Even the overall incidence is decreasing and the proportion of early gastric cancer is increasing from the national mass screening program, still gastric cancer is the major issue in Korea. Multimodality approach and the development of novel therapeutic agents enabled us to improve the survival rate of gastric cancer. However, the proper treatment strategy for the subgroups of patients is necessary, which is now categorized based on the clinicopathologic parameters. We need more in-depth information regarding the molecular biology of gastric cancer, and the development of novel targeted biological agents and the biomarkers for the future. Currently, the recent chemotherapeutic agents showed the improved response in advanced gastric cancer. Hence, the basic concept of adjuvant chemotherapy, palliative chemotherapy, neoadjuvant treatment with or without incorporation of radiotherapy become settle down with more evidences from several phase III trials. Especially, after understanding the difference between Asia and Western countries including biology, ethnic difference, operation technology, and the treatment approaches, the qualified, well-designed multinational clinical trials are on-going. Based on the current results, here, I describe the current status of gastric cancer treatment strategy.
Asia ; Biological Agents ; Biomarkers ; Biology ; Chemotherapy, Adjuvant ; Humans ; Incidence ; Korea ; Mass Screening ; Molecular Biology ; Neoadjuvant Therapy ; Stomach Neoplasms ; Survival Rate

Based on recently developed biotechnology, many new drugs have been developed for improving patient treatment outcomes. To develop novel drugs, proper clinical trials are essential. As clinical trials involve humans in research, the protection of participants is important not only for the participants' safety but also for future patients. Ethics in a clinical trial is not the same as in clinical practice with enough evidence. Hence, the whole procedure of a clinical trial should be well organized, scientifically and ethically planned, and monitored properly by an Institutional Review Board (IRB). Here the importance of ethics in clinical trials, related issues, and the monitoring system will be discussed.
Biotechnology ; Ethics Committees, Research ; Humans

PURPOSE: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are associated with increased angiogenesis, growth, and metastasis in solid tumors. But, until today, the importance of theses factors on leukemia, especially childhood acute lymphocytic leukemia (ALL) has received limited attention. Therefore, this study examined the bone marrow plasma VEGF and bFGF levels in ALL patients and normal controls. PATIENTS AND METHODS: Bone marrow plasmas at diagnosis from 33 ALL patients (median age 5.9 years; range 1.8-13.9 years) were used for analysis. The bone marrow levels of bFGF and VEGF were determined by enzyme-linked immunosorbent assay (R & D Systems) and compared with the bone marrow levels of 7 healthy control subjects (median age 11.98 years; 6 months -13.6 years). RESULTS: Average VEGF was higher in relapse ALL (N=7, 216.6 +/- 79.9pg/mL) compared to standard (N=9, 36.8 +/- 12.1pg/mL) (p=0.013) or high risk ALL (N=17, 80.0 +/- 12.2pg/mL) (p=0.023). bFGF levels were also significantly higher in relapse than standard-, or high-risk ALL patients (relapse ALL; 48.6 +/- 15.4pg/mL, standard risk ALL; 18.9 +/- 5.5pg/mL, high risk ALL; 19.0 +/- 3.5pg/mL, normal control; 18.6 +/- 4.0pg/mL) (p=0.003). Three patients with refractory relapse and death had much higher VEGF and bFGF values (VEGF; 420.0 +/- 81.6pg/ mL, bFGF; 85.6 +/- 3.2pg/mL). CONCLUSION: Our data suggest that the increased levels of VEGF and bFGF in bone marrow may play an important role in prognosis of childhood ALL.

