Awareness and Attitude Change after End-of-Life Care Education for Medical Students / 한국호스피스완화의료학회지

PURPOSE: Most medical schools in Korea do not provide adequate education in end-of-life care. This study was designed to illustrate the need to improve end-of-life care education and to assess the effect of the education on fourth-year medical students' awareness and attitude towards hospice and palliative care for terminally ill patients. METHODS: One hundred sixty six fourth-year medical students were surveyed with questionnaires on end-of-life care before and after they received the education. RESULTS: Before receiving the education, students most frequently answered "at the end of life" (33.6%) was appropriate time to write an advance medical directive. After the education, the most frequent answer was "in healthy status" (58.7%). More students agreed to withholding or withdrawing futile life-sustaining treatment increased after the education (48.1% vs. 92.5% (P<0.001) for cardiopulmonary resuscitation, 38.3% vs. 92.5% (P<0.001) for intubation and mechanical ventilation, 39.1% vs. 85.8% (P<0.001) for inotropics, 60.9% vs. 94.8% (P<0.001) for dialysis and 27.8% vs. 56.0% (P<0.001) for total parenteral nutrition). Significantly more students opposed euthanasia after the education (46.6% vs. 82.1%, P<0.001). All students agreed to the need for education in end-of-life care. CONCLUSION: After reflecting on the meaning of death through the end-of-life care education, most students recognized the need for the education. The education brought remarkable changes in students' awareness and attitude towards patients at the end of life. We suggest end-of-life care education should be included in the regular curriculum of all medical schools in Korea.

Malignant Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis type 1

Neurofibromatosis type 1 (von Recklinghausen's disease, NF-1) is an autosomal-dominant neurocutaneous disorder characterized by abnormal skin pigmentation (cafe au lait spots and axillary freckling), cutaneous and plexiform neurofibromas, skeletal dysplasias, and Lisch nodules (pigmented iris hamartomas). Gastrointestinal stromal tumors (GISTs) are the most common tumors of mesenchymal origin in the gastrointestinal tract, mesentery, omentum, and retroperitoneum. Here, we report a case of GIST in the ileum of a 76-year-old woman previously diagnosed as NF-1. She was admitted due to sudden onset of abdominal pain. Contrast enhanced CT scan revealed a moderately defined, peripherally enhanced soft tissue mass of about 8.8 x 7.3 cm, originating from the small bowel in the left of the abdomen. Surgical excision was performed and the tumor was found to be composed of tumor cells that were positive for c-kit protein. The patient started imatinib treatment a month later, but stopped medication due to dyspepsia after a few months and eventually progressed after 18 months.

Vascular Complications in Patients with Essential Thrombocythemia / 대한혈액학회지

BACKGROUND: Essential thrombocythemia (ET) has a chronic course, but its main clinical features are thrombosis and hemorrhage. We evaluated the clinical features, including the vascular complications in patients with ET, during the disease courses and we determined the predictable risk factors for major vascular complications. METHODS: From 1991 to 2004, the medical records for 69 patients with ET were retrospectively reviewed for evaluating the clinical features, including the vascular complications, and the predictable risk factors for major vascular complications were analyzed. RESULTS: Major vascular thrombotic and hemorrhagic complications were observed in 16 patients (23.2%) and 6 patients (8.7%) at the time of diagnosis, and in 13 (18.8%) and 9 patients (13.0%) during follow-up. The incidence of major vascular thromboses in the older group (age >60 years) was higher than that in the younger group (< or =60 years) (34.2% vs 9.7%, respectively, P=0.016) at the time of diagnosis. During follow-up, the major vascular thrombosis risk was increased in patients with a previous thrombosis history (37.5% vs 13.2%, respectively, P=0.029) and in patients with 2 or more combined cardiovascular risk factors (44.4% vs 15.0%, respectively, P=0.035). The probability of 10-year survival in patients with thrombo-hemorrhagic complications during the disease course was lower than that in patients without complication (60.5% vs 93.7%, respectively, P=0.046). CONCLUSION: Advanced age, a previous thrombosis history and the combined cardiovascular risk factors were the risk factors for major vascular thrombosis in patients with ET. Prevention of thrombo-hemorrhagic complications is the most important therapeutic goal. Treatment strategies according to risk factors ought to be prospectively investigated.

