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Several studies have compared the molecular responses between e14a2 and e13a2 BCR::ABL1 transcripts in chronic myeloid leukemia (CML) patients treated with front-line imatinib, but there were very limited studies on nilotinib or dasatinib-treated patients. We retrospectively analyzed the molecular responses in 1124 CML patients with the e14a2 or e13a2 transcript receiving front-line imatinib, nilotinib or dasatinib treatment. Patients with the e14a2 transcript had higher optimal response rates than those with the e13a2 transcript at 12 months in the imatinib-treated group, and 6 and 12 months in the nilotinib-treated group. The optimal response rates were not significantly different between the two transcripts in the dasatinib-treated group at landmark molecular responses. With a median follow-up time of 48.4 months, higher cumulative incidences of BCR::ABL1 International Scale ≤1% and major molecular response were observed in patients with the e14a2 rather than the e13a2 transcript receiving front-line imatinib or nilotinib treatment, but not in dasatinib-treated patients. The progression-free survival and overall survival did not differ between the two transcripts in all three treatment groups. In view of the speed and depth of molecular responses, BCR::ABL1 transcript subtypes might provide helpful information in selecting a front-line tyrosine kinase inhibitor for individual young patients with future potential treatment-free remission.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph

Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC50) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G1 population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor.

Background Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. However, the real-world evidence regarding the long-term safety (primary) and effectiveness (secondary) of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers. The objective was to collect the long-term safety (primary) and effectiveness (secondary) data in patients treated with nilotinib under the real clinical practice for up to three years. Results Of the 129 enrolled patients, 32 patients (24.8%) discontinued the study, predominately due to AEs (n = 8; 6.2%), discontinuing nilotinib or switching to other treatments (n = 7; 5.4%), and death (n = 5; 3.9%). The median age of the study population was 49 years (range, 20 - 53 years), of whom 77 were male (59.7%). At enrollment, the median time from initial CML diagnosis was 22 days (range, 0.0 - 602 days), and three of them had their CML diagnosed for more than one year. Across the 3-year observational period, a total of 1,466 AEs were reported in 127 (98.4%) patients, of which 151 AEs in 44 (34.6%) patients were serious adverse events (SAEs) and 524 AEs in 37 (29.1%) patients were nilotinib-related. The most commonly reported non-hematological AEs (regardless of relationship to nilotinib, incidence ≥ 20 %) were rash (24.8%); while that for hematological AEs were thrombocytopenia (31.0%; Grade 3 or above: 13.2%) (Table 1). Nilotinib discontinuation, and dose reduction or interruptions were only reported in 9 (7.1%) and 11 (8.7%) patients, respectively. Five (3.9%) patients expired, of whom 2 were due to CML progression. Favorable efficacy outcomes were observed in this real-world study. From 3 to 36 months, the rates of clinical response increased over time, from 72.5% to 98.3% for complete hematological response (CHR), from 48.3% to 92.5% for complete cytogenetic response (CCyR), from 16.7% to 85.8% for major molecular response (MMR), from 4.2% to 65.0% for MR4.0 (BCR-ABL ≥ 4 log reduction), and from 3.3% to 45.0% for MR4.5 (BCR-ABL ≥ 4.5 log reduction) (Figure 1). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. Non-hematological and hematological AEs were comparable with previous studies, with no new safety signal detected. This NOVEL-1st study demonstrated a lower percentage of patients withdrawing nilotinib owing to AEs (NOVEL-1st vs. prior: 7.1% vs. 10.0%) and an extremely lower incidence of AEs leading to dose reduction or interruption (8.7% vs. 37 - 55%). It was inferred that the high tolerability and patient adherence further contributed to high treatment response in terms of complete molecular response (CMR [i.e., MR4.5], 45% vs. 32%), molecular response 4.0 (MR4.0, 65% vs. 50%), and major molecular response (MMR, 85.5% vs. 73%) at 3 years. Over the 3 years of follow-up, there was no newly onset of hepatitis or hepatitis B flare. This NOVEL-1st study also reported lower incidence rates of CV events (NOVEL-1st vs. prior: 2.3% vs. 3.5 - 6.0%), diabetes (2.3% vs. 20.2%), and hyperglycemia (3.1% vs. 42.1%) than prior studies. None of them was judged as related to nilotinib treatment (Table 1). Conclusions Across the 3-year observational period, nilotinib demonstrated comparable efficacy and had lower risk of hepatitis flare, CV event, diabetes and hyperglycemia among Ph+CML-CP patients in a real world setting in Taiwan. Long-term good patient adherence and holistic care could contribute to good treatment outcome in this chronic disease under the first-line treatment with nilotinib. Disclosures Chen: Novartis: Current Employment. Lee:Novartis: Current Employment. Ku:Novartis: Current Employment.

Cantharidin, a natural toxin from blister beetles, has shown potent anticancer activities on many solid tumor cells. Recently, cantharidin and its analogue, norcantharidin, were also shown to suppress nonsolid tumors such as chronic myeloid leukemia, acute myeloid leukemia (AML), and leukemic stem cells. However, there is no available information to address the effects of cantharidic acid (CAC), a hydrolysis product of cantharidin, on human AML cells. The present study showed that CAC, at a range of concentrations (0-20 μM), concentration-dependently inhibited cell proliferation in the HL-60 AML cell line. Western blot and flow cytometric assays demonstrated that CAC induced several features of apoptosis such as sub G1-phase cell increase, phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Moreover, treatment of HL-60 cells with CAC induced concentration- and time- dependent activation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). Only JNK-, but not p38 MAPK-specific inhibitor can reverse the CAC-induced activation of the caspase-8, -9, and -3. We concluded that CAC can induce apoptosis in human leukemic HL-60 cells via a caspases-dependent pathway, and that the apoptosis-inducing effect of CAC can be regulated by JNK activation signaling.

Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. Results showed that tricetin inhibited cell viability in various types of AML cell lines. Tricetin induced morphological features of apoptosis such as chromatin condensation and phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Of note, tricetin-induced cell growth inhibition was dramatically reversed by a pan caspase and caspase-8- and -9-specific inhibitors, suggesting that this compound mainly acts through a caspase-dependent pathway. Moreover, treatment of HL-60 cells with tricetin induced sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and inhibition of ERK and JNK by their specific inhibitors respectively promoted and abolished tricetin-induced cell apoptosis. Dichlorofluorescein (DCF) staining showed that intracellular reactive oxygen species (ROS) levels were higher in tricetin-treated HL-60 cells compared to the control group. Moreover, an ROS scavenger, N-acetylcysteine (NAC), reversed tricetin-induced JNK activation and subsequent cell apoptosis. In conclusion, our results indicated that tricetin induced cell death of leukemic HL-60 cells through induction of intracellular oxidative stress following activation of a JNK-mediated apoptosis pathway. A combination of tricetin and an ERK inhibitor may be a better strategy to enhance the anticancer activities of tricetin in AML.

Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative that was shown to have anti-inflammatory and anticancer activities in various solid tumors. The anticancer effect of nobiletin on nonsolid tumor remains unclear. Herein, the molecular mechanisms by which nobiletin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. The results showed that nobiletin suppressed cell proliferation in various types of AML cell lines. Moreover, nobiletin induced cell-cycle arrest of HL-60 AML cells at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. Furthermore, nobiletin effectively induced apoptosis of HL-60 cells through caspase-8, caspase-9, and caspases-3 activation concomitantly with a marked induction of p38 mitogen-activated protein kinase (MAPK) activation, but without affecting expression levels of Bcl-2, Bax, or Bid. Taken together, our results suggest that nobiletin inhibited HL-60 cell proliferation through inducing cell-cycle arrest and apoptosis and could serve as a potential additional chemotherapeutic agent for treating AML.

Background Vascular endothelial growth factor C (VEGF-C), an angiogenic/lymphangiogenic factor with high expression levels in tumor tissues, plays important roles in the development of several malignancies including hepatocellular carcinoma (HCC). The purpose of this study was to examine whether VEGF-C gene polymorphisms are associated with susceptibility to HCC and its clinicopathological development. Methods Genetic polymorphisms of VEGF-C of 135 patients with HCC and 520 noncancer controls were analyzed by a real-time polymerase chain reaction (PCR). Results We found that a significantly (P = 0.021) higher risk for HCC was shown in individuals with the VEGF-C rs1485766 A/A genotype compared to those with wild-type homozygotes; a high frequency of an advanced stage and a low frequency of being positive for cirrhosis were respectively shown in HCC patients with the VEGF-C rs7664413 CT/TT and rs3775194 GC/CC genotypes. Moreover, we found that the GGACA, GACTG, CGATG, and GGCTG haplotypes of five VEGF-C single-nucleotide polymorphisms (SNPs) combined were also related to the risk of HCC. Conclusions Our results suggest that the VEGF-C rs1485766 SNP and either of five haplotypes combined might contribute to a prediction of susceptibility to HCC. The genetic polymorphism of VEGF-C rs7664413 might be a predictive factor for advanced-stage HCC.

Plasma YKL-40 level has been reported as playing a significant role in community-acquired pneumonia (CAP). However, the correlation between plasma level of YKL-40 and the severity of CAP has not been reported. This study identifies the relationship between plasma level changes of the YKL-40 gene in adult patients hospitalized with CAP. The ELISA was used to measure the plasma YKL-40 level from 61 adult CAP patients before and after antibiotic treatment and from 60 healthy controls. The plasma YKL-40 levels were significantly increased in patients with CAP compared to normal controls. Moreover, the plasma concentration of YKL-40 correlated with the severity of CAP based on the pneumonia severity index (PSI) score (r = 0.630, p < 0.001), the CURB-65 (confusion, uremia, respiratory rate, BP, age 65 years) score (r = 0.640, p < 0.001), the Acute Physiology And Chronic Health Evaluation II (APACHE II) score (r = 0.539, p < 0.001) and length of hospital stay (r = 0.321, p = 0.011), respectively. In conclusion, plasma YKL-40 may play a role in the diagnosis and clinical assessment of CAP severity, which could potentially guide the development of treatment strategies.

Hispolon is an active phenolic compound of Phellinus igniarius, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML.

Background The selective tyrosine kinase inhibitor (TKI) nilotinib has been approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. The NOVEL-1st study was conducted to examine the long-term safety and efficacy of nilotinib in this group of patients in routine clinical practice in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers across Taiwan between January 2013 and June 2016. The follow-up period was 36 months. The primary objective was to collect long-term safety data on nilotinib. Secondary objectives were to evaluate the efficacy of nilotinib by clinical response, disease progression, and survival. Results The median age of the enrolled patients was 49.7 (20.2-89.6) years of whom 58.3% were males. The median duration from CML diagnosis to study enrolment was 25.5 days. Of the 129 enrolled patients, 59 (45.7%) had completed the study, 29 (22.5%) had withdrawn from the study and other patients are still under follow up. The most common reasons included adverse events (AE) (n = 8), discontinuing nilotinib (n = 6), and death (n = 4). All 129 patients were included in the safety analysis, while 122 patients in whom molecular response data were collected were included in the efficacy assessment. At the time of data cut-off, a total of 1,278 AEs were reported by 120 (93.0%) patients, of which 140 (11.0%) AEs in 41 (34.2%) patients were serious and 499 (39.0%) AEs in 40 (33.3%) patients were drug-related. Non-hematological and hematological AEs were consistent with other reports, with no new safety signal detected. Common hematological AEs (incidence ≥ 10 %) included thrombocytopenia (29.5%), anemia (19.4%), and leukopenia (14.0%). Frequent non-hematological AEs (incidence ≥ 10 %) included rash (21.7%), upper respiratory tract infection (19.4%), pruritus (18.6%), cough (17.1%), constipation (14.7%), diarrhea (12.4%), increased alanine aminotransferase (11.6%), increased bilirubin (10.1%), and insomnia (10.1%). Compared to previous studies, we observed lower rates of cardio- or cerebrovascular events (1.6%), fluid retention (2.3%), and hyperglycemia (2.3%) of all grades, but a higher rate of hepatotoxicity (20.9%) was seen in the study population. Five (3.9%) patients expired during the study of whom 2 were due to CML progression. The efficacy outcomes were comparable to other first-line studies of nilotinib. From 3 to 36 months, the rates of clinical response increased over time, from 67.4% to 91.5% for complete hematological response (CHR), 45.0% to 86.0% for complete cytogenetic response (CCyR), 15.5% to 79.1% for major molecular response (MMR), 3.9% to 56.6% for MR4.0 (BCR-ABL ≥ 4 log reduction), and 2.3% to 38.8% for MR4.5 (BCR-ABL ≥ 4.5 log reduction). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 88.7% of patients. MR4.0 and MR4.5 were significantly higher for patients with deeper EMR, confirming an association between early and long-term deep molecular response. To date, the median OS and PFS were not reached as death and disease progression were only observed in 5 and 2 patients, respectively. Conclusions The initial results of NOVEL-1st were comparable to other published first-line studies of nilotinib and demonstrated that nilotinib as a first-line treatment for Ph+ CML-CP patients was well-tolerated and efficacious in the real-world setting. Clinical response was observed as early as 3 months. Early molecular response is a potential predictor of long-term clinical outcome. The final analysis will be conducted when all patients have completed the study. Disclosures No relevant conflicts of interest to declare.

Background The aim of this study was to investigate the differential plasma levels of lipocalin 2 (LCN2) and its complex with MMP-9 (where MMP is matrix metalloproteinase) before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). Method Plasma LCN2 and LCN2/MMP-9 complex levels were measured in 61 adult patients with CAP and 60 healthy controls using commercial enzyme-linked immunosorbent assay (ELISA). Results A decrease in the number of white blood cells (WBCs) and neutrophils and decreases in the levels of C-reactive protein (CRP), LCN2, and LCN2/MMP-9 complex were observed after antibiotic treatment. The plasma level of LCN2, but not that of CRP, was correlated with the severity of CAP based on the Pneumonia Severity Index (PSI; r = 0.333, P = 0.009), confusion, urea, respiratory rate and blood pressure (CURB)-65 (r = 0.288, P = 0.024), and Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (r = 0.328, P = 0.010). LCN2 levels were also significantly correlated with LCN2/MMP-9 levels and the numbers of WBCs or neutrophils. Conclusions Plasma levels of LCN2 and the LCN2/MMP-9 complex can act as adjuvant diagnostic biomarkers for CAP. Plasma LCN2 might play a further role in the clinical assessment of the severity of CAP, which could potentially guide the development of future treatment strategies.

