Seung Hyun Nam

Early Imatinib Mesylate-Induced Hepatotoxicity in Chronic Myelogenous Leukaemia

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

Validation of the Edmonton Symptom Assessment System in Korean Patients With Cancer

CONTEXT The Edmonton Symptom Assessment System (ESAS) is a brief, widely adopted, multidimensional questionnaire to evaluate patient-reported symptoms. OBJECTIVES To develop a Korean version of the ESAS (K-ESAS) and to perform a psychometric analysis in Korean patients with advanced cancer. METHODS We tested the K-ESAS in two pilot studies with 15 patients each. We assessed internal consistency, test-retest reliability, and concurrent validity in 163 Korean patients, who completed the K-ESAS along with the Korean versions of the M. D. Anderson Symptom Inventory (K-MDASI) and the Hospital Anxiety and Depression Scale (K-HADS) twice. A total of 38 patients completed the questionnaires again seven days later to assess responsiveness. RESULTS The K-ESAS scores had good internal consistency, with a Cronbachs alpha coefficient of 0.88, indicating that no questions had undue influence on the score. Pearson correlation coefficients for K-ESAS symptom scores between baseline and after two to four hours ranged from 0.72 (95% CI 0.64-0.79) to 0.87 (95% CI 0.82-0.90), indicating strong test-retest reliability. For concurrent validity, Pearson correlation coefficients between K-ESAS symptom scores and corresponding K-MDASI symptom scores ranged from 0.70 (95% CI 0.62-0.77) to 0.83 (95% CI 0.77-0.87), indicating good concurrent validity. For the K-HADS, concurrent validity was good for anxiety (r=0.73, 95% CI 0.65-0.79) but moderate for depression (r=0.4, 95% CI 0.26-0.52). For responsiveness, changes in K-ESAS scores after seven days were moderately correlated with changes in K-MDASI scores but weakly correlated with changes in K-HADS scores. CONCLUSION The K-ESAS is a valid and reliable tool for measuring multidimensional symptoms in Korean patients with cancer.

Prevention of Venous Thromboembolism, 2nd Edition: Korean Society of Thrombosis and Hemostasis Evidence-Based Clinical Practice Guidelines

In 2010, we proposed the first Korean Guidelines for the Prevention of Venous Thromboembolism (VTE). It was applicable to Korean patients, by modifying the contents of the second edition of the Japanese guidelines for the prevention of VTE and the 8th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines. From 2007 to 2011, we conducted a nationwide study regarding the incidence of VTE after major surgery using the Health Insurance Review and Assessment Service (HIRA) database. In addition, we have considered the 9th edition of the ACCP Evidenced-Based Clinical Practice Guidelines, published in 2012. It emphasized the importance of clinically relevant events as opposed to asymptomatic outcomes with preferences for both thrombotic and bleeding outcomes. Thus, in the development of the new Korean guidelines, three major points were addressed: 1) the new guidelines stratify patients into 4 risk groups (very low, low, moderate, and high) according to the actual incidence of symptomatic VTE from the HIRA databases; 2) the recommended optimal VTE prophylaxis for each group was modified according to condition-specific thrombotic and bleeding risks; 3) guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and/or physician advice. Graphical Abstract

Varicella-zoster virus-specific cell-mediated immunity and herpes zoster development in multiple myeloma patients receiving bortezomib- or thalidomide-based chemotherapy

BACKGROUND The incidence of herpes zoster is substantial during bortezomib treatment in patients with multiple myeloma (MM). OBJECTIVES This study aimed to elucidate the effect of chemotherapy with or without bortezomib in MM patients on their herpes zoster incidence and varicella zoster virus (VZV)-specific cell-mediated immunity (CMI). STUDY DESIGN Peripheral blood mononuclear cells were collected at baseline and after 1 month of bortezomib-based or thalidomide-based chemotherapy and then analyzed using VZV-specific interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. The clinical data from these patients were analyzed in relation to the ELISPOT results. RESULTS Of 58 patients analyzed, 39 patients received bortezomib and the other 19 patients, thalidomide. Among them, 5 patients developed herpes zoster during chemotherapy; all 5 were being treated with the bortezomib-based regimen and were not receiving prophylactic anti-viral agents. The median onset of herpes zoster was 32 days (range, 15-95 days) from the initiation of chemotherapy. Among patients who received bortezomib therapy, acyclovir prophylaxis significantly reduced the risk for herpes zoster (100-day cumulative incidence, 0% vs. 49.5%; p<0.001). Spot-forming cell (SFC) counts in the IFN-γ ELISPOT assay decreased from baseline after bortezomib (p=0.011) or thalidomide (p=0.096) treatment. Patients with baseline SFCs greater than 20/10(6) mononuclear cells exhibited significantly higher incidence of herpes zoster (100-day cumulative incidence, 34.8% vs. 0%; p=0.040). CONCLUSIONS Bortezomib treatment significantly reduced VZV-specific CMI, and high baseline SFC counts in patients receiving this treatment without acyclovir prophylaxis were associated with a significantly increased risk for herpes zoster.