BACKGROUND: Although pulmonary resection is the standard approach for the management of pulmonary metastases from soft tissue sarcoma, most of them are unresectable and chemotherapy remains the only option. The effectiveness of the cytotoxic drugs may be limited by the toxicities that occur before the therapeutic dose is reached. The regional administration of doxorubicin using pulmonary arterial perfusion in a rodent model can produce 10 to 25 times higher concentrations in the lung than systemic administration with minimal systemic toxicities. However, it is unclear whether a high concentration of doxorubicin has beneficial effects for killing cancer cells. MATERIAL AND METHOD: We studied this to evaluate the dose-dependent cytotoxic and apoptotic effects of doxorubicin on methylcholanthrene-induced rat fibrosarcoma(MCA) cells. This study examined the cytotoxicity and apoptosis-related gene expressions(Fas, FasL, Bax, caspase 1, caspase 2, caspase 8, Bcl-2, Bcl-xL, Bcl-xS) in MCA cells after 24 hours exposure to various concentrations of doxorubicin such as 1, 5, 10, 50, and 100 micrometer. RESULT: Dose-dependent cytotoxicity was observed after 24 hours exposure to doxorubicin. However, peak apoptosis after 24 hours exposure was observed at 5 micrometer of doxorubicin. Above 5 micrometer, apoptotic activity was decreased with dose-increment. All mRNA levels of apoptosis-related genes after 24 hours exposure were up-regulated above the control level at 1 micrometer of doxorubicin and then decreased by doxorubicin dose-increment except caspase 8, which showed higher levels than the control level at 5 micrometer. Apoptosis-related protein levels were highest at 1 micrometer of doxorubicin and then decreased by doxorubicin dose-increment. However, Bax and Bcl-xL proteins steadily showed higher levels than the control throughout the different concentrations of doxorubicin. CONCLUSION: These results suggest that apoptosis is the main cytotoxic mechanism in low concentrations of doxorubicin in MCA cells and apoptosis-related genes, such as Bax, caspase 8, a can kill MCA cells, even when apoptosis is inhibited, and have its propriety for achieving much cytotoxicity against MCA cells.
Animals ; Apoptosis* ; bcl-X Protein ; Caspase 1 ; Caspase 2 ; Caspase 8 ; Doxorubicin* ; Drug Therapy ; Fibrosarcoma ; Homicide ; Lung ; Neoplasm Metastasis ; Perfusion ; Rats* ; RNA, Messenger ; Rodentia ; Sarcoma

Despite the rarity of primary bone tumors, osteosarcoma and Ewing sarcoma are the most common primary malignant bone tumors in children and adolescents. Multiagent chemotherapy regimens for neoadjuvant and adjuvant treatment remarkably improved the survival outcome for patients with osteosarcoma and Ewing sarcoma, therefore, most patients are now limb-salvage candidates. However, survival rate reached a plateau for last decades and is still unsatisfactory in the metastatic and relapse setting. Therefore, as seen in denosumab in giant cell tumor, further clinical trials based on molecular mechanism are warranted. This article reviews the current state of the art of systemic chemotherapy by focusing on the clinical heterogeneity of each subtype.
Adolescent ; Child ; Drug Therapy* ; Giant Cell Tumors ; Humans ; Osteosarcoma ; Population Characteristics ; Recurrence ; Sarcoma, Ewing ; Survival Rate ; Denosumab

Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone.Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents.HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

PURPOSE: We compared the relative sensitivity and specificity between the urine cytology and fluorescence in situ hybridization (FISH) for the detection of urothelial carcinoma. MATERIALS AND METHODS: FISH was used a mixture of fluorescent labeled probes to the centromeres of chromosomes 3, 7 and 17, and band 9p21 (P16/CDKN2A gene). Washing urine specimens were analyzed from 37 patients, including 27 with a known bladder urothelial carcinoma and 10 without a history of urothelial carcinoma. The sensitivity and specificity of the FISH was compared to that of urine cytology. FISH positivity was defined as more than 2 urothelial cells with an abnormal signal copy number of any one out of 4 probes. RESULTS: In the bladder urothelial cancer group (n=27), the overall sensitivity of the urine cytology was 59.3% versus 88.9% for FISH (p=0.046). The sensitivity of urine cytology for pTa-1 (6 cases), and pT2-pT4 (11 cases) tumors were 37.5%, and 90.9%, respectively, and the sensitivity of FISH for pTa-1 (13 cases), and pT2-pT4 (11 cases) tumors were 81.3%, and 100%, respectively. The sensitivity of urine cytology were 33.3% (5 cases) for low grade tumors, and 91.7% (11 cases) for high grade tumors. The sensitivities of FISH were 80.0% (12 cases) for low grade tumors, and 100% (12 cases) for high grade tumors. FISH was significantly more sensitive than urine cytology for pTa-1 (p=0.021), low grade tumors (p=0.023) and all tumors (p=0.046). In the control group (n=10), the specificity of urine cytology and FISH was 90.0% and 100%, respectively (p=0.056). CONCLUSIONS: With these results, the sensitivity of FISH for the detection of urothelial carcinoma is superior to that of urine cytology, and the specificity of FISH and urine cytology for urothelial carcinoma are not significantly different. FISH, in particular, is more sensitive in the detection of low grade, low stage bladder tumors. Further prospective studies are required but FISH can successfully be used as supplementary methods to detect low grade, low stage urothelial tumors.
Centromere ; Fluorescence* ; Humans ; In Situ Hybridization* ; Sensitivity and Specificity ; Urinary Bladder Neoplasms ; Urinary Bladder*

