into the immunophenotypic and cytogenetic changes in acute leukaemia at relapse, 99 Korean patients treated at a single institution were studied: acute myelogenous leukaemia (AML, n = 46), acute lymphoblastic leukaemia (ALL, n = 44) and biphenotypic and mixed leukaemia (n = 9). Immunophenotypic changes at relapse were observed in 51 of 99 patients (51.5%) with almost even distribution in AML and ALL. Overall expression of aberrant markers on leukaemic cells was more frequent at relapse than at initial diagnosis (P < 0.05), and this finding was most prominent in B lineage ALL (41.4% versus 10.3%, P = 0.007). Gain of aberrant CD13 or CD33 at relapse of B lineage ALL was most frequently observed. Cytogenetic changes at relapse were observed in 28 of 46 patients (60.8%). The initially abnormal karyotypes were more frequently associated with clonal changes at relapse compared to initially normal karyotypes (78.3% versus 43.5%, P = 0.016). Cytogenetic changes were more frequent in B lineage ALL than in AML (90% versus 47.8%, P = 0.05). In ALL, patients showing cytogenetic changes at relapse were significantly younger than those showing no changes (mean age of 15.0 versus 38.8, P = 0.002), whereas in AML there was no significant difference between the two groups. In conclusion, the gain of aberrant markers and cytogenetic changes at relapse, which are suggestive of clonal instability, are more prevalent in B lineage ALL compared to AML, and lymphoid leukaemic cells of younger patients are more susceptible to clonal changes at relapse.