A phase II study of etoposide (VP-16), ifosfamide, and carboplatin combination chemotherapy plus concurrent thoracic irradiation for limited stage small cell lung cancer / 대한내과학회지

BACKGROUND: Small cell lung cancer (SCLC) is very sensitive to both chemotherapy and radiation therapy. In limited disease of SCLC, the addition of radiation therapy to chemotherapy improves survival and decrease local relapse over chemotherapy alone. This study evaluated the response rate, duration of response, overall survival and toxicity for the combination of etoposide, ifosfamide, carboplatin given concurrently with thoracic irradiation in limited SCLC. METHODS: Twenty eight patients with histologically proven SCLC who have a measurable disease and previously untreated, were enrolled in this study. Each cycle consisted of VP-16 100 mg/m2 IV days 1~3, ifosfamide 1,200 mg/m2 IV days 1~3 with mesna, carboplatin AUC 6 IV day 1. Cycles were repeated every 21days. Patients received a total of median 6,000 cGy thoracic radiation therapy (180~200 cGy/day) starting on the first day of chemotherapy. Prophylactic cranial irradiation was given to complete remission after chemoradiotherapy. RESULTS: The overall response rate in 27 evaluable patients was 93% (41% of complete response, 52% of partial response). The median time to progression was 10.3 months. The median disease free survival was 18.4 months in patients with complete response. The median overall survival was 16.7 months in all evaluable patients. Hematologic toxicities (> or = Grade3) of 129 cycles of chemotherapy were leukopenia in 38% and fever with infection in 26%. Nonhematologic toxicities (> or = Grade2) of evaluable 27 patients included alopecia in 11%, post-irradiation esophagitis in 44% and pneumonitis in 11%. CONCLUSIONS: VIC combination chemotherapy with concurrent thoracic irradiation is effective in limited SCLC. It's maior toxicity is myelosuppression.

Thalidomide for Treating Metastatic Hepatocellular Carcinoma: A Pilot Study

BACKGROUND: Thalidomide has been reported to have antitumor activity for treating metastatic hepatocellular carcinoma (HCC). We evaluated the safety and efficacy of using thalidomide for treating selected patients with unresectable or metastatic HCC, and their disease was refractory to systemic chemotherapy. METHODS: Eight patients with measurable and metastatic HCC that had progressed with prior systemic chemotherapy and who desired further active therapy were enrolled in this study. Thalidomide was given orally at bedtime and it was started at 200 mg/day with no further dose escalation. The response was measured at 2-month intervals. RESULTS: The median age was 44 years (range: 34-52 years) and all the patients had received doxorubicin-based systemic chemotherapy prior to their enrollment. Each patient received thalidomide for a median of 152 days (range: 5-422 days). One partial response was observed (12.5%, 95% CI; 0-42%) along with 4 cases of stable diseases. The most commonly encountered toxicity was somnolence; grade 3 somnolence was noted for one patient, which led to treatment discontinuation. Skin rash was observed in one responding patient. CONCLUSIONS: The results indicate that thalidomide may feasibly offer disease stabilization to metastatic HCC patients. Further dose escalation of thalidomide, or its combination with other chemotherapeutic agents, may be of interest and this should be investigated for treating patients with metastatic HCC.

A Pilot Study of Cisplatin, Irinotecan, Leucovorin and 5-fluorouracil (PILF) Combination Chemotherapy for Advanced Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Irinotecan, in combination with leucovorin/ 5-fluorouracil (FU) or with cisplatin, is known to be active for treating advanced gastric cancer (AGC). This pilot study evaluated a novel three-drug combination of irinotecan, leucovorin/FU and cisplatin as a first-line treatment of AGC. The primary endpoint was to assess the feasibility in anticipation of conducting a larger phase II study. MATERIALS AND METHODS: Chemotherapy-naive AGC patients received irinotecan 150 mg/m2 on day 1, and leucovorin 200 mg/m2 and a 22-h infusion of FU 1000 mg/m2 on days 1 and 2. Cisplatin 30 mg/m2 was administered on day 2. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity. RESULTS: Of the 17 eligible patients, two patients had an ECOG performance status of 2 and their median age was 48 years (range: 31 to 69). A total of 117 chemotherapy cycles were delivered (median: 6, range: 1 to 12). The causes of treatment discontinuation were disease progression in 9 patients (53%), refusal (35%) and toxicity (12%). Although grade 3 or 4 neutropenia (41% of patients) was the major toxicity that required dose adjustments, only one episode of febrile neutropenia occurred. Grade 3 or 4 nausea and vomiting, diarrhea and fatigue were observed in 35%, 35% and 29% of patients, respectively. None of the patients died of toxicity during treatment. Of the 16 patients who were evaluable for response, 7 (44%) experienced a partial response. CONCLUSION: This novel multi-drug combination was tolerated well in patients with AGC. Based on the encouraging efficacy and tolerability, a randomized phase II study is ongoing in this disease setting.

Expression of Cyclooxygenase-2 in Human Breast Cancer: Relationship with HER-2/neu and other Clinicopathological Prognostic Factors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Previous epidemiologic studies have demonstrated that nonsteroidal anti-inflammatory drugs can reduce the risk of breast cancer, and this possibly happens via cyclooxygenase (COX) inhibition. Moreover, growth factor-inducible COX-2, which is overexpressed in neoplastic tissue, is an attractive therapeutic target. Thus, we evaluated the expression of COX-2 in breast cancer tissues, and we assessed the association between COX-2 expression and HER-2/neu expression and also with several clinicopathological features. MATERIALS AND METHODS: We analyzed the surgical specimens from 112 women with breast cancer who had undergone lumpectomy or mastectomy. The expressions of COX-2, HER-2/neu, MMP-2 and TIMP-2 were determined immunohistochemically. The correlations between COX-2 expression and several variables, including clinicopathological factors, HER-2/neu expression, MMP-2 expression and TIMP-2 expression were analyzed. Survival analysis was also performed with respect to COX-2 overexpression. RESULTS: The overexpression of COX-2 protein was observed in 28.6% of the breast cancer tissues. Tumors with lymph node metastasis more frequently showed COX-2 overexpression than did those tumors without metastasis (p=0.039), and the increased COX-2 expression correlated positively with HER-2/neu overexpression (p=0.000). No significant differences were found for the MMP-2 or TIMP-2 expression rates in the COX-2 positive and negative groups. The survival analysis revealed no significant differences according to the COX-2 expression. CONCLUSION: This study results suggest that increased COX-2 expression is related with the progression of breast cancer, e.g., with lymph node invasion. COX-2 overexpression found to be related with HER-2/neu overexpression, but not with MMP-2 or TIMP-2 expression. These results support the potential use of selective agents that inhibit COX-2 or HER-2/neu for the management of breast cancer.

A Case of POEMS Syndrome with Unclassifiable Myeloproliferative Disorder / 대한혈액학회지

POEMS syndrome is a rare multisystemic syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. We report a case of POEMS syndrome associated with unclassifiable myeloproliferative disorder presenting with polyneuropathy, hepatosplenomegaly, hypothyroidism, hyperprolactinemia, monoclonal gammopathy, hyperpigmentation, hypertrichosis, ascites, peripheral edema, and pulmonary hypertension.

The Prognostic Significance of the Overexpression of HER-2/ neu in Korean Gastric Carcinomas and the In Vitro Effects of Anti-HER-2/neu Antibody on Cell Growth in the Gastric Carcinoma Cell Lines / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185(HER2)) that has partial homology with the epidermal growth factor receptor (EGFR) and shares intrinsic tyrosine kinase activity. The HER2 gene has been found to be amplified in various human cancers and to be associated with poor prognosis. The authors investigated the correlation between clinicopathologic factors and the overexpression of the p185(HER2) in Korean gastric adenocarcinoma patients, and determined whether the antiproliferative effects of anti- p185(HER2) antibody can also be observed on gastric cancer cell lines that overexpress this growth factor receptor. MATERIALS AND METHODS: We evaluated the relationship between p185(HER2) overexpression and clinicopathological features in 94 (M: F=52: 42) gastric adenocarcinoma patients (median age 59 years). Protein expression was analysed by immunohistochemical staining in paraffin embedded tissues with monoclonal antibody for p185(HER2). To explore the role of humanized anti-p185(HER2) monoclonal antibody trastuzumab (Herceptin ) in vitro, the growth curve of Korean gastric cancer cells that overexpress the p185(HER2) protein was studied and a cell cycle analysis was performed. RESULTS: p185(HER2) overexpression correlates positively with lymph node metastasis (p=0.002), distant metastasis (p=0.01), AJCC classification (p=0.01), higher relapse rate p=0.001), and a tendential association with the pT stage (p=0.054). p185(HER2) overexpression was found to be more frequent in advanced gastric cancer than early gastric cancer (54.1% vs 24.2%, p=0.008). Patients with overexpression of p185(HER2) were found to have significantly lower relapse-free (p=0.003) and overall survival (p= 0.0004) than patients without overexpression. Among several Korean gastric cancer cell lines, SNU-1, SNU-5, and SNU-620 overexpress p185(HER2). Trastuzumab inhibited the proliferation of p185(HER2) overexpressed Korean gastric cancer cell line by 21% with down-regulation of p185(HER2) protein expression. DNA fluorescence flow cytometry of propidium iodide-stained nuclei showed a reduction in the fraction of the S phase following treatment with trastuzumab. CONCLUSIONS: Taken together, our observations suggest the potential prognostic significance of p185(HER2) overexpression in Korean gastric adenocarcinoma patients and point to the need for further research on this mechanism. This suggests the possible use of p185(HER2) as a therapeutic target in gastric cancer.

The Significance of Vascular Endothelial Growth Factor Expression and Angiogenesis in Acute Myelogenous Leukemia / 대한혈액학회지

BACKGROUND: Angiogenesis plays a key role in the growth and metastasis of solid tumor. But it is not known whether the hematopoietic tumor depends on angiogenesis. To evaluate the prognostic roles of vascular endothelial growth factor (VEGF) expression and angiogenesis in patients with acute myelogenous leukemia, we analyzed the relationships between the level of VEGF expression, microvessel counts (MVC) in the bone marrow specimen of acute myelogenous leukemia patient and remission, relapse, and overall survival. METHODS: We evaluated bone marrow biopsy from 32 adult patients with newly diagnosed acute myelogenous leukemia and 16 controls with normal bone marrow. VEGF expression and MVC were assessed by immunohistochemical stain with monoclonal antibody to VEGF and polyclonal antibody to factor VIIIRAg, respectively. RESULTS: VEGF expression was higher in acute myelogenous leukemia than that of control (56.4+/-32.8% vs 19.0+/-25.9%, P=0.004). MVC was also higher in acute myelogenousleukemia than that of control (14.7+/-10.3 vs 6.2+/-3.8, P<0.001). Between high VEGF expression group and low VEGF expression group, there were no significant differences in the complete remission (CR), relapse and overall survival. There was no significant difference of MVC between CR group and non- CR group. Relapse group tends to have higher MVC than non-relapse group without statistical significance (P=0.06). There were no significant differences of MVC between hypervascular group and hypovascular group in remission, relapse and overall survival. CONCLUSION: In patients with acute myelogenous leukemia, VEGF expression and MVC were significantly higher than those of control. These findings suggest angiogenesis may play an important role in the pathogenesis of acute myelogenous leukemia. But there was no clinical correlation between the level of VEGF expression, MVC and remission, relapse and overall survival in this study. Further study willbe necessary for the establishment of prognostic role of VEGF expression and angioge-nesis and clinical efficacy of angiogenic inhibitors in acute myelogenous leukemia.

