A Randomized Phase III Study of Patients With Advanced Gastric Adenocarcinoma Without Progression After Six Cycles of XELOX (Capecitabine Plus Oxaliplatin) Followed by Capecitabine Maintenance or Clinical Observation

Purpose@#Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. @*Materials and Methods@#Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. @*Results@#Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250–0.890; P=0.020). @*Conclusions@#After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS.

Efficacy of the granisetron transdermal system for the control of nausea and vomiting induced by highly emetogenic chemotherapy: a multicenter, randomized, controlled trial

Background/Aims@#We compared the efficacy of the granisetron transdermal system (GTS) with that of ondansetron for controlling chemotherapy-induced nausea and vomiting (CINV) in patients treated with highly emetogenic chemotherapy (HEC). @*Methods@#We randomized a total of 389 patients to groups treated by GTS and ondansetron before HEC. The primary endpoint was the percentage of patients achieving complete response (CR; no retching/vomiting/rescue medication) of CINV from the time of chemotherapy initiation to 24 hours after the last administration of chemotherapy (prespecified non-inferiority margin of 15%). Quality of life (QoL) was also assessed using the Functional Living Index-Emesis (FLIE). @*Results@#The per protocol analysis included 152 (47.80%) and 166 patients (52.20%) in the GTS and ondansetron groups, respectively. In the full analysis set, the most common diagnosis, regimen, and period of chemotherapy were lung cancer (149 patients, 40.27%), cisplatin-based regimen (297 patients, 80.27%), and 1 day chemotherapy (221 patients, 59.73%). The CR rates were 86.84% and 90.36% in the GTS and ondansetron groups, respectively; the treatment difference was −3.52% (95% confidence interval, −10.52 to 3.48) and met the primary endpoint, indicating that GTS was not inferior to ondansetron. Patient satisfaction, assessed on the FLIE, showed significantly higher scores in the GTS group compared to the ondansetron group (mean ± standard deviation, 1,547.38 ± 306.00 and 1,494.07 ± 312.05 mm, respectively; p = 0.0449). @*Conclusions@#GTS provided effective, safe, and well-tolerated control of CINV and improved the QoL in HEC.

Experience of serious intestinal hemorrhage and perforation in small bowel lymphoma: a case report

There have been several reports of complications of small bowel lymphoma, such as bleeding, obstruction, and perforation, often require emergency surgery. It is hardly showed complications of bleeding and wound dehiscence for diffuse large B cell lymphoma with distal ileum involvement, which needed urgent surgery and medical management. A 65-year-old man with diffuse large B-cell lymphoma with distal ileum involvement experienced both intestinal bleeding and perforation during the course of treatment. As the patient was diagnosed with stage III disease, resection before chemotherapy was not considered due to the resulting delay in chemotherapy, which necessitated sufficient tissue healing. Chemotherapy is important when treating small bowel lymphoma, complications such as bleeding and perforation should always be considered for the treatment of small bowel lymphoma, and surgery is necessary in this situation. After surgery of the small bowel, subsequent chemotherapy could cause wound dehiscence and perforation; therefore, adequate recovery time should be given before chemotherapy.

Intracerebral Hemorrhage due to Thrombosis with Thrombocytopenia Syndrome after Vaccination against COVID-19: the First Fatal Case in Korea

Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4). This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein. Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis. A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination. He developed severe headache with vomiting 9 days after the vaccination. Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage.Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzymelinked immunosorbent assay antibody test was reported to be strongly positive. Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination. Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients. Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis.

Intracerebral Hemorrhage due to Thrombosis with Thrombocytopenia Syndrome after Vaccination against COVID-19: the First Fatal Case in Korea

Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4). This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein. Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis. A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination. He developed severe headache with vomiting 9 days after the vaccination. Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage.Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzymelinked immunosorbent assay antibody test was reported to be strongly positive. Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination. Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients. Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis.

Multicenter Retrospective Analysis of Clinical Characteristics, Treatment Patterns, and Outcomes in Very Elderly Patients with Diffuse Large B-Cell Lymphoma: The Korean Cancer Study Group LY16-01 / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The treatment strategy for elderly patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) has not been established because of poor treatment tolerability and lack of data. MATERIALS AND METHODS: This multicenter retrospective study was conducted to investigate clinical characteristics, treatment patterns and outcomes of patients older than 80 years who were diagnosed with DLBCL at 19 institutions in Korea between 2005 and 2016. RESULTS: A total of 194 patients were identified (median age, 83.3 years). Of these, 114 patients had an age-adjusted International Prognostic Index (aaIPI) score of 2-3 and 48 had a Charlson index score of 4 or more. R-CHOP was given in 124 cases, R-CVP in 13 cases, other chemotherapy in 17 cases, radiation alone in nine cases, and surgery alone in two cases. Twenty-nine patients did not undergo any treatment. The median number of chemotherapy cycles was three. Only 37 patients completed the planned treatment cycles. The overall response rate from 105 evaluable patients was 90.5% (complete response, 41.9%). Twentynine patients died due to treatment-related toxicities (TRT). Thirteen patients died due to TRT after the first cycle. Median overall survival was 14.0 months. The main causes of death were disease progression (30.8%) and TRT (27.1%). In multivariate analysis, overall survival was affected by aaIPI, hypoalbuminemia, elevated creatinine, and treatment. CONCLUSION: Age itself should not be a contraindication to treatment. However, since elderly patients show higher rates of TRT due to infection, careful monitoring and dose modification of chemotherapeutic agents is needed.

Genetic–pathologic characterization of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P<0.001), an increase in chromosomal abnormalities (P<0.001) and a poor prognosis (P<0.001). Moreover, among patients with overt fibrosis, all patients with wild-type JAK2/CALR/MPL (triple-negative) showed genomic alterations by genome-wide microarray study and revealed the poorest overall survival, followed by JAK2-mutated MPNs. The genetic–pathologic characteristics provided the information for understanding disease pathogenesis and the progression of MPNs. The prognostic significance of the driver mutation and BM fibrosis suggests the necessity of a prospective therapeutic strategy to improve the clinical outcome.

Patient's Factors at Entering Hospice Affecting Length of Survival in a Hospice Center / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: In order to provide effective hospice care, adequate length of survival (LOS) in hospice is necessary. However the reported average LOS is much shorter. Analysis of LOS in hospice has not been reported from Korea. We evaluated the duration of LOS and the factors associated with LOS at our hospice center. MATERIALS AND METHODS: We retrospectively examined 446 patients who were admitted to our hospice unit between January 2010 and December 2012. We performed univariate and multivariate analysis for analysis of factors associated with LOS. RESULTS: The median LOS was 9.5 days (range, 1 to 186 days). The LOS of 389 patients (86.8%) was< 1 month. At the time of admission to hospice, 112 patients (25.2%) were completely bedridden, 110 patients (24.8%) had mouth care only without intake, and 134 patients (30.1%) had decreased consciousness, from confusion to coma. The median time interval between the day of the last anticancer treatment and the day of hospice admission was 75 days. By analysis of the results of multivariate analysis, decreased intake and laboratory results showing increased total white blood cell (WBC), decreased platelet count, increased serum creatinine, increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) level were poor prognostic factors for survival in hospice. CONCLUSION: Before hospice admission, careful evaluation of the patient's performance, particularly the oral intake, and total WBC, platelet, creatinine, AST, ALT, and LDH level is essential, because these were strong predictors of shorter LOS. In the future, conduct of prospective controlled studies is warranted in order to confirm the relationship between potential prognostic factors and LOS in hospice.

HPV-Related Retroperitoneal Squamous Cell Carcinoma of Unknown Primary: A Case Report / Journal of the Korean Cancer Association, 대한암학회지

A 56-year-old female was referred to our hospital due to a mass measuring 5 cm in size in the left pelvic cavity, which was found incidentally during a health examination by ultrasonography. Exploratory laparotomy was performed and the mass was located at the left retroperitoneal parametrium without invasion of the uterus and ovary. The pathology report confirmed squamous cell carcinoma. Even after further studies, we did not find any other primary lesion. Human papillomavirus (HPV) DNA chip test (HPV 9G DNA Membrane Kit, Biometrixtechnology Inc.) showed that the surgical specimen was positive for HPV 18. She received adjuvant chemotherapy and would receive radiation therapy for the possibility of occult gynecologic cancer. Retroperitoneal squamous cell carcinoma of unknown primary is extremely rare and little is known about it. It is reported that HPV may be associated with the disease. Hence, the result of HPV test could have an impact on finding a suspicious primary lesion and treatment modality in this case.

Clinical characteristics and treatment outcome of acute myeloid leukemia in elderly patients in Korea: a retrospective analysis

BACKGROUND: The clinical characteristics of elderly patients with AML differ from those of younger patients, resulting in poorer survival and treatment outcomes. We analyzed retrospectively the clinical data of AML patients 65 years old and above to describe patients' characteristics and treatment patterns, and to define meaningful prognostic factors of survival in the Korean population. METHODS: Basic patients' characteristics, clinical outcomes according to treatments, and prognostic factors associated with survival and treatment intensity were examined in a total of 168 patients diagnosed in 5 institutes between 1996 and 2012 as having AML. RESULTS: Herein, 84 patients (50.0%) received high-intensity regimens (HIR), 18 (10.7%) received low-intensity regimens (LIR), and 66 (39.3%) received supportive care (SC) only. The median survival of all patients was 4.5 months; and median survival times with HIR, LIR, and SC were 6.8 months, 10.2 months, and 1.6 months, respectively. Median survival times with HIR and LIR were significantly longer than that with SC (P<0.0001 and P=0.006, respectively). Multivariate analysis identified age, Eastern Cooperative Oncology Group-performance status (ECOG-PS), hemoglobin (Hb) level, and serum creatinine (Cr) level as statistically significant prognostic factors for survival. In the HIR group, prognostic factors for survival were ECOG-PS, Hb level, and C-reactive protein level. CONCLUSION: Even in elderly AML patients, an intensive treatment regimen could be beneficial with careful patient selection. Further prospective studies designed to identify specific prognostic factors are required to establish an optimal treatment strategy for elderly AML patients.

The prevalence and clinical characteristics of cancer among anemia patients treated at an outpatient clinic

BACKGROUND: Anemia is the most common hematologic condition encountered in outpatient clinics. It is often overlooked because it is common among patients; however, anemia is one of the leading indicators of cancer. This study examined the prevalence and characteristics of cancer among anemia patients who visited an outpatient clinic. METHODS: The data were collected by reviewing the records of an outpatient clinic from January 2007 to December 2011. RESULTS: In total, 502 patients (52 males, 450 females) were diagnosed with anemia. Cancer prevalence among anemia patients was 5.57% (25.0%, men; 3.3%, women); further, the most frequently diagnosed cancer was colorectal cancer (22.5%), followed by advanced gastric cancer (16.1%), breast cancer (9.6%), myelodysplastic syndrome (9.6%), cervical cancer (6.4%), renal-cell carcinoma (6.4%), and thyroid cancer (6.4%). The prevalence of cancer was 4.1% in those aged 40-49 years, 4.2% in the subjects in their fifties, 8.0% in those in their sixties, 21.6% in those in their seventies, and 55.6% in those aged over 80 years. The cancer prevalence among iron deficiency anemia (IDA) patients was 6.18% (28.8%, men; 3.5%, women). The cancer prevalence in postmenopausal and premenopausal female IDA patients was 16.0% and 1.6%, respectively. CONCLUSION: Among anemia patients, male patients aged over 40 years and female patients aged over 60 years, along with postmenopausal female patients, were more likely to be diagnosed with cancer. Consequently, male IDA patients, and female patients aged over 60 years must be carefully evaluated for the possibility of malignancy.

The prevalence and clinical characteristics of cancer among anemia patients treated at an outpatient clinic

BACKGROUND: Anemia is the most common hematologic condition encountered in outpatient clinics. It is often overlooked because it is common among patients; however, anemia is one of the leading indicators of cancer. This study examined the prevalence and characteristics of cancer among anemia patients who visited an outpatient clinic. METHODS: The data were collected by reviewing the records of an outpatient clinic from January 2007 to December 2011. RESULTS: In total, 502 patients (52 males, 450 females) were diagnosed with anemia. Cancer prevalence among anemia patients was 5.57% (25.0%, men; 3.3%, women); further, the most frequently diagnosed cancer was colorectal cancer (22.5%), followed by advanced gastric cancer (16.1%), breast cancer (9.6%), myelodysplastic syndrome (9.6%), cervical cancer (6.4%), renal-cell carcinoma (6.4%), and thyroid cancer (6.4%). The prevalence of cancer was 4.1% in those aged 40-49 years, 4.2% in the subjects in their fifties, 8.0% in those in their sixties, 21.6% in those in their seventies, and 55.6% in those aged over 80 years. The cancer prevalence among iron deficiency anemia (IDA) patients was 6.18% (28.8%, men; 3.5%, women). The cancer prevalence in postmenopausal and premenopausal female IDA patients was 16.0% and 1.6%, respectively. CONCLUSION: Among anemia patients, male patients aged over 40 years and female patients aged over 60 years, along with postmenopausal female patients, were more likely to be diagnosed with cancer. Consequently, male IDA patients, and female patients aged over 60 years must be carefully evaluated for the possibility of malignancy.

Evidence-based Guidelines for Empirical Therapy of Neutropenic Fever in Korea

Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3 5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers.

Randomized, Multicenter, Phase III Trial of Heptaplatin 1-hour Infusion and 5-Fluorouracil Combination Chemotherapy Comparing with Cisplatin and 5-Fluorouracil Combination Chemotherapy in Patients with Advanced Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Heptaplatin (Sunpla) is a cisplatin derivative. A phase IIb trial using heptaplatin resulted in a 34% response rate with mild nephrotoxicity. We conducted a randomized phase III trial of heptaplatin plus 5-FU compared with cisplatin plus 5-FU in patients with advanced gastric cancer. MATERIALS AND METHODS: One hundred seventy-four patients (heptaplatin, n=88; cisplatin, n=86) from 13 centers were enrolled. The eligibility criteria were as follows: patients with pathologically-proven adenocarcinoma, chemonaive patients, or patients who had received only single adjuvant chemotherapy, and who had a measurable or evaluable lesion. On day 1, heptaplatin (400 mg/m2) or cisplatin (60 mg/m2) was given over 1 hour with 5-FU (1 gm/m2) on days 1~5 every 4 weeks. RESULTS: At the time of survival analysis, the median overall survival was 7.3 months in the 5-FU + heptaplatin (FH) arm and 7.9 months in the 5-FU + cisplatin (FP) arm (p=0.24). Of the FH patients, 34.2% (complete response [CR], 1.3%; partial response [PR], 32.9%) experienced a confirmed objective response compared with 35.9% (CR 0%, PR 35.9%) of FP patients (p=0.78). The median-time-to-progression was 2.5 months in the FH arm and 2.3 months in the FP arm. The incidence of neutropenia was higher with FP (28%) than with FH (16%; p=0.06); grade 3~4 nausea and vomiting were more frequent in the FP than in the FH arm (p=0.01 and p=0.05, respectively). The incidence of increased proteinuria and creatininemia was higher with FH than with FP; however, there was no statistical difference. There were no treatment-related deaths. CONCLUSION: Heptaplatin showed similar effects to cisplatin when combined with 5-FU in advanced gastric cancer patients with tolerable toxicities.

Hereditary Hemolytic Anemia in Korea: a Retrospective Study from 1997 to 2006 / 대한혈액학회지

BACKGROUND: The aim of this study was to investigate the prevalence, clinical and laboratory findings of hereditary hemolytic anemia (HHA) in Korea from 1997 to 2006 and to develop the appropriate diagnostic approach for HHA. METHODS: By the use of questionnaires, information on the clinical and laboratory findings ofHHA diagnosed from 1997 to 2006 in Korea was collected and analyzed retrospectively. A total of 431 cases were enrolled in this study from 46 departments of 35 hospitals. RESULTS: The overall frequency of HHA did not change through the 10-year period for pediatrics but did show an increasing tendency for internal medicine. The overall male to female sex ratio did not show sex predominance (1.17:1), but a significant male predominance with a ratio of 1.49:1 was seen for pediatrics while a significant female predominance with a ratio of 1:1.97 was seen forinternal medicine. Of the total cases, 74.2% (282/431) were diagnosed before the age of 15 years. The etiologies of HHA were classified as red cell membrane defects, hemoglobinopathies, red cell enzyme deficiencies and unknown causes. There were 382 cases (88.6%) of red cell membrane defects with 376 cases (87.2%) of hereditary spherocytosis and 6 cases (1.4%) of hereditary elliptocytosis, 20 cases (4.6%) of hemoglobinopathies with 18 cases (4.2%) of beta-thalassemia, a case (0.2%) of alpha-thalassemia and a case (0.2%) of Hemoglobin Madrid, 7 cases (1.6%) of red cell enzyme deficiencies with 5 cases (1.2%) of glucose-6- phosphate dehydrogenase (G-6-PD) deficiency, a case (0.2%) of pyruvate kinase (PK) deficiency and a case (0.2%) of enolase deficiency, and 22 cases (5.1%) of unknown causes. The most common chief complaint in pediatric patients was pallor and that in adult patients was jaundice. In the red cell membrane defect group of patients, the level of hemoglobin was significantly higher than in adult patients. The mean corpuscular volume, mean corpuscular hemoglobin, corrected reticulocyte count, total and indirect bilirubin level and lactate dehydrogenase levels in the hemoglobinopathy group of patients were significantly lower than the values in the red cell membrane defect group of patients. The mean concentration of G-6-PD was 0.8+/-0.7U/1012RBC in the G-6-PD deficient patients, PK was 1.7U/1010 RBC in the PK deficient patient, and the level of enolase was 0.04U/g of Hb in the enolase deficient patient. CONCLUSION: The most prevalent cause of HHA in Korea during 1997 to 2006 was hereditary spherocytosis, but HHA by other causes such as hemoglobinopathy and red cell enzyme deficiency gradually increased with the development of molecular diagnostic methods and increasing general interest. However, the etiologies of HHA need to be pursued further in 5.1% of the patients. An systematic standard diagnostic approach is needed in a nationwide prospective study for correct diagnoses and appropriate management of HHA.

