Showing papers in "Cancer Research and Treatment in 2004"

2002 annual report of the Korea Central Cancer Registry: based on registered data from 139 hospitals.

Abstract: PURPOSE To estimate the number of cancer cases during 2002 in Korea through a nationwide hospital based cancer registration by the Korea Central Cancer Registry (KCCR). MATERIALS AND METHODS One hundred and thirty nine hospitals participated in the KCCR program in 2002. Cancer cases were coded and classified according to the International Classification of Diseases for Oncology 2(nd) edition (ICD-O-2). The software program "IARC Check" was used to evaluate the quality of registered cancer cases. Of the 122,770 malignancies registered, 11,732 (9.6%) duplicated malignancies were excluded. Among the remaining 102,677 malignancies, 3,652 (3.6%) cases with carcinoma in situ (Morphology code/2) were separated. Finally, 99,025 malignancies were analyzed. RESULTS Of the total of 99,025 malignancies, 55,398 (55.9%) cases were males and 43,627 (44.1%) were females. More than one third of cases were from the elderly (65 years old and more). The six leading primary cancer sites in the order of their relative frequency, were stomach (24.0%), followed by the lung (16.0%), the liver (15.4%), the colorectum (11.6%), the bladder (3.2%), and the prostate (3.0%) among males. In females, the breast (16.8%) was the common cancer site, followed by the stomach (15.3%), the colorectum (10.7%), the thyroid gland (9.5%), the cervix uteri (9.1%), and the lung (6.6%). CONCLUSION With the continued increase in cancer cases especially prostate cancer among males and thyroid cancer among females, the total number of registered cancer cases in Korea continues to rapidly increase.

An analysis of the risk factors and management of lymphocele after pelvic lymphadenectomy in patients with gynecologic malignancies.

Abstract: Objectives The incidence and risk factors of lymphocele development after pelvic lymphadenectomy were evaluated and its management investigated.

HIF-1alpha: a valid therapeutic target for tumor therapy.

Abstract: Hypoxia plays a major role in the induction of angiogenesis during tumor development. One mechanism by which tumor cells respond to a reduced oxygen level is via the activation of hypoxia-inducible factor-1 (HIF-1). HIF-1 is an oxygen-dependent transcriptional activator that plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and the highly regulated HIF-1alpha subunits. The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, phosphorylation and sumoyaltion. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, SUMO and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)-mediated ubiquitin/proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, under the hypoxia condition, the HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Under hypoxic conditions, HIF-1 eventually acts as a master regulator of numerous hypoxia-inducible genes. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation and survival, and to glucose and iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1alpha itself or the blocking of HIF-1alpha interacting proteins inhibits tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. Therefore, this review summarizes the molecular mechanism of HIF-1alpha stability, the biological functions of HIF-1 and its potential applications for cancer therapies.

Long-term results of proximal and total gastrectomy for adenocarcinoma of the upper third of the stomach.

Abstract: Purpose: The choice of surgical strategy for patients with adenocarcinoma of the upper one third of the stomach is controversial. This study was performed to analyze the surgical results of a 11-year experience with these lesions. Materials and Methods: From January 1990 to December 2000, 259 patients with upper third gastric cancer underwent proximal gastrectomy (n=74) or total gastrectomy (n=185) through an abdominal approach. Morbidity, mortality, recurrence patterns, and survival were compared between these two groups retrospectively. Results: There were no significant differences in general complication and mortality rates between the two groups. However, the incidences of reflux esophagitis (16.2%) and anastomotic stricture (35.1%) were more common in the proximal gastrectomy group compared with the total gastrectomy group (0.5 and 8.1%). Regar-ding the main patterns of recurrence, local recurrence was dominant in the proximal gastrectomy group, whereas distant recurrence was dominant in the total gastrectomy group. Five-year overall survival (54.8 versus 47.8%) and survival according to tumor stage were no different between the groups. Multivariate analysis showed that the extent of resection was not an independent prognostic factor. Conclusion: The extent of resection for upper third gastric cancer did not appear to affect long-term outcome. However, proximal gastrectomy is associated with an increased risk of reflux esophagitis, anastomotic stricture, and local recurrence.

Predictive Value of Preoperative Serum CEA, CA19-9 and CA125 Levels for Peritoneal Metastasis in Patients with Gastric Carcinoma

Abstract: Purpose Peritoneal metastasis is a crucial factor for the prognosis in gastric cancer, but its diagnosis is difficult before laparotomy. This study analyzed the usefulness of diagnostic imaging and various tumor markers in the detection of peritoneal metastasis in gastric cancer. Materials and methods The sera from 768 patients with gastric cancer were measured for CEA, CA19-9 and CA125 levels using a commercial immunoradiometric assay. All the patients underwent diagnostic imaging with computed tomography (CT) and ultrasound (US) before laparotomy. Results Preoperative levels of CEA, CA19-9 and CA125 were above the cut-off levels in 15.4%, 8.7% and 5.7% of all cases, respectively. Eighty-eight patients were diagnosed with peritoneal metastasis by laparotomy. CT and US revealed peritoneal dissemination in 15 of 88 patients (17%). Among the three tumor markers, CA19-9 and CA125 showed similar detection rates of peritoneal metastasis (37.5% and 38.6%, respectively). In particular, the serum CA125 levels showed the best sensitivity (38.6%), specificity (98.4%), and diagnostic accuracy (91.5%), and the highest odd ratio (24.46, 95% CI: 11.17 approximately 53.57) for predicting peritoneal metastasis among the markers tested. CEA did not add significant predictive information (p=0.471). Conclusion Preoperative serum CA19-9 and CA125 levels may provide a predictable value in determining peritoneal metastasis in patients with gastric cancer.