Antiangiogenesis Gene Therapy Using Adenovirus-mediated Antisense-VEGF in Glioblastoma Multiforme / 대한암학회지

PURPOSE: Vascular endothelial growth factor (VEGF) is a major positive effector of angiogenesis. We investigated the mechanism of tumor growth inhibition by adenoviral transfer of antisense- VEGF in glioma and the role of VEGF for in vivo growth of human glioma cells according to the stage of the tumor growth. MATERIALS AND METHODS: Replication-deficient adenoviral vector containing the VEGF cDNA in an antisense orientation (Ad5CMV-alphaVEGF) were constructed to increase the in vivo applicability of antisense sequence. The effect of Ad5CMV-alphaVEGF was studied in vitro and in vivo with human glioma cell line U-87 MG. Immunohistochemical staining of the subcutaneous tumor with anti-VEGF antibody and CD34 antibody were performed to compare VEGF protein expression and the microvessel count respectively. RESULTS: The growth curve of U-87 MG cells treated with Ad5CMV-alphaVEGF remained as same as that of mock-infected and Ad5(dl312)-infected U-87 MG cells in vitro, suggesting that Ad5CMV-alphaVEGF does not have direct cytotoxic effect. The growth of subcutaneous human glioma xenografts was inhibited by early intratumoral injection of Ad5CMV-alphaVEGF. Immuno histochemical staining of tumors showed that VEGF protein expression and mean microvessel counts were decreased in early Ad5CMV-alphaVEGF treatment group. CONCLUSION: The efficient down-regulation of VEGF produced by tumor cells using Ad5CMV- alphaVEGF in early stage of glioma growth has an antitumor effect in vivo through antiangiogenic mechanism.

The Role of Radiotherapy in Patients with Brain Metastasis / 대한방사선종양학회지

PURPOSE: Brain metastases are the most frequent metastatic neurologic complication of systemic cancer. Even if the prognosis of brain metastases is grave, with available treatments, most patients experience effective palliation of neurologic symptoms and meaningful extension of life. We evaluated the clinical features and prognostic factors of the patients who were diagnosed as solid tumors with brain metastasis and received radiotherapy for brain metastases. MATERIALS AND METHODS: Between January 1987 and January 1998, 71 patients with brain metastases from solid malignancy were included. We reviewed neurologic symptoms and signs of patients and evaluated improvememt of neurologic symptoms and signs. Survival durations after brain metastasis were analysed according to several factors such as age, performance status, primary malignancies, the presence of brain metastasis at initial diagnosis of primary tumor, multiplicity of brain metastass, the presence of metastases other than brain, and treatment method. RESULTS: Frequent symptoms associated with brain metastasis were headache (47.9%), motor weakness (40.8%), nausea and vomiting (19.7%) and mental change (19.7%). Palliation of these symptoms was accomplished in 64.9% of cases. The overall median survival time was 16 weeks and 1- and 2-year survival rates were 15.0% and 5.1% respectively. Patients without extracranial metastases (n=27) had longer median survival than patients with extracranial metastases (33 weeks vs 10 weeks, p=0.0018). In patients with single brain metastasis (n=37), the median survival time was longer in patients treated with surgery plus radiotherapy than in patients treated with radiotherapy alone (40 weeks vs 16 weeks, p=0.0438). CONCLUSION: Patients who has brain metastases only constitute a prognostically favorable group and they may be benefited from radiotherapy and surgery if indicated.

Acute Management of Intrathecal Methotrexate Overdose in a Patient with Acute Lymphocytic Leukemia / 대한혈액학회지

Methotrexate is the most widely used intrathecal antineoplastic agent and is potentially neurotoxic. Accidental intrathecal overdose of methotrexate can produce severe and life-threatening toxicities. A 17-year-old girl with acute lymphocytic leukemia, in complete remission, inadvertently received a 10-fold overdose of intrathecal methotrexate instead of intended dose (100mg vs 10mg). Exchange of lumbar cerebrospinal fluid with normal saline via intrathecal indwelling catheter was started 2 hours later. Leucovorin and dexamethasone were given intravenously. After exchange of cerebrospinal fluid, the total amount of methotrexate removed was about 37mg. Cerebrospinal fluid and plasma methotrexate levels at 18 hours were about 3- to 5- fold higher than those previously reported in patients following standard dose of intrathecal methotrexate who did not develop neurotoxicity. But no methotrexate induced neurologic sequelae were observed in this patient. CSF exchange is a simple and effective method for the treatment of acute intrathecal methotrexate overdose.