PURPOSE: We determined the clinical significance of telomerase activity and telomere length in breast cancer patients and also developed the measuring system of telomerase activity change with RNAse A pre-treatment. MATERIALS AND METHODS: We measured the telomerase activity in 71 breast cancer tissues and paired normal tissues with TRAP (Telomeric Repeat Amplification Protocol) assay. Telomerase activity was calculated by computer-assisted densitometry compared to telomerase activity of the 293 control cell line. To develop the measuring system of telomerase activity modulation, we measured the telomerase activity after the treatment with RNAse A, 150microgram/ml, which inhibited 70% of telomerase activity compared to control in the 293 control cell line. In 59 paired tissues with telomerase activity, terminal restriction fragment (TRFs) length were measured using Southern blotting. RESULTS: Sixty-three out of 71 cancer tissues showed telomerase activity (88.7%), while no telomerase activity was detected in their paired normal tissues. Telomerase activity was correlated to the node metastasis (p=0.02) and stage (p=0.005), but not to the tumor size or the hormonal receptor status. TRFs were neither specific to tumor tissues nor related to any of the clinical parameters. However, changes of TRFs of the tumor tissues from their paired normal tissues were correlated to the telomerase activities. Also the patients with different TRFs between cancer and normal tissues were in more advanced stage. After pre-treatment with the 150microgram/ml of RNAse A, telomerase activity in the tumor tissues showed variable inhibition. Relative inhibition, the ratio of inhibited telomerase activity in each tumor tissue compared to the inhibition of 293 control cell line, was proportional to the telomerase activity. CONCLUSION: In breast cancer, telomerase activity was specific to the tumor tissues and correlated to tumor progression. A combination of telomerase activity and TRFs changes can be used as a guidline in detecting a better candidate for telomerase inhibition. Semi-quantitative assay with RI system can be used in evaluating the changes of telomerase activity after treatment with a new telomerase inhibitor with TRAP assay.
Biological Therapy* ; Blotting, Southern ; Breast Neoplasms* ; Breast* ; Cell Line ; Densitometry ; Humans ; Neoplasm Metastasis ; Ribonuclease, Pancreatic ; Telomerase* ; Telomere

PURPOSE: The cDNA microarray has become a useful tool for observing the expression of thousands of genes simultaneously. However, obtaining good quality microarray data is not easy due to the inherent noise at various stages of the experiment. Therefore, it is essential to understand the source of the variation in the microarray experiment and its size as an initial step of the data analyses. MATERIALS AND METHODS: The total RNA extracted from HT-1080 fibrosarcoma and normal rat tissues were hybridized to the cDNA microarrays with 0.5 K human and 5 K rat genes, respectively. A homotypic reaction and dye swap experiments were used to identify the sources of the variation. RESULTS: The relative fluorescent intensities of the microarray, if unnormalized, have a large variation, particularly in the lower intensity region. The distribution of the log intensity ratios also exhibit some departure from a band around zero, which is the distribution pattern expected when the majority of genes in the microarray are not regulated. Normalization of the log ratios is usually required as a means of preprocessing the data. We claim that a within-print tip group, an intensity-dependent normalization through a loess fit adjustment will be useful for this purpose, particularly in the initial stages of the microarray experiment. CONCLUSION: For proper data analysis, an understanding the source of the variation and preprocessing of data with a suitable normalization method will be important. It is important to have an interactive cooperation between a researcher and a statistician from the early stages of the study design and to the final stages of data analysis.
Animals ; DNA, Complementary* ; Fibrosarcoma ; Humans ; Noise ; Oligonucleotide Array Sequence Analysis* ; Rats ; RNA ; Statistics as Topic

Carcinoembryonic antigen (CEA) has been studied in the field of gynecologic malignancy to determine whether it can be used as a tumor marker for early detection of recurrence or evaluation of therapeutic results. From January 1985 through December 1989, a total of 239 cervical cancer patients were entered for an analysis of plasma CEA level in the group with cervical cancer compared to the control group consisting of 65 normal healthy women and 18 women with benign gynecologic disease. Plasma CEA levels appear to be directly related with the tumor extension and as stages advance, the incidence of patients with abnormal plasma CEA levels is increased. Also, there seems to be a little higher incidence of abnormal CEA levels in patients with adenocarcinomas or adenosquamous carcinoma but not statistically significant because of small number of patients. When the patients developed recurrence, plasma CEA levels are markedly elevated in the majority, particularly in patients with hepatic metastases. In conclusion, serial plasma CEA checks could be used to detect recurrence during follow-up after treatment of cervical cancer.
Adenocarcinoma ; Carcinoembryonic Antigen ; Carcinoma, Adenosquamous ; Female ; Follow-Up Studies* ; Genital Diseases, Female ; Humans ; Incidence ; Neoplasm Metastasis ; Plasma* ; Recurrence ; Uterine Cervical Neoplasms