Prognostic significance of CD24 expression in gastric carcinoma.

Abstract: PURPOSE: The human CD24 antigen is a small heavily glycosylated cell surface protein, which is expressed in hematological malignancies, as well as in a large variety of solid tumors. Its expression is now known to be related to the prognosis of several kinds of tumors. This study is designed to examine the prognostic significance of CD24 in Korean gastric cancer patients. MATERIALS AND METHODS: In the present study, we examined CD24 expression in 300 consecutive cases of gastric carcinoma by immunohistochemical staining using the tissue-array method. We also investigated the clinicopathological profiles related to CD24 expression. RESULTS: One hundred and three cases out of 300 (34.3%) showed the positive expression of CD24. The altered expression of CD24 was significantly associated with differentiated cancer (p=0.003), the intestinal subtype according to the Lauren classification (p<0.001), the advanced stage cancer (p=0.027), with lymphatic invasion (p=0.038) and with vascular invasion (p=0.006). The survival analysis revealed that the patients with CD24 positive expression showed significantly poorer survival than those without CD24 expression. Moreover, a combined evaluation revealed that PTEN+/CD24- cases showed the best survival compared to other groups (p=0.01). CONCLUSION: Positive CD24 expression occurs in a subset of gastric carcinomas and it correlates significantly with lymphatic invasion, blood vessel invasion and poor survival.

Radioresponse of hepatocellular carcinoma-treatment of lymph node metastasis.

Abstract: PURPOSE To analyze the radioresponse of hepatocellular carcinomas (HCC), using accurate measurements of the tumor size in extrahepatic lymph node metastasis, and to obtain information for the future treatment of primary intrahepatic lesions. MATERIALS AND METHODS Fifty-one extrahepatic lymph node metastases from primary HCCs, which could be treated by external radiotherapy alone, were included in this study. The radiation dose ranged from 30 to 51 Gy with fraction sizes of 2.0 approximately 3.0 Gy. Responses were determined by measuring the areas on CT scans 0, 1 and 3 months after the completion of radiotherapy. The median follow-up period of the surviving patients was 10 months. RESULTS The overall response rate was 76%, and the important factors were; total dose of radiation, time dose fractionation (TDF) value and the biologically effective dose (BED). A dose of 45 Gy or higher showed an objective response rate of 93%, and if the TDF value was higher than 90, a similar result was observed. In about half (47%) of the patients the maximum response was observed at 3 months or later. The response duration was observable in 14 patients surviving 12 months or longer. Regrowth of irradiated lesions were observed in 4 (66.7%) patients among those who received less than 45 Gy, and in 4 (50%) among those who were treated with 45 Gy or more. There was a statistically significant difference in the survivals between the responders and non-responders (p=0.008). Gastrointestinal bleeding or ulceration was observed in 8 patients, including 3 with NCI common toxicity criteria grade III or higher. CONCLUSION Radiotherapy was an effective palliative modality for extrahepatic metastasis in HCCs. A radiation dose of 45 Gy or higher (or a TDF value >or=90), was required for a major response.

Transcription Factors in the Cellular Signaling Network as Prime Targets of Chemopreventive Phytochemicals

Abstract: Accumulating evidence from epidemiologic and laboratory studies support an inverse relationship between a regular consumption of fruits and vegetables and the risk of specific cancers. Numerous phytochemicals derived from edible plants have been reported to possess ability to interfere with a specific stage of carcinogenic process. Multiple mechanisms have been proposed to account for the anti-carcinogenic actions of dietary constituents, but more attention has recently focussed on intracellular signaling cascades as common molecular targets of a wide variety of chemopreventive phytochemicals.

Photodynamic effects of Radachlorin on cervical cancer cells.

Abstract: PURPOSE Photodynamic therapy (PDT) is a novel treatment modality, which produces local tissue necrosis with laser light following the prior administration of a photosensitizing agent. Radachlorin has recently been shown to be a promising PDT sensitizer. In order to elucidate the antitumor effects of PDT using Radachlorin on cervical cancer, growth inhibition studies on a HPV-associated tumor cell line, TC-1 cells in vitro and animals with an established TC-1 tumor in vivo were determined. MATERIALS AND METHODS TC-1 tumor cells were exposed to various concentrations of Radachlorin and PDT, with irradiation of 12.5 or 25 J/cm(2) at an irradiance of 20 mW/cm(2) using a Won-PDT D662 laser at 662 nm in vitro. C57BL/6 mice with TC-1 tumor were injected with Radachlorin via different routes and treated with PDT in vivo. A growth suppression study was then used to evaluate the effects at various time points after PDT. RESULTS The results showed that irradiation of TC-1 tumor cells in the presence of Radachlorin induced significant cell growth inhibition. Animals with established TC-1 tumors exhibited significantly smaller tumor sizes over time when treated with Radachlorin and irradiation. CONCLUSION PDT after the application of Radachlorin appears to be effective against TC-1 tumors both in vitro and in vivo.

Prognostic Significance of Immunohistochemical Expression of EGFR and C-erbB-2 Oncoprotein in Curatively Resected Gastric Cancer

Abstract: Purpose The purpose of this study was to investigate the prognostic significance of the expression of EGFR and C-erbB-2 gene products by immunohistochemical analysis for curatively resected gastric adenocarcinoma. Materials and methods Between January 1996 and December 2001, 739 patients with curatively resected gastric cancer patients underwent immunohistochemical staining for EGFR and C-erbB-2 proteins, and we retrospectively analyzed their correlation with the clinical outcome. Results The over expressions of EGFR and C-erbB-2 were 25.4% and 26.2%, respectively. The over expressions of EGFR was associated with the more poorly differentiated tumor (p=0.000) and with neuronal invasion (p=0.03). Over expression of C-erbB-2 was associated with less vascular invasion (p=0.001). Tumor depth or node metastasis was not related to the over expression of EGFR or C-erbB-2. The seven-year overall survival and relapse-free survival rates were 87.2% and 75.8%, respectively. Upon multivariate Cox regression analysis, the tumor stage, tumor size and patient age were important prognostic factors for overall survival, and tumor stage was the important factor for relapse-free survival. Over expressions of EGFR or c-erbB-2 were not significant prognostic factors. Conclusion Immunohistochemical staining of EGFR and C-erbB-2 gene products were not independent prognostic factors for predicting the overall survival and the relapse-free survival in curatively resected gastric cancer.

Expression of Caspase-3 and c-myc in Non-Small Cell Lung Cancer

Abstract: Purpose Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death, but little has been studied clinically on caspase-3 in lung cancer. Increased c-myc expression can result in mitosis or apoptosis, and its contribution to the pathogenesis and prognosis of lung cancer has gained interest. In the present study, the expressions of caspase-3 and c-myc, along with their possible correlations with prognostic variables, were analyzed in resected non-small cell lung carcinomas (NSCLC). Materials and methods Archival tumor tissues from 147 previously untreated NSCLC patients were examined by immunohistochemistry for the expressions of caspase-3 and c-myc proteins. Clinical information was obtained through the computerized retrospective database from the tumor registry. Results The expressions of caspase-3 and c-myc were detected in 60 (88/147) and 16% (24/147) of tumors, respectively. No association was found between caspase-3 and c-myc expressions. A multivariate analysis demonstrated the N status and pathologic stage to be significantly correlated with poor survival (p-value=.018 and .002, respectively), but positive expression of caspase-3 was associated with a good prognosis (p=.03). Conclusion Our data suggest the involvement of caspase-3 in the tumorigenesis of NSCLC. It is also noteworthy that caspase-3 expression might be a favorable prognostic indicator in these tumors.

2001 annual report of the Korea Central Cancer Registry: based on registered data from 134 hospitals.

Abstract: PURPOSE To estimate the number of cancer cases during 2001, in Korea, through a nationwide hospital based cancer registration by the Korea Central Cancer Registry (KCCR). MATERIALS AND METHODS One hundred and thirty four hospitals participated in the KCCR program in 2001. Cancer cases were coded and classified according to the International Classification of Diseases for Oncology 2(nd) edition (ICD-O-2). The software program "IARC Check" was used to evaluate the quality of the registered cancer cases. Of the 111,816 malignancies registered, 10,106 (9.0%) duplicated malignancies were excluded. Among the remaining 95,542 malignancies, 3,598 (3.8%) cases with carcinoma in situ (Morphology code/2) were separated. Finally, 91,944 malignancies were analyzed. RESULTS Of the total 91,944 malignancies, 51,753 (56.3%) cases were males and 40,191 (43.7%) were females. More than one third of cases were from the elderly (65 years old and more). The six leading primary cancer sites, in the order of their relative frequency, were stomach (24.1%), followed by the lung (16.0%), the liver (16.0%), the colorectum (10.5%), the bladder (3.4%), and the prostate (2.8%) among males. In females, the breast (16.1%) was the common cancer site, followed by the stomach (15.3%), the colorectum (10.5%), the cervix uteri (10.1%), the thyroid gland (8.3%) and the lung (6.6%). CONCLUSION With the continued increase in cancer cases, the total number of registered cancer cases in Korea continues to rapidly increase.

Activity of green tea polyphenol epigallocatechin-3-gallate against ovarian carcinoma cell lines.

Abstract: Purpose A constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG), is known to possess anti-cancer properties. In this study, the time-course of the anticancer effects of EGCG on human ovarian cancer cells were investigated to provide insights into the molecular-level understanding of the growth suppression mechanism involved in EGCG-mediated apoptosis and cell cycle arrest. Materials and methods Three human ovarian cancer cell lines (p53 negative, SKOV-3 cells; mutant type p53, OVCAR-3 cells; and wild type p53, PA-1 cells) were used. The effect of EGCG treatment was studied via a cell count assay, cell cycle analysis, FACS, Western blot and macroarray assay. Results EGCG exerts a significant role in suppressing ovarian cancer cell growth, showed dose dependent growth inhibitory effects in each cell line and induced apoptosis and cell cycle arrest. The cell cycle was arrested at the G1 phase by EGCG in SKOV-3 and OVCAR-3 cells. In contrast, the cell cycle was arrested in the G1/S phase in PA-1 cells. EGCG differentially regulated the expression of genes and proteins (Bax, p21, Retinoblastoma, cyclin D1, CDK4 and Bcl-X(L)) more than 2 fold, showing a possible gene regulatory role for EGCG. The continual expression in p21WAF1 suggests that EGCG acts in the same way with p53 proteins to facilitate apoptosis after EGCG treatment. Bax, PCNA and Bcl-X are also important in EGCG-mediated apoptosis. In contrast, CDK4 and Rb are not important in ovarian cancer cell growth inhibition. Conclusion EGCG can inhibit ovarian cancer cell growth through the induction of apoptosis and cell cycle arrest, as well as in the regulation of cell cycle related proteins. Therefore, EGCG-mediated apoptosis could be applied to an advanced strategy in the development of a potential drug against ovarian cancer.

Esophageal squamous cell carcinoma recurring as a solitary renal mass.

Abstract: Herein, a case of solitary, unilateral renal metastasis in a patient with curatively resected thoracic esophageal carcinoma, who achieved a pathological complete remission after neoadjuvant concurrent chemoradiotherapy, is reported. The kidney is the 4th or 5th most common visceral metastasis site of a primary esophageal carcinoma. More than 50% of renal metastases typically show bilateral involvement. Solitary, unilateral renal metastasis is extremely rare. Renal metastases from a primary esophageal carcinoma are usually latent and its diagnosis is very unusual in a live patient. The solitary renal metastasis in this case was not accompanied by metastases to other sites. The value of a nephrectomy in solitary renal metastasis of esophageal cancer is not known due to the rarity of such cases. A nephrectomy could be justified in limited situations, such as with uncertainty of histological diagnosis, severe life-threatening hematuria, which cannot be controlled by embolization, or solitary renal metastasis with a long disease-free interval.

Three cases of synchronous solid tumor and multiple myeloma.

Abstract: The association between a multiple myeloma and a secondary solid tumor is not well established. Some reports showed an increased risk of secondary solid neoplasms in multiple myeloma patients, but others have not. Three cases of the synchronous occurrence of multiple myelomas and solid tumors, namely, a small cell carcinoma of the lung, an adenocarcinoma of the colon and a squamous carcinoma of the pyriform sinus were experienced at our hospital. Therefore, herein is reported the clinical courses and treatment results. The stage of multiple myeloma was Durie-Salmon stage I in all of three cases; therefore, the solid tumors were treated as a primary target because the prognosis of early stage multiple myeloma is generally better than that of advanced solid tumor, while a smoldering or stage I myeloma do not need primary therapy until progression of the multiple myeloma. Two patients died of their solid tumors, but one patient is alive.

Reduced expression of E-cadherin in human non-small cell lung carcinoma.

Abstract: PURPOSE: E-cadherin, a calcium-dependent cell to cell adhesion molecule, plays a key role in the maintenance of tissue integrity. Reduction or loss of E-cadherin has been reported to have a role in the development of human malignancies. The expression of E-cadherin was analyzed in human non-small cell lung carcinoma (NSCLC) to elucidate the role in pulmonary carcinogenesis and determine the relationship with several clinicopathological factors and the prognosis. MATERIALS AND METHODS: Sixty five human cases of NSCLC were evaluated by immunohistochemical analysis for the expression of E-cadherin. The immunostaining results for E-cadherin were semiquantitatively interpreted, as preserved and reduced, in the tumor tissues. The E-cadherin expression was analyzed in relation to several clinicopathological data and the survival. The cell proliferation index of the tumors was evaluated by immunostaining with the Ki-67 antigen. RESULTS: Reduced E-cadherin expression was found in 51 cases of NSCLC tissues (78.4%) compared to that in the normal controls. Reduced E-cadherin expression was significantly correlated with male smokers and squamous cell type of the cancer, but not with histological grade, TNM stage and survival. The E-cadherin expression showed a weak inverse relationship with the proliferative activity of tumor cells, which was measured using the Ki-67 antigen. CONCLUSION: Our data support the hypothesis that reduced E-cadherin expression may play a role in the pathogenesis of human NSCLC, which might be associated with the control for cell proliferation. (Cancer Res Treat. 2004;36:56-61)

Microarray applications in cancer research.

Abstract: DNA microarray technology permits simultaneous analysis of thousands of DNA sequences for genomic research and diagnostics applications. Microarray technology represents the most recent and exciting advance in the application of hybridization-based technology for biological sciences analysis. This review focuses on the classification (oligonucleotide vs. cDNA) and application (mutation-genotyping vs. gene expression) of microarrays. Oligonucleotide microarrays can be used both in mutation-genotyping and gene expression analysis, while cDNA microarrays can only be used in gene expression analysis. We review microarray mutation analysis, including examining the use of three oligonucleotide microarrays developed in our laboratory to determine mutations in RET, beta-catenin and K-ras genes. We also discuss the use of the Affymetrix GeneChip in mutation analysis. We review microarray gene expression analysis, including the classifying of such studies into four categories: class comparison, class prediction, class discovery and identification of biomarkers.

DNA damage response mediated through BRCA1.

Abstract: The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast and ovarian cancer syndromes in women. The tumor suppressor, BRCA1 is known as a major player in the DNA damage response. These are evident from its loss, which causes malignant transformation in breast and ovary, and renders cells to become sensitive to a wide variety of DNA damaging agents. Here, we have implications on functional coupling of the pleiotropic roles of BRCA1, including DNA damage signal networking, DNA repair, transcription, and checkpoint of cell cycle, to tumor suppression by examining the molecular mechanisms and functions of BRCA1. The breast cancer susceptibility 1 (BRCA1) gene was identified and mapped to chromosome 17q21 by analyzing families at high risk from breast and ovarian cancer, and was first cloned in 1994 (1). The BRCA1 gene encodes a large nuclear protein that is ubiquitously expressed in a number of tissues. BRCA1 shares little structural resemblance to the majority of other known proteins (Fig. 1). Its ortholog is only found in mammals but not in yeast, fly, worm, or zebra fish, indicating that BRCA1 may come later in evolution and it may have more specialized and tissue-specific functions in mammalian cells. Although a number of studies delineating and deciphering the real biological roles of BRCA1 have accumulated, understanding these BRCA1 unique features still remains to be challengingly elucidated. Fig. 1 A schematic diagram of the BRCA1 polypeptide and its interaction with different proteins. BRCA1 polypeptide has the phosphorylation sites (Ⓟ) shown as the seine residues that are phosphorylated and the kinases responsible. The proteins that are ... BRCA1 as a tumor suppressor The BRCA1 mutations account for about 80% of families whose members have a high incidence of both breast and ovarian cancers (2). The BRCA1 gene fits the profile of a classical 'tumor suppressor gene,' since the breast and ovarian cancers that develop in carriers of BRCA1 gene mutations almost always exhibit loss of the wild-type BRCA1 allele (1). The BRCA1 protein consists of 1863 amino acids (Fig. 1) and is expressed in most proliferating cells (1). The C-terminus of BRCA1 contains an amino-acid sequence motif, now known as a BRCT domain (Fig. 1), recognized in many DNA repair proteins. The BRCT domain of BRCA1 mediates protein interactions that are critical to its role in transcriptional regulation, signaling networking, and the response to DNA damage. The germline mutations in the BRCA1 mutation carriers are frequently found in the BRCT domain, suggesting that the BRCT domain is important for its diverse biological roles. In the N-terminus, there is a ring-finger domain (Fig. 1), also allowing for protein-protein interactions, and thought to be involved in protein ubiquitination. Disruption of the ring domain (by the mutations C61G or C64G) blocked the ability of BRCA1 to repress estrogen receptor-α (ER-α) signaling and to modulate DNA repair, chemosensitivity, and apoptosis. These findings suggest that the ring domain mediates critical protein interactions, and disruption of which contributes to carcinogenesis. Additionally, a variety of structural domains in BRCA1 with these distinct functions hint at diverse roles of BRCA1 in multiple cellular processes. Recent epidemiologic studies indicate that BRCA1 mutation carriers have a high lifetime risk of breast cancer of up to 80%. In addition to the breast cancer risk, women with BRCA1 mutations have an increased risk of ovarian cancer. These works solidify the concept that BRCA1 functions as a tumor suppressor. Despite the multiple lines of strong evidences supporting the function of BRCA1 as a tumor suppressor, the mechanisms and the precise roles through which BRCA1 loss leads to tumorigenesis remain to be determined.

Expression profiling of the cellular processes in uterine leiomyomas: omic approaches and IGF-2 association with leiomyosarcomas

Abstract: Purpose This study utilized both cDNA microarray and 2D protein gel electrophoresis technology to investigate the multiple interactions of the genes and proteins involved in the pathophysiology of uterine leiomyomas. Also, Gene Ontology (GO) analysis was used to systematically characterize the global expression profiles, which were found to correlate with the leiomyosarcomas. Materials and methods The uterine leiomyoma biopsies were obtained from patients in the Department of Obstetrics and Gynecology, The Catholic University of Korea. Differentially expressed transcriptome and proteome, in 6 paired leiomyoma and normal myometrium, were profiled. The total RNAs from the leiomyoma and normal myometrium were labeled with Cy5 and Cy3. All specimens were punch-biopsy-obtained, and frozen in liquid nitrogen. Results Screening of up to 17,000 genes identified 71 that were either up-regulated or down-regulated (21 and 50, respectively). The gene expression profiles were classified into 420 mutually dependent functional sets, resulting in 611 cellular processes, according to the gene ontology. Also, the protein analysis, using 2D gel electrophoresis, identified 33 proteins (17 up-regulated and 16 down-regulated) with more than 500 total spots, which were classified into 302 cellular processes. O f these functional profilings, transcriptomes and proteoms down-regulations were shown in the cell adhesion, cell motility, organogenesis, enzyme regulator, structural molecule activity and responses to external stimulus functional activities, which are supposed to play important roles in the pathophysiology. In contrast, up-regulation was only shown in the nucleic acid binding activity. The CDKN2A, ADH1A, DCX, IGF2, CRABP2 and KIF5C were found to increase the reliability of this study, and correlate with the leiomyosarcomas. Conclusion Potentially significant pathogenetic cellular processes showed that down-regulated functional profiling has an important impact on the discovery of the pathogenic pathways in leiomyomas and leiomyosarcomas. GO analysis can also overcome the complexity of the expression profiles of cDNA microarrays and 2D protein analyses, via a cellular process level approach. Thereby, a valuable prognostic candidate gene, with real relevance to disease-specific pathogenesis, can be found at cellular process levels.

Combination of gemcitabine and cisplatin as first-line therapy in advanced non-small-cell lung cancer.

Abstract: Purpose The prognosis of patients with advanced non-small-cell lung cancer (NSCLC) is extremely poor. Many prospective randomized trials on patients with advanced NSCLC suggested systemic chemotherapy improves both the survival and quality of life. A phase II trial was conducted to evaluate the efficacy and safety profile of the combination chemotherapy of gemcitabine and cisplatin in advanced NSCLC.

Role of microarray in cancer diagnosis.

Abstract: Current cancer diagnosis and classification relies on clinical and histopathological information. However, some cases bring diagnostic confusion due to incomplete clinical information and atypical histopathologic features, together with the fact that criteria for histopathologic information is subjective. Molecular diagnosis using tumor biomarkers offers precise and objective tumor diagnosis. Chromosomal changes and genetic mutations can be used in the molecular diagnosis of tumors. Loss of the long arm of chromosome 14 and activating mutation of c-kit are objective genetic changes in gastrointestinal stromal tumors (1-3), and gene rearrangement of bcr/abl is a diagnostic marker for acute myelogenous leukemia (4). However, molecular diagnosis is not generally accepted because of the scant number of objective tumor markers. Moreover, most of the genetic changes are not specific enough to accurately diagnose the tumors and comprehensive mutation databases for the tumors have not been explored (5). Recently, DNA micro-array-based tumor gene expression profiles have been developed and used in the tumor diagnosis and classification. Many studies have demonstrated that a subset of genes is characteristically expressed in ovarian cancers (6), oral cancers (7), melanomas (8), colorectal carcinomas (9,10) and prostate carcinomas (11,12). Molecular classifications using DNA micro-array is useful for the determination of primary sites in metastatic carcinomas (13) and the classification of soft tissue sarcomas (14). Gene expression profiles by DNA microarray analysis show remarkable intertumoral variations in the same histologic type of tumors. These intertumoral variations can be used for precise molecular classifications and can provide opportunities for the evaluation of genetic changes. Gene expression profiles can successfully differentiate the type of leukemia (15) and the oncogenetic pathway for the T-cell leukemia (16). Additionally, several studies have demonstrated a subset of genes representing different genetic and biological changes in solid tumors. Hereditary breast carcinomas differed in germline mutation status of BRCA1 or BRCA2 (17), and hence, prognosis-related molecular classifications were possible in prostate carcinomas (12), lymphomas (18), and gastric carcinomas (19). Although DNA micro-array analysis for tumor diagnosis and classification is a promising diagnostic modality for the future, currently, there are many limitations. First of all, accurate diagnoses of individual tumors by gene expression profile alone are not always possible. This may be because no reference databases for comprehensive gene expression for cancer has been explored, and no specific group of biomarkers for the diagnosis of specific tumors have yet been developed. Secondly, the gene expression data shows remarkable variations within the same tumor. This may result from different gene expression profiles in the tumors and the different peritumoral lymphoid or stromal reaction status. Thirdly, early tumor detection is not possible by the gene expression profile. Currently, cancer diagnosis with the DNA micro-array is possible only when large amounts and high fractions of tumor cells are prepared. Detection of the membrane protein fragments or specific mutations in circulating tumor cells from body fluids is more effective and a popular approach in the early detection of tumors. The analysis of cancer specific mRNAs from body fluids containing tumor cells is another promising way; however, this can be more effectively carried out by RT-PCR (20,21) han by DNA micro-array. In spite of these limitations, DNA microarray can be best used for molecular classification based on genetic and biological changes. In this month's issue, Bae et al (22). reported gene expression profiling of uterine leiomyomas. The authors analyzed the gene expression profiles of leiomyomas by using the cDNA micro-array. They compared the gene expression profile of leiomyomas to that of normal myometrium and found 21 up-regulated and 50 down-regulated genes. Interestingly, most of the up-regulated genes were ones known to have nucleic acid binding activity. This study is a good model for the evaluation of genes involved in multi-step carcinogenesis. The uterine myometrium is mostly composed of homogeneous myometrial cells, and leiomyoma is also a homogeneous tumor originating from myometrial cells. Moreover, leiomyosarcoma is another homogeneous mesenchymal tumor originating from myometrial cells, thus eliminating the heterogeneous peritumoral reaction. This unusual homogeneity of research materials enables one to find many valuable target genes by expression proteomics analysis. It has been reported that DNA micro-array analysis can be a new method for the classification of soft tissue tumors (14). This method can further improve the method based on histological findings. Specific expression of target genes, such as KIT expression in gastrointestinal stromal tumors, was noted within gene sets that distinguished different soft tissue tumors. DNA micro-array analysis for the multi-step model of malignant transformation in soft tissue tumors, such as leiomyomas and leimyosarcomas, will give important information for genes involved in malignant transformation of soft tissue tumors.