A 43-year-old male patient with follicular B-cell lymphoma was referred for a FDG PET/CT scan due to severe left lower abdominal pain to rule out recurrent cancer. These FDG PET/CT images and previous FDG PET/CT images 5 months ago both revealed an air bubble in the urinary bladder on the CT images. He had a recurrent urinary tract infection history for 6 months. A list-mode dynamic data acquisition with diuresis intravenous injection revealed linear FDG activity extending from the upper-left portion of the bladder to a soft tissue mass in the lower-left pelvic region. An enterovesical fistula was confirmed by surgery.

Some chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitor (TKI) do not respond or relapse. BCR-ABL1 mutations are the principal cause of TKI resistance, but the kinetics of emerging mutations in CML patients treated with imatinib remain to be determined. To investigate the emergence dynamics of mutations and their effects on outcomes, we conducted a systematically longitudinal study of BCR-ABL1 mutation dynamics during TKI therapy. Seminested polymerase chain reaction followed by denaturing high-performance liquid chromatography with sequence confirmation were used to detect BCR-ABL1 mutations in 202 CML patients with imatinib resistance at different CML phases. We detected 68 mutations in 58 imatinib-failure patients. Mutations were present in 27.6% of patients who failed front-line imatinib therapy and in 68.1% with advanced disease. Mutations were not detected in patients before commencing imatinib treatment. Pyrosequencing was then used to quantitatively monitor the mutant levels sequentially and also traced back for their earlier appearance. The mutants differed in rapidity of emergence which appeared to arise in different time frame as well as in speed of rising mutant levels. In the 78 front-line imatinib-failure patients, mutation positive patients had significantly higher risk of disease progression or relapse and inferior progression-free survival compared to those without mutations (p=0.006). Our study demonstrates kinetics of different BCR-ABL1 mutant emergence and an association between BCR-ABL1 mutations and disease progression.

Background and Objectives The aim of this study was to examine the potential associations of two hypoxia inducible factor-1α (HIF-1α) gene polymorphisms, C1772T and G1790A, with the susceptibility and clinicopathological status of hepatocellular carcinoma. Methods A total of 449 subjects, including 347 healthy controls and 102 patients with hepatocellular carcinoma, were recruited in this study and subjected to polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analyses to estimate the impact of these two polymorphic variants on hepatocellular carcinoma. Results G1790A heterozygotes showed a higher risk for hepatocellular carcinoma, compared with GG genotypes after adjusting for other confounders (AOR = 3.97; 95%CI = 1.70–9.22), indicating a significant association between hepatocellular carcinoma susceptibility and G1790A polymorphism. Moreover, results also revealed the presence of synergistic effect between gene polymorphism of HIF-1α G1790A and environmental risk factors, such as tobacco and alcohol consumptions while there was no significant association between HIF-1α gene polymorphism and clinicopathological parameters of hepatocellular carcinoma. Conclusions Genetic polymorphism at G1790A of HIF-1α is an important factor for determining the susceptibility to hepatocellular carcinoma. The interaction effects of G1790A heterozygotes to tobacco and to alcohol consumption significantly increase the risk to develop hepatocellular carcinoma. J. Surg. Oncol. 2010;102:163–169. © 2010 Wiley-Liss, Inc.

Our goal was to compare the expression of plasma monocyte chemotactic protein 1 (MCP-1) and the gene polymorphism in patients with pelvic inflammatory disease (PID) and healthy controls. The enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were, respectively, used to measure the plasma MCP-1 level and MCP-1 polymorphism in 70 healthy controls and in 64 patients with PID before and after they received routine treatment protocols. We found plasma MCP-1 was significantly elevated in patients with PID compared to that in normal controls and decreased significantly compared to that in patients with PID after they received treatment. The increased expression of plasma MCP-1 was significantly correlated with the cell counts of white blood cells (WBCs) in blood and the level of plasma C-reactive protein (CRP) of patients with PID before they received treatment. There was no association between MCP-1 -2518G/A SNP and its gene expression levels and PID susceptibility. Elevated plasma MCP-1 could be a biological marker for the diagnosis and to be a new strategy for target therapy of pelvic inflammatory disease.

In this paper we study some properties of involutively bordered words. When θ is a morphic involution, the relationship between the θ - d -descent of words in Dθ (i) and Dθ (k), k < i is derived. We provide methods to construct words in for k ⩾ 1 . We also obtain that the annohilator αub (u) of unbordered word u is a disjunctive post-plus language.

Timosaponin AIII (TAIII) is a steroidal saponin isolated from Anemarrhena asphodeloides that has been shown to inhibit cell growth and induce apoptosis in cancer. However, the effect of TAIII on acute myeloid leukemia (AML) remains unclear. Here, the molecular mechanism by which TAIII-induced apoptosis affects human AML cells was investigated. The results showed that TAIII significantly inhibited cell proliferation of four AML cell lines (MV4-11, U937, THP-1, and HL-60). Furthermore, TAIII induced apoptosis of HL-60 cells through caspase-3, caspase-8, and caspase-9 activations and PARP cleavage in a dose- and time-dependent manner. Moreover, Western blot analysis also showed that TAIII increased phosphorylation of JNK1/2 and p38 MAPK in a dose-dependent manner. Inhibition of JNK1/2 by specific inhibitors significantly abolished the TAIII-induced activation of the caspase-8. Taken together, our results suggest that TAIII induces HL-60 cell apoptosis through JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.

A 67-year-old man with a biopsy proving prostate diffuse large B-cell lymphoma was referred for an F-FDG PET/CT scan for postchemotherapy treatment monitoring. The FDG PET/CT scan revealed a significant reduction of prostate lymphoma and a prostatorectal fistula formation. The patient developed Klebsiella pneumoniae sepsis, and a follow-up FDG PET/CT 3 months later revealed multifocal lung, bone, and muscle infection. The FDG PET/CT scans of this patient not only demonstrated the effectiveness of chemotherapy for prostate lymphoma but also the complications of a prostatorectal fistula and multiple infectious foci.

Intercellular adhesion molecule (ICAM)-1, a cell adhesion molecule, is reportedly overexpressed in several cancers and may contribute to tumorgenesis and metastasis. The current study explored the effect of ICAM-1 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. A total of 558 participants, including 279 healthy people and 279 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms of the ICAM-1 gene were assessed by a real-time polymerase chain reaction with the TaqMan assay. After adjusting for other covariants, the individuals carrying at least one G allele at ICAM-1 rs5498 had a 1.603-fold risk of developing UCC than did wild-type (AA) carriers. Furthermore, UCC patients who carried at least one G allele at rs5498 had a higher invasive stage risk (p

Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK-Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-κB, as well as the binding ability of NF-κB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent.

Background Avulsion of the aortic valve commissure as a cause of acute aortic valve regurgitation is mostly due to trauma, infective endocarditis, or ascending aortic dissection. Nontraumatic avulsion of the aortic valve commissure is very rare. We reviewed the literature and analyzed potential risk factors of nontraumatic avulsion. Case presentation An 80-year-old male with hypertension was seen in the emergency department with acute onset dyspnea. Echocardiogram revealed left ventricular hypertrophy with adequate systolic function, prolapse of the noncoronary cusp, and incomplete coaptation of the right coronary and noncoronary cusps with severe aortic valve regurgitation. Surgery revealed an avulsion between the left coronary and noncoronary cusps. Histopathology examination of the aortic valve showed myxoid degeneration, fibrosis, and calcification. Examination of the ascending aorta revealed myxoid degeneration and fragmentation of elastic fibers. Aortic valve replacement was performed, and the patient was alive and well 4 years after surgery. A review of the literature showed that more than three-fourths of the similar cases occurred in males, and about half in patients with hypertension and those 60 years of age or older. Conclusions In the case of acute aortic regurgitation without a history of trauma, infection, or valvotomy, when 2 prolapsed aortic cusps are observed by echocardiography in the absence of an intimal tear of the ascending aorta, an avulsion of the aortic commissure should be suspected, especially in males with hypertension who are 60 years of age or older.

The aim of this study was to examine the plasma level changes of soluble Axl (sAxl) prior to and following treatment with antibiotics in hospitalized adult patients with community-acquired pneumonia (CAP), and to investigate the correlating clinical and laboratory manifestations of CAP with plasma sAxl levels. Blood samples were obtained from 61 adult CAP patients (prior to and following treatment with antibiotics) and 60 healthy controls in order to measure the plasma concentrations of sAxl using the enzyme-linked immunosorbent assay. The plasma-soluble Axl concentration level was markedly elevated in patients with CAP prior to treatment, compared with the controls, and decreased markedly following treatment. The levels of white blood cells, neutrophils, and C-reactive protein decreased markedly following treatment with antibiotics and did not correlate with the concentration level of sAxl. However, the plasma concentration of sAxl correlated with the severity of CAP with the pneumonia severity index score (r=0.350, P=0.006, n=61), the CURB-65 score (r=0.281, P=0.028, n=61) and the acute physiology and chronic health evaluation II score (r=0.313, P=0.014, n=61). In conclusion, plasma sAxl may be involved in the clinical assessment of the severity of CAP, which may guide the development of treatment strategies and predict the clinical outcome.