The Effect of Auranofin on Thrombomodulin Expression in Acute Promyelocytic Leukemia Cell / 대한혈액학회지

BACKGROUND: Acute promyelocytic leukemia (APL) is distinguished from other forms of leukemia by its association with bleeding diatheses. All-trans retinoic acid (ATRA) and arsenic trioxide (As2O3), which have been effectively used in the treatment of the APL, promptly improve coagulation/bleeding syndromes by regulating the expressions of tissue factor (TF) and thrombomodulin (TM). We have previously shown a novel activity of auranofin (AF), in that it induced apoptosis and differentiation of NB4 cells. To study whether AF also possesses similar anticoagulant effects to those of ATRA and As2O3, its effects on the expressions of TM and TF were investigated. METHODS: NB4 cells derived from APL were incubated with 1 micrometer of AF. After incubation for 12, 24 and 48 hours, the AF-regulated expressions of TM and TF were analyzed by RT-PCR, Northern blot and Western blot. The assay for the TM antigen on the cell surface was performed using a flow cytometry. RESULTS: The expression of the TM gene was increased for upto 12 hours after the AF treatment, but no change was observed in the expression of the TF gene. Western blot analysis also demonstrated that AF increased the level of TM proteinin a time-dependent manner. FACS data showed the TM antigen on the cell surface to gradually increase for upto 48 hours in AF-treated cells. CONCLUSION: The results of this study indicate that AF can have an antithrombotic function via the up-regulation of the expression of TM, which suggests it may partially contribute to the improvement of coagulopathies in APL.

Eugenol Induces a Reactive Oxygen Species-mediated Apoptosis in HL-60 Human Promyelocytic Leukemia Cells / 대한혈액학회지

BACKGROUND: Eugenol is a major component of the essential oil isolated from Eugenia caryophyllata (Myrtaceae), and has been widely used as a traditional medicine. In this study, the effects of eugenol on the cytotoxicity, induction of apoptosis and putative pathways of its actions were investigated in human promyelocytic leukemia cells (HL-60). METHODS: After applying eugenol to cultured HL-60, the changes in the mitochondrial membrane potential of the cells were monitored after double staining with propidium iodide and rhodamine 123, with 2', 7'-dicholorofluorescin diacetate was used to measure of levels of reactive oxygen species (ROS) RESULTS: Eugenol was shown to be a potent inducer of apoptosis; transducing the apoptotic signal via ROS generation; thereby, inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. The production of ROS, mitochondrial alteration and subsequent apoptotic cell death in eugenol-treated cells were blocked by the antioxidant, N-acetylcystein (NAC). CONCLUSION: Taken together, the present study has demonstrated that eugenol induces ROS-mediated mitochondrial permeability transition and resultant cytochrome c release.