Prospective phase II study of preoperative chemoradiation with capecitabine in locally advanced rectal cancer.

Abstract: PURPOSE: Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer. MATERIALS AND METHODS: A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m(2) capecitabine in two portions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation. RESULTS: Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed. CONCLUSION: Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.

p63 and p73 in tumor suppression and promotion.

Abstract: The recent discovery of two genes, termed p63 and p73, encoding transcription factors highly homologous to p53 presents unexpected challenges and opportunities for the understanding and treatment of cancers. The questions raised are many but center on determining whether these new genes possess novel tumor suppressor functions, cooperate with p53, or impart oncogenic effects. At present there is considerable discord in the field concerning these concepts with some favoring a tumor suppressor role for the p53 family members and others an oncogenic influence. In support of a tumor suppressor role is the ability of p73 and p63 isoforms to transactivate p53 target genes and the large body of work linking p73, and to some extent p63, in apoptotic events in response to cellular stresses generally considered the purview of p53. More recently, p73 has been implicated in cell death following T cell activation, the response of cancers to chemotherapy, and finally, along with p63, to the function of p53 itself. Opposing this view is the fact that the p73 and p63 genes are rarely mutated in cancers and the stark absence of tumors in the p73 null mouse. Moreover, the high expression of dominant negative (dn) versions of the p73 and p63 proteins supports an anti-p53 function and therefore possibly an oncogenic effect. Indeed, the p63 gene is located in a region of chromosome three amplified in squamous cell carcinomas and the number of reports of dn-p63 overexpression in these diseases is increasing. This review will examine both sides of these arguments in an attempt to decipher common themes and to identify opportunities these genes represent for understanding tumorigenesis.

Radical Radiotherapy for Locally Advanced Cancer of Uterine Cervix

Abstract: Purpose This study was performed to evaluate the treatment results, prognostic factors and complication rates in patients with locally advanced cancer of uterine cervix after radiotherapy with high-dose rate (HDR) brachytherapy.

Isolated Diaphragmatic Metastasis Originated from Adenocarcinoma of the Colon

Abstract: Isolated diaphragmatic metastasis arising from colorectal cancer has been reported only one case in the literature presently. Here, we presented a new case and discussed the possible pathogenesis and the treatment options. A 42-year-old male patient had received anterior resection for sigmoid colon cancer. Although the increased serum CEA level was detected 20 months after the surgery, metastatic lesion could not be detected by repeated colonoscopy, CT scan, bone scan or PET scan for 35 months. We could detect a suspicious metastatic lesion on the liver by CT scan at 56 month after the surgery. During a second-look operation, we found a solitary metastasis on the diaphragm and removed it along with the 1 cm tumor-free resection margin. Although the prognosis associated with skeletal metastasis is poor, the complete resection of isolated diaphragmatic metastasis and subsequent appropriate adjuvant chemotherapy may achieve a cure the disease provided that other metastatic lesions are absent.

The differential gene expression profiles between sensitive and resistant breast cancer cells to adriamycin by cDNA microarray.

Abstract: Purpose: Adriamycin is one of the most commonly used drugs in the treatment of breast cancer. This study was performed to understand the molecular mechanisms of drug resistance in breast cancer cells. Materials and Methods: We have analyzed the MCF-7 breast cell line and its adriamycin-resistant variants, MCF-7/ADR using human 10 K element cDNA microarrays. Results: We defined 68 genes that were up-regulated (14 genes) or down-regulated (54 genes) in adriamycin resistant breast cancer cells. Several genes, such as Gprotein-coupled receptor kinase 5, phospholipase A2, guanylate cyclase 1, vimentin, matrix metalloproteinase 1 are up-regulated in drug resistant cells. Several genes, such as interferon, alpha-inducible protein 27, forkhead box M1, mitogen-activated protein kinase 6, regulator of mitotic spindle assembly 1 and tumor necrosis factor superfamily are down-regulated in adriamycin resistant cells. The altered expression of genes observed in microarray was verified by RT-PCR. Conclusion: These findings show that cDNA microarray analysis can be used to obtain gene expression profiles reflecting the effect of anticancer drugs on breast cancer cells. Such data may lead to the assigning of signature expression profiles of drug-resistant tumors which may help predict responses to drugs and assist in the design of tailored therapeutic regimens to overcome drug resistance.