Acute motor axonal neuropathy (AMAN), a variant of Guillain Barre syndrome (GBS), is frequently induced by the antecedent infection of some atypical pathogen, such as Campylobacter jejuni, Mycoplasma pneumonia and some virus. It is generally accepted that corticosteroids and immunosuppressants are not recommended in patients with GBS including AMAN. However, if systemic autoimmune reaction developed, the principle of management might be changed.We report a young man who rapidly developed acute motor axonal neuropathy. Although plasma exchange had been given, the violent immunological reaction was unable to be controlled, prolonged leukemoid reaction and high level of autoimmunological titers, including C-reactive protein (CRP), rheumatoid factor (Rf), and antineutrophil cytoplasmic autoantibody (ANCA) persisted. Consequently, two months later, this patient developed acute respiratory distress syndrome (ARDS) and type 3 of rapidly progressive glomerulonephritis (RPGN) with rapid decline of renal function until immunosuppressants were given.AMAN combined with the violent systemic autoimmune reaction strongly indicated an uneven disease course and implied that only standard plasmapheresis is not sufficient and corticosteroids with immunosuppressant should be added in early stage.

BACKGROUND: The aim of this study was to investigate the differential plasma levels of lipocalin 2 (LCN2) and its complex with MMP‐9 (where MMP is matrix metalloproteinase) before and after antibiotic treatment in hospitalized adult patients with community‐acquired pneumonia (CAP). METHOD: Plasma LCN2 and LCN2/MMP‐9 complex levels were measured in 61 adult patients with CAP and 60 healthy controls using commercial enzyme‐linked immunosorbent assay (ELISA). RESULTS: A decrease in the number of white blood cells (WBCs) and neutrophils and decreases in the levels of C‐reactive protein (CRP), LCN2, and LCN2/MMP‐9 complex were observed after antibiotic treatment. The plasma level of LCN2, but not that of CRP, was correlated with the severity of CAP based on the Pneumonia Severity Index (PSI; r = 0.333, P = 0.009), confusion, urea, respiratory rate and blood pressure (CURB)‐65 (r = 0.288, P = 0.024), and Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (r = 0.328, P = 0.010). LCN2 levels were also significantly correlated with LCN2/MMP‐9 levels and the numbers of WBCs or neutrophils. CONCLUSIONS: Plasma levels of LCN2 and the LCN2/MMP‐9 complex can act as adjuvant diagnostic biomarkers for CAP. Plasma LCN2 might play a further role in the clinical assessment of the severity of CAP, which could potentially guide the development of future treatment strategies.

After bathing at a hot spring resort, a 75-year-old man presented to the emergency department because of seizure-like attack with loss of conscious. This is the first case of primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri in Taiwan. PAM was diagnosed based on detection of actively motile trophozoites in cerebrospinal fluid using a wet-mount smear and the Liu's stain. The amoebae were further confirmed by PCR and gene sequencing. In spite of administering amphotericin B treatment, the patient died 25 days later.

The aim of this study was to examine the potential associations of two hypoxia inducible factor-1alpha (HIF-1alpha) gene polymorphisms, C1772T and G1790A, with the susceptibility and clinicopathological status of hepatocellular carcinoma.A total of 449 subjects, including 347 healthy controls and 102 patients with hepatocellular carcinoma, were recruited in this study and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses to estimate the impact of these two polymorphic variants on hepatocellular carcinoma.G1790A heterozygotes showed a higher risk for hepatocellular carcinoma, compared with GG genotypes after adjusting for other confounders (AOR = 3.97; 95%CI = 1.70-9.22), indicating a significant association between hepatocellular carcinoma susceptibility and G1790A polymorphism. Moreover, results also revealed the presence of synergistic effect between gene polymorphism of HIF-1alpha G1790A and environmental risk factors, such as tobacco and alcohol consumptions while there was no significant association between HIF-1alpha gene polymorphism and clinicopathological parameters of hepatocellular carcinoma.Genetic polymorphism at G1790A of HIF-1alpha is an important factor for determining the susceptibility to hepatocellular carcinoma. The interaction effects of G1790A heterozygotes to tobacco and to alcohol consumption significantly increase the risk to develop hepatocellular carcinoma.

Both epigenetic and genetic alternations are involved in cancer formation. In this study, we have identified the methylation frequency of p16 and endothelin receptor type B (EDNRB) of 26 leukemia patients and 8 randomly selected normal blood donors in Taiwan. Promoter methylation of p16 was detected in 85% of acute lymphocytic leukemia (ALL), 83% in acute myeloid leukemia (AML) whereas no methylation was detected in chronic myeloid leukemia (CML) in blast crisis. Hypermethylation of EDNRB was observed in 92% of ALL, 75% AML and 100% in CML in blast crisis. No aberrant methylation of p16 and EDNRB was found in 8 normal blood donors. Taken together, aberrant methylation of p16 and EDNRB was highly prevalent in leukemia patients in Taiwan.