A combination of melphalan, prednisone, and 50 mg thalidomide treatment in non-transplant-candidate patients with newly diagnosed multiple myeloma.

Background/Aims The clinical efficacy and safety of a three-drug combination of melphalan, prednisone, and thalidomide were assessed in patients with multiple myeloma who were not candidates for high-dose therapy as a first-line treatment. Because the side effects of thalidomide at a dose of ≥ 100 mg daily can be a barrier to effective treatment for these patients, we evaluated the efficacy and safety of a reduced dose of thalidomide, 50 mg, for non-transplant candidates. Methods Twenty-one patients were treated in 4-week cycles, receiving 4 mg/m2 melphalan and 40 mg/m2 prednisone on days 1-7 and 50 mg thalidomide daily. The primary efficacy outcome was the overall response rate. Aspirin (100 mg daily) was also provided as prophylactic treatment for thromboembolism. Results The overall response rate was 57.1%; a complete response was seen in 23.8% of patients, a partial response in 33.3%, and stable disease in 9.5%. After a median follow-up time of 16.1 months, the median time to progression was 11.4 months (95% confidence interval, 2.1 to 20.6); the median overall survival was not reached. Grades 3 and 4 adverse events included infection (10%), peripheral neuropathy (5%), diarrhea (5%), thrombosis (10%), and loss of consciousness (10%). Two patients discontinued treatment due to loss of consciousness and neuropathy. Conclusions Low-dose thalidomide (50 mg) plus melphalan and prednisone is an effective combination drug therapy option for newly diagnosed myeloma patients who are ineligible for high-dose chemotherapy.

A prospective, open-label, multicenter, observational study to evaluate the efficacy and safety of bortezomib-melphalan-prednisone as initial treatment for autologous stem cell transplantation-ineligible patients with multiple myeloma.

Bortezomib-melphalan-prednisone (VMP) showed superior efficacy versus MP as first-line treatment for transplantation-ineligible multiple myeloma (MM). This study investigated the efficacy of VMP for Korean patients with MM. Overall, 177 MM patients received 9 cycles of VMP in this prospective, multicenter, observational study. The primary endpoint was 2-year progression-free survival (PFS). Thirty-nine (22%) patients were aged ≥ 75 years and 83 (47.4%) patients had International Staging System stage III. A median of 5 cycles were delivered. Overall response rate (ORR) was 72.9%, and complete response (CR) rate was 20.3%. With a median follow-up of 11.9 months, median PFS was 17 months. The 2-year PFS and overall survival (OS) rates were 29.2% and 80.0%, respectively. Median OS was not reached. PFS was significantly different depending on performance status (Eastern Cooperative Oncology Group < 2 vs. ≥ 2; p = 0.0002), β2-microglobulin level (< 5.5 vs. ≥ 5.5 mg/L; p = 0.0481), and cumulative dose of bortezomib (< 35.1 vs. ≥ 35.1 mg/m2; p < 0001). The common adverse events (AEs) were in line with the well-known toxicity profiles associated with VMP. In conclusion, VMP is a feasible and effective front-line treatment for transplant-ineligible older patients with MM in Korea. Continuing therapy with prompt adjustment of treatment according to AEs may be important to improve outcomes of elderly patients.

Hydroxyapatite Coated Iron Oxide Nanoparticles: A Promising Nanomaterial for Magnetic Hyperthermia Cancer Treatment