Proteome analysis of differential protein expression in cervical cancer cells after paclitaxel treatment.

Abstract: Purpose It is well known that infection with HPV (human papillomavirus) is the main cause of cervical cancer and certain types of HPV are recognized as carcinogens. At present, there is little information regarding the antineoplastic mechanism of paclitaxel against cervical carcinoma cells. We thus tried to analyze differential protein expression and antineoplastic mechanism-related proteins after paclitaxel treatment on cervical cancer cells by using a proteomic analysis and to investigate the mechanism of action.

Oxaliplatin with Biweekly, Low Dose Leucovorin and Bolus and Continuous Infusion 5-fluorouracil (Modified FOLFOX 4) as First-line Therapy for Patients with Metastatic Colorectal Cancer

Abstract: PURPOSE To determine the activity and toxicities of low dose leucovorin (LV) plus fluorouracil (5-FU) regimen, combined with oxaliplatin every two weeks (modified FOLFOX 4), as a first-line therapy for patients with metastatic colorectal cancer. MATERIALS AND METHODS Between March 2001 and August 2003, fifty-five patients were enrolled in this study. Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion at days 1 plus LV 20 mg/m(2) over 10 minutes, followed by 5-FU bolusa 400 mg/m(2) bolus and 22 hour continuous infusion of 600 mg/m(2) 5-FU at day 1 approximately 2. This treatment was repeated in 2 week intervals. RESULTS The objective response rate was 40% on an intent-to-treatment analysis. Three patients (6%) demonstrated a complete response and nineteen patients (38%) showed a partial response. Sixteen patients (32%) showed a stable disease and eleven patients (22%) progressed during the course of the treatment. The median time to progression and overall survival time were as 6.6 months (95% CI: 4.98 approximately 8.02 months) and the median overall survival time was 17.0 months (95% CI: 9.15 approximately 24.85 months) from the start of the chemotherapy, respectively. A total of 275 cycles were analyzed for toxicity. Major hematologic toxicities included grade 1 approximately 2 anemia (23.5%), neutropenia (25.3%) and thrombocytopenia (10.6%). There were only 2 cycles of neutropenic fever. The most common non-hematologic toxicities were grade 1 approximately 2 nausea/vomiting (10.9%), diarrhea (9.1%) and grade 1 neuropathy (18.0%). There was no treatment related death. CONCLUSION The modified folfox 4 regimen is safe and effective regimen as a first-line therapy in advanced colorectal cancer patients.

Randomized phase III trial of cisplatin, epirubicin, leucovorin, 5-fluorouracil (PELF) combination versus 5-fluorouracil alone as adjuvant chemotherapy in curative resected stage III gastric cancer.

Abstract: PURPOSE The combination of cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) administration, as adjuvant chemotherapy after curative resection for gastric cancer, was compared with 5-fluorouracil (5-FU) administration alone. This paper reports the results of a prospective randomized comparison of the two regimens, PELF and 5-FU. METHODS From August 1996 to July 1999, 54 patients were selected subsequent to being diagnosed with stage III cancer after a curative resection for gastric cancer. The patients were stratified according to stage IIIA/IIIB and subtotal/total gastrectomy, and then they were randomized into each treatment group, i.e. the PELF or 5-FU alone groups. RESULTS 54 assessable patients were enrolled in this study: 28 received PELF and 26 received 5-FU alone. 12 patients relapsed in each group and the median follow-up duration was 42 months (range: 10 approximately 77 months). The overall survival rate and disease-free survival rate (DFS) were not significantly different between two groups, (5-year survival of PELF vs. 5-FU: 57% vs. 64%, 5-year DFS: 54% vs. 51%). The PELF combination was more toxic in terms of anemia, anorexia, nausea and diarrhea than the 5-FU. CONCLUSIONS This study showed that the PELF combination, as an adjuvant therapy for gastric cancer after a curative resection, was a less effective treatment, and it had more toxic effects than the 5-FU.

Synthetic CDCA derivatives-induced apoptosis of stomach cancer cell line SNU-1 cells.

Abstract: Purpose This study was conducted to explore whether CDCA derivatives induce apoptosis in a stomach cancer cell line, and to dissect the detailed mechanism underlying apoptosis Materials and methods The human stomach cancer cell line, SNU-1, cells were treated with the synthetic CDCA derivatives, HS-1199 and HS-1200 DNA and mitochondrial stains were used to detect apoptotic cells by fluorescence imaging or flow cytometry The caspase-3 activity was measured by Western blotting Results Both the HS-1199 and HS-1200 induced decreased viabilities of the SNU-1 cells, in time-dependent manners The CDCA derivatives demonstrated various apoptosis hallmarks, such as mitochondrial changes (reduction of MMP, cytochrome c release, and Smac/ DIABLO translocation), activation of caspase-3 (resulting in the degradation of PARP and DFF45), DNA fragmentation and nuclear condensation Conclusion The CDCA derivatives, HS-1199 and HS-1200, both induced apoptosis of the SNU-1 gastric cancer cells in caspase- and mitochondria-dependent fashions Many important issues relating to their therapeutic applications remain to be elucidated