[Graphic][1] Introduction and Aims : Recent reports demonstrated the importance of early molecular response (EMR) in chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors. However, there were rare reports focusing on the clinical outcomes if patients did not meet EMR at 3 months but achieved optimal response later. We aimed to compare the cumulative incidence (CI) of major molecular response (MMR), MR4.5, and progression-free survival (PFS) and overall survival (OS) in front-line imatinib (IM)-treated CML-CP patients who achieved EMR at 3 months with those who achieved optimal response later on at 6 or 12 months. Methods: Newly diagnosed CML-CP patients enrolled in Taiwan CML Study from Jun-2004 to Jun-2013 who had available BCR-ABL1 levels at 3, 6, or 12 months and had been followed for at least 12 months were included. Peripheral blood BCR-ABL1 levels were measured every 3 months by RQ-PCR assay expressed as International Scale (IS) in a central laboratory. Patients were divided according to the IS levels: Group I (IS ≤ 10% at 3 months), Group II (IS > 10% at 3 months, but IS ≤ 1% at 6 months), Group III (IS >10% at 3 months, IS >1% at 6 months, but IS ≤ 0.1% at 12M), and Group IV (IS > 10% at 3 months, IS > 1 % at 6 months, and IS > 1% at 12 months). CI of MMR, MR4.5, disease progression, PFS and OS were compared between Group I and other group. Results: Four hundred and twenty-five newly diagnosed CML-CP patients (males 255), with a median age of 45.6 years and median follow-up time of 45.6 months, were included. In total, 250 patients achieved MMR (58.9%, median time to MMR 12.7 months) and 107 patients achieved MR4.5 (25.2%, median time to MR4.5 31.5 months). Accelerated phase (AP, N=10)/Blastic crisis (BC, N=12) occurred in 22 (5.2%) patients with 7 acute lymphoblastic leukemia (ALL)-BC and 5 acute myeloid leukemia (AML)-BC. Four of 7 patients with ALL-BC occurred within 6 months (1.8, 2.3, 3.4, and 4.8 months, respectively). The median time from IM treatment to ALL-BC was 4.6 months (range 1.8 - 35.6 months) which occurred more rapidly than patients with AML-BC (22.9 months, range 14.9 - 43.0 months). CML-related death occurred in 12 (2.8%) patients. Two hundred and thirty-five patients were classified as Group I, 38 Group II, 24 Group III, and 128 Group IV. Outcomes following IM treatment according to group stratification are summarized in Table 1. Group IV patients had a higher incidence of disease progression than Group I ( P 10% | ≤ 1% | - | 38 ( 9.0) | 0 ( 0.0) | 88.3% | 34.8% | 100% | 100% | | III | >10% | >1% | ≤ 0.1% | 24 (5.6) | 0 ( 0.0) | 100% | 20.5% | 100% | 100% | | IV | >10% | >1% | >1% | 128 (30.1) | 19 (14.8) | 15.2% | 5.7% | 73.1% | 80.5% | | P -value: I vs. II | 1.000 | 0.884 | 0.455 | 0.469 | 0.702 | | P -value: I vs. III | 1.000 | 0.614 | 0.015 | 0.564 | 0.794 | | P -value: I vs. IV | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | Abstract 4544. Table 1. Clinical outcomes of CML patients treated with front-line IM according to the group stratification by BCR/ABL1 transcript levels at 3, 6, or 12 months MMR: major molecular response; PFS: progression-free survival; OS: overall survival. Grant support: XMRPG1A0083 Disclosures No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif

Background Pterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated. Methodology and Principal Findings Results showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B. Conclusion Taken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.

BACKGROUND: Glabridin, a prenylated isoflavonoid of G. glabra L. roots, has been associated with a wide range of biological properties such as regulation of energy metabolism, estrogenic, neuroprotective, anti-osteoporotic, and skin-whitening in previous studies. However, the effect of glabridin on tumor cells metastasis has not been clearly clarified. Here, the molecular mechanism by which glabridin anticancer effects in human promyelocytic leukemia cells was investigated. METHODOLOGY AND PRINCIPAL FINDINGS: The results showed that glabridin significantly inhibited cell proliferation of four AML cell lines (HL-60, MV4-11, U937, and THP-1). Furthermore, glabridin induced apoptosis of HL-60 cells through caspases-3, -8, and -9 activations and PARP cleavage in dose- and time-dependent manner. Moreover, western blot analysis also showed that glabridin increase phosphorylation of ERK1/2, p38 MAPK and JNK1/2 in dose- and time-dependent manner. Inhibition of p38 MAPK and JNK1/2 by specific inhibitors significantly abolished the glabridin-induced activation of the caspase-3, -8 and -9. CONCLUSION: Taken together, our results suggest that glabridin induced HL-60 cell apoptosis through p38 MAPK and JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.