Distribution of Adenoviral Vector in Brain after Intravenous Administration

The delivery of transgenes to the central nervous system (CNS) can be a valuable tool to treat CNS diseases. Various systems for the delivery to the CNS have been developed; vascular delivery of viral vectors being most recent. Here, we investigated gene transfer to the CNS by intravenous injection of recombinant adenoviral vectors, containing green fluorescence protein (GFP) as a reporter gene. Expression of GFP was first observed 6 days after the gene transfer, peaked at 14 days, and almost diminished after 28 days. The observed expression of GFP in the CNS was highly localized to hippocampal CA regions of cerebral neocortex, inferior colliculus of midbrain, and granular cell and Purkinje cell layers of cerebellum. It is concluded that intravenous delivery of adenoviral vectors can be used for gene delivery to the CNS, and hence the technique could be beneficial to gene therapy.

Effects of Cyclosporin A, FK506, and 3-Deazaadenosine on Acute Graft-versus-host Disease and Survival in Allogeneic Murine Hematopoietic Stem Cell Transplantation

BACKGROUND: We investigated the effect of donor marrow T cell depletion, administration of FK506, cyclosporin A (CSA), and 3-deazaadenosine (DZA) on graft versus host disease (GVHD) after allogeneic murine hematopoietic stem cell transplantation (HSCT). METHODS: We used 4 to 6 week old Balb/c (H-2(d), recipient), and C3H/He (H-2(k), donor) mice. Total body irradiated recipients received 1x10(7) bone marrow cells (BM) and 0.5x10(7) splenocytes of donor under FK506 (36 mg/kg/day), CSA (5 mg/kg/day, 20 mg/kg/day), and DZA (45 mg/kg/day), which were injected intraperitoneally from day 1 to day 14 daily and then three times a week for another 2 weeks. To prevent the GVHD, irradiated Balb/c mice were transplanted with 1x10(7) rotor-off (R/O) cells of donor BM. The severity of GVHD was assessed daily by clinical scoring method. RESULTS: All experimental groups were well grafted after HSCT. Mice in experimental group showed higher GVHD score and more rapid progression of GVHD than the mice with R/O cells (R/O group) (p<0.01). There were relatively low GVHD scores and slow progressions in FK506 and low dose CSAgroups than high dose CSA group (p<0.01). The survival was better in FK506 group than low dose CSA group. All mice treated with CSA died within 12 days after HSCT. The GVHD score in DZA group was low and slow in comparison with control group (p<0.05), but severity and progression were similar with low dose CSA group (p=0.11). All mice without immunosuppressive treatment died within 8 days, but all survived in R/O group (p<0.01). Survival in low dose CSA group was longer than in control group (p<0.05), but in high dose CSA group, survival was similar to control group. The survival benefit in DZA group was similar with low dose CSA group. FK506 group has the best survival benefit than other groups (p<0.01), comparable with R/O group (p=0.18), although probability of survival was 60%. CONCLUSION: We developed lethal GVHD model after allogeneic murine HSCT. In this model, immunosuppressive agents showed survival benefits in prevention of GVHD. DZA showed similar survival benefits to low dose CSA. We propose that DZA can be used as a new immunosuppressive agent to prevent GVHD after allogeneic HSCT.

Induction Chemotherapy for Patients with Acute Myeloid Leukemia Aged over 60 Years / 대한혈액학회지

BACKGROUND: Clinical and biologic characteristics of elderly patients with acute myeloid leukemia (AML) have not been well defined yet and there is no consensus on the appropriate treatment approach. We analyzed the outcome of these patients in terms of complete remission (CR) and the long-term life expectancy. METHODS: Twenty patients received mitoxantrone at the dose range of 4~8 mg/m2/ day for 3 days according to the patients' condition based on age and performance status, low-dose cytosine arabinoside 10mg/m2 subcutaneously at every 12 hours for 10~14 days, and etoposide 100mg/day per os for 10~14 days. Most of patients achieving CR received at least 1~3 more courses of post-remission therapy with same initial regimen. Nine out of 17 patients receiving more than two courses of post-remission chemotherapy received their cryopreserved peripheral bloods stem cells after the second or third consolidation chemotherapy. RESULTS: Overall, CR was achieved in 16 (80%) out of 20 patients and the median CR duration was 6 months (range 2~17 months). The most frequent complication during the induction chemotherapy was pneumonia (55%). CONCLUSION: The induction chemotherapy regimen including mitoxantrone, cytosine arabinoside, and etoposide seems to be promising in elderly AML patients in terms of CR rate, while its duration was short. Hopefully, it is necessary to develop a new post-remission therapy to maintain long-term disease-free survival in elderly AML patients.