Targeting cancer cells without injuring normal cells is the prime objective in treatment of cancer. In this present study, solvothermal and wet chemical precipitation techniques were employed to synthesize iron oxide (IO), hydroxyapatite (HAp), and hydroxyapatite coated iron oxide (IO-HAp) nanoparticles for magnetic hyperthermia mediated cancer therapy. The synthesized well dispersed spherical IO-HAp nanoparticles, magnetite, and apatite phases were confirmed by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR) and Field emission transmission electron microscopy (FETEM) with Energy Dispersive X-ray spectroscopy (EDS). The non-toxic behavior of synthesized IO-HAp nanoparticles was confirmed by cytotoxicity assay (Trypan blue and MTT assay). The synthesized nanoparticles revealed a remarkable magnetic saturation of 83.2 emu/g for IO and 40.6 emu/g for IO-HAp nanoparticles in presence of 15,000 Oe (1.5 T) magnetic field at room temperature (300 K). The magnetic hyperthermia study that was performed with IO-HAp nanoparticles showed an excellent hyperthermia effect (SAR value 85 W/g) over MG-63 osteosarcoma cells. The in vitro hyperthermia temperature (~45 °C) was reached within 3 min, which shows a very high efficiency and kills nearly all of the experimental MG-63 osteosarcoma cells within 30 min exposure. These results could potentially open new perceptions for biomaterials that are aimed for anti-cancer therapies based on magnetic hyperthermia.

Gefitinib Trial in a Fanconi's Anemia Patient with Multiple Squamous Cell Carcinomas and Hepatocellular Carcinoma

FA (Fanconis Anemia) is an autosomal recessive disorder that is characterized by pancytopenia with bone marrow hypoplasia, diverse congenital abnormalities and an increased predisposition towards malignancy. The mainstay of the treatment for these cancers has been surgery, because of the hypersensitive reactions of FA patients to DNA cross- linking agents or radiation. Therefore, there has been no effective therapy for advanced squamous cell carcinoma. We report here on a patient suffering from advanced multiple squamous cell carcinoma and hepatocellular carcinoma along with an FA, and this patient was treated with gefitinib.

Clinical Features and Prognosis of Lung Cancer with Brain Metastasis.

PURPOSE Brain metastasis is estimated to occur in 20~40% of solid tumor patients and the most common primary tumor is lung cancer. Even though the prognosis of brain metastasis is grave and the 1-year survival rate is only 15%, symptom palliations are made with whole brain radiation therapy. We retrospectively evaluated the clinical features and prognostic factors of lung cancer with brain metastasis. MATERIALS AND METHODS From January 1987 to October 1999, 50 lung cancer patients with brain metastasis underwent whole brain radiation therapy. We reviewed the improvement in neurologic symptoms and survival according to the following parameters; performance status, histological type, presence of brain metastasis at the initial diagnosis of lung cancer, presence of extracranial metastasis, multiplicity of brain lesion, presence of primary lung symptom and treatment modalities. RESULTS The most frequent symptom with brain metastasis was a headache (50%). Palliation of the headache and other symptoms was achieved in 81% of the patients. Median overall survival after brain metastasis was 21 weeks and the 1 year survival rate was 15%. Patients without extracranial metastasis had a longer median survival than those with, 38 weeks versus 15 weeks, respectively (p=0.01). CONCLUSION In lung cancer with brain metastasis, neurologic symptoms can be palliated with whole brain radiation therapy, and in this study among such patients, absence of extracranial metastasis can be a good prognostic factor.

Effect of dose escalation with single opioid, fentanyl matrix in patients not controlling cancer pain: a multicenter, prospective, observational study in Korea.

Purpose End-of-dose failure (EOD) is a clinically common observation and many cancer patients increase the frequency of opioid administration. Fentanyl matrix use is known to be effective in patients with chronic cancer pain. To measure the effectiveness of increase in a single dose of fentanyl matrix in patients whose pain was not controlled sufficiently, we perform this study. Materials and Methods A multi-center, open-label, prospective, observational study was conducted in 30 hospitals in Korea, between August and December 2008. Results A total of 452 patients were enrolled; 404 patients completed the study. The mean pain intensity decreased from 5.27 at the first visit to 3.37 at the end of the trial. There was a significant difference in pain intensity (p < 0.001) between the first and last visits. The percentage of pain intensity difference was 30.1%. The prevalence of EOD at the first visit was 73% from the 452 enrolled patients. After the use of fentanyl patch, EOD decreased from 73% to 56%. Pain intensity of patients experiencing EOD was 5.64 at the baseline compared to 4.27 in patients without EOD. On final visit, pain intensity in patients with and without EOD was 4.02 and 2.54, respectively. The observed adverse events were mainly nausea, asthenia, constipation and diarrhea. Conclusion This study demonstrated that increasing dose of fentanyl patch decreased pain intensity and decreased the rate of patients experiencing EOD. Thus, fentanyl patch may be an effective modality in cancer patients whose pain was previously not controlled sufficiently; the side effects were as could be expected with an opioid.