Background The enhancer of zeste 2 (EZH2) gene encodes the histone methyltransferase that is the catalytic component of the polycomb repressive complex-2, which initiates epigenetic silencing of genes. The expression level of EZH2 in hepatocellular carcinoma (HCC) is highly correlated with tumor progression; however, it has not been determined if specific EZH2 genetic variants are associated with the risk of HCC. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with HCC susceptibility and its clinicopathologic characteristics. Methodology/Principal Findings A total of 220 HCC patients and 552 cancer-free controls were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, the individuals carrying at least one C allele at EZH2 rs6950683 and rs3757441 had a 0.611-fold and a 0.660-fold lower risk of developing HCC than did wild-type (TT) carriers, respectively. The CCCA or CCTA haplotype among the four EZH2 sites (rs6950683, rs2302427, rs3757441, and rs41277434), respectively, was also associated with a reduced risk of HCC. Furthermore, HCC patients who carried at least one C allele at rs6950683 or rs3757441 had a higher lymph–node-metastasis risk but a lower liver-cirrhosis risk than did patients carrying the wild-type allele. Conclusions The rs6950683 and rs3757441 polymorphic genotypes of EZH2 might contribute to the prediction of susceptibility to and pathological development of HCC. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of HCC in Taiwan.

Abstract 3620 Background: Deferasirox (DFX) was recently found to have anti-leukemia effect both in vitro and in vivo. DFX can also potently inhibit the generation of intracellular reactive oxygen species (ROS). On the other hand, the generation of ROS by Doxorubicin (DOX) is critical for the cytotoxicity on both leukemia and normal heart cells. It is not known whether combining DFX and DOX will have synergistic or antagonizing effect on leukemic cells. Similarly, it is also unknown whether adding DFX to DOX will have protective effect on normal heart cell. Method: Cells of human acute myeloid leukemia (AML) cell line THP1, mice AML cell line WEHI3, and rat normal heart cell line H9C2 were treated with Doxorubicin 5microM for various duration in the presence of absence of DFX pretreatment (100microM for 10 minutes). Intracellular ROS generation was measured by the detection of 2,7-dichlorodihydrofluorescein (DCF) fluorescence intensity using flow cytometry. Apoptosis was determined by Annexin V-Propidium Iodide staining using flow cytometry. Cytotoxicity was determined by Trypan blue exclusion assay. Results: Although intracellular ROS was reduced, DFX alone induced apoptosis of THP1 (from 3% to 18%) and WEHI3 (from 31% to 49%) AML cells. DOX-induced ROS production was also significantly reduced when THP1, WEHI3, and H9C2 cells were pretreated with DFX (Figure 1a, 1b, 1c respectively). However, the DOX-induced apoptosis of THP1 and WEHI3 AML cells were not antagonized by DFX (Figure 2a). 24 hours after exposure to this physiological dose DOX, all the WEHI3 cells died in both DFX treated or untreated group (figure 2b). More importantly, DFX-pretreated H9C2 heart cells had fewer cell death (3.7%) after exposure to DOX (5microM for 24 hours) compared to non-DFX pretreated cells (8.5%). Conclusions: DFX alone induced apoptosis in two different AML cell lines. DFX also markedly reduced the ROS generation due to DOX treatment. However, DFX did not negatively influence the pro-apoptotic and cytotoxic effect of DOX on these AML cell lines. Interestingly, DFX also markedly reduced the DOX-induced ROS generation and DOX-induced cell death in normal rat heart cell, which might have protective effect on DOX-related cardiomyopathy. We are now using Balb/c-WEHI3 AML mice model to test whether DFX can protect cardiomyocytes from DOX-related damage while maintain the cytotoxic effect of DOX on AML cells. Disclosures: No relevant conflicts of interest to declare.

A 67-year-old woman presented with a history of dilated cardiomyopathy with congestive heart failure since 2003, who subsequently developed lower rectal cancer (adenocarcinoma) with liver, bone, and lymph node metastasis. Abdominoperineal resection and hepatectomy were performed. The patient received two rounds of intravenous chemotherapy, including 12 and six courses of FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin; 85 mg/m2 per cycle). She underwent a third round of intravenous FOLFOX4 because of tumor progression. During the 21st course of FOLFOX4 regimen, the patient developed ST segment depression in lead II and prolongation of QT interval with polymorphic ventricular tachycardia, torsades de pointes right after the start of oxaliplatin infusion. Immediate defibrillation and cardiopulmonary resuscitation were administered, and the patient regained spontaneous circulation and consciousness. Twelve-lead electrocardiogram showed ST segment elevation in III, aVF, and ST segment depression in V4–6 after resuscitation. To our knowledge, prolongation of QT interval with torsades de pointes and coronary spasm with myocardial injury that were stabilized in one patient following oxaliplatin infusion has not been reported. We present a patient with these rare complications.