Phase II Study of Docetaxel, Nedaplatin, and 5-Fluorouracil Combined Chemotherapy for Advanced Esophageal Cancer.

BACKGROUND: We performed a prospective, multi-institutional, phase-II, clinical trial of a docetaxel, nedaplatin, and 5-fluorouracil (DNF) regimen in patients with unresectable esophageal cancer. Our goal was to determine the efficacy and feasibility of this DNF protocol. METHODS: Thirty-four patients with unresectable esophageal cancer were enrolled and received DNF therapy. The DNF regimen was repeated every 4 weeks for up to 8 weeks, based on the following recommended doses: docetaxel, 60 mg/m(2) (day 1); nedaplatin, 70 mg/m(2) (day 1); and 5-fluorouracil, 700 mg/m(2) (days 1-5). The primary endpoint was the response rate. The secondary endpoints were overall survival and chemotherapy toxicities. RESULTS: The complete response rate and response rate were 5.9 and 47.1 %, respectively. The 2-year overall survival rate and progression-free survival rate were 44.3 and 27.3 %, respectively. The median survival time was 594 days. The median progression-free time was 277 days. No treatment-related deaths occurred. Thirty patients (30/34) with grade 3, 4 neutropenia improved relatively quickly with administration of granulocyte colony-stimulating factor. CONCLUSIONS: DNF combination chemotherapy is a useful regimen with relatively minor adverse events and may serve as an effective protocol in patients with unresectable esophageal cancer.

STC2: a predictive marker for lymph node metastasis in esophageal squamous-cell carcinoma.

BACKGROUND: We sought to identify genes associated with the progression and metastasis of esophageal squamous-cell cancer by comparing the expression profiles of normal, primary cancer, and metastatic cancer cells isolated with laser microdissection. METHODS: Oligo microarray analysis identified several lymph node-specific, metastasis-related genes. STC2 (stanniocalcin 2), which was overexpressed in esophageal cancer cases, was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were used to explore the clinicopathologic significance of STC2 expression status in 70 cases. Additionally, the functional role of STC2 in esophageal cancer was studied by the attenuation of STC2 in an esophageal cancer cell line. RESULTS: Laser microdissection and oligo microarray analysis identified 63 candidate genes. Among them, STC2 showed higher expression in cancer tissue than in corresponding normal tissue (P < 0.001). STC2 expression was significantly correlated with lymph node metastasis, lymphatic invasion, and distant metastasis (P = 0.005, 0.007, and 0.038, respectively). Patients whose tumors had high STC2 expression had a worse 5-year survival rate than patients whose tumors had a low STC2 expression level (P = 0.016). STC2 transfected cells had a significantly higher proliferation rate than control cells (P < 0.001). Additionally, STC2 transfected cells were more invasive in vitro (P < 0.001) than control cells. These findings were validated by means of RNA interference assays. CONCLUSIONS: We identified lymph node-specific, metastasis-related genes in esophageal cancer cells. One of these, STC2, may be associated with lymph node metastasis, making it a potential prognostic marker for esophageal cancer patients.

Clinical significance of stanniocalcin 2 as a prognostic marker in gastric cancer.

BACKGROUND: Stanniocalcins are glycoprotein hormones that were originally found in the endocrine gland of bony fish. Microarray expression data from 32 paired samples of gastric cancer and normal mucosa in a public microarray database showed that the expression level of Stanniocalcin 2 was higher in gastric cancer than in normal gastric mucosa. The clinical significance of Stanniocalcin 2 expression has been observed for several cancers. However, the relationship between Stanniocalcin 2 and clinicopathological factors in gastric cancer has not yet been investigated. MATERIALS AND METHODS: We examined the clinical significance of Stanniocalcin 2 in gastric cancer in 108 gastric cancer samples using real-time reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical studies were conducted with paraffin sections. The suppression analysis of Stanniocalcin 2 using siRNA was done to determine Stanniocalcin 2's biological roles. RESULTS: The level of Stanniocalcin 2 in cancer tissues was higher than in normal tissues (P = .0002). The high Stanniocalcin 2 expression group (n = 54) had more progressive lymph node metastasis (P = .07) and venous invasion (P = .028) than the low-expression group (n = 54). High Stanniocalcin 2 expression was an independent prognostic factor in gastric cancer patients (P = .02). Moreover, siRNA suppression of Stanniocalcin 2 in a gastric cancer cell line inhibited cellular proliferation (P < .05). CONCLUSIONS: The high expression level of Stanniocalcin 2 in gastric cancer tissues could be a very powerful marker of poor prognosis. Therefore, Stanniocalcin 2 is a promising candidate for a molecular target for the treatment of gastric cancer.

Clinicopathological significance of stanniocalcin 2 gene expression in colorectal cancer.

Laser microdissection (LMD) and microarray were used to identify genes associated with colorectal cancer. Stanniocalcin 2 (STC2) expression and clinicopathological significance in 139 clinical colorectal cancer samples were specifically investigated using real-time quantitative reverse transcription-polymerase chain reaction. A number of genes upregulated in colorectal cancer cells compared to normal colorectal epithelial cells were identified including STC2. STC2 gene expression in cancer tissue was higher than in corresponding normal colorectal epithelial tissue in 124 of 139 cases (89.2%, p < 0.01). Tumors with high STC2 expression showed higher frequencies of lymph node metastasis, lymphatic invasion, tumor depth, tumor size and AJCC Stage classification (p < 0.01). Patients with high STC2 expression also showed significantly worse overall survival rates than those with low STC2 expression (p < 0.01). Furthermore, STC2 gene appeared to be associated with colorectal cancer progression and may be a useful prognostic indicator for colorectal cancer.

Cancer stem cells and chemoradiation resistance.

Cancer is a disease of genetic and epigenetic alterations, which are emphasized as the central mechanisms of tumor progression in the multistepwise model. Discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. The heterogeneity of tumors can be explained with the help of CSCs supported by antiapoptotic signaling. CSCs mimic normal adult stem cells by demonstrating resistance to toxic injuries and chemoradiation therapy. Moreover, they might be responsible for tumor relapse following apparent beneficial treatments. Compared with hematopoietic malignancies, conventional therapy regimes in solid tumors have improved the overall survival marginally, illustrating the profound impact of treatment resistance. This implies that the present therapies, which follow total elimination of rapidly dividing and differentiated tumor cells, need to be modified to target CSCs that repopulate the tumor. In this review article, we report on recent findings regarding the involvement of CSCs in chemoradiation resistance and provide new insights into their therapeutic implications in cancer.

Biological and genetic characteristics of tumor-initiating cells in colon cancer.

BACKGROUND: Human prominin-1 (PROM1, CD133) was used as a marker to detect stem cells (progenitor cells) and cancer stem cells (tumor-initiating cells) in various tissues. The purpose of this study was to investigate the biological and genetic characteristics of tumor-initiating cells in colon cancer with both in vitro and in vivo analyses. METHODS: The CD133 expression of 12 colon cancer cell lines was evaluated. CD133+ cells were isolated by flow cytometry and examined for in vivo tumor formation, in vitro proliferation, colony formation, and invasion ability. Additionally, we used microarray analysis to compare gene expression profiles between CD133+ and CD133- isolated cells. RESULTS: CD133+ cells were found in 5 of 12 colon cancer cell lines. Isolated CD133+ cells from the HT29 colon cancer cell line exhibited a higher tumorigenic potential than CD133- cells in the in vivo tumor formation assay. Furthermore, it was shown that CD133+ cells are more proliferative and have higher colony-forming and invasive abilities than CD133- cells in vitro. Microarray analysis found differential gene expression correlating with CD133 expression. CONCLUSIONS: It was confirmed that CD133+ cells in colon cancer are useful markers for the detection of tumor-initiating cells. Intimate biological and genetic features of CD133+ cells in colon cancer cell lines were also revealed. The biological characteristics of CD133+ cells and differentially expressed genes in these cells will help elucidate more details of tumor-initiating cells in colon cancer.

The additional value of integrated PET/CT over PET in initial lymph node staging of esophageal cancer.

The purpose of the present study was to assess the contribution of simultaneous functional/anatomical imaging using integrated 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), compared with PET alone for the evaluation of initial lymph node staging in esophageal cancer. We studied 167 consecutive patients with thoracic esophageal squamous cell carcinoma (SCC) who had radical esophagectomy performed between January 1999 and April 2007. For individual nodal group evaluation, PET/CT showed 46.0% sensitivity (p<0.05 vs. PET), 99.4% specificity, 95.1% accuracy (p<0.05 vs. PET), 87.0% positive and 95.5% negative predictive values. PET showed 32.9% sensitivity, 98.9% specificity, 93.1% accuracy, 74.7% positive predictive value and 93.9% negative predictive value. Thus, the sensitivity and accuracy of PET/CT were significantly higher than those of PET. Comparisons between CT, PET and PET/CT in detecting lymph node metastasis by each region showed that PET/CT had a higher sensitivity in lower thoracic regions than PET and CT (p<0.05 vs. CT and PET). Lymph node staging (N0 vs. N1) was not significantly different, but staging per lymph nodal group was significantly better with PET/CT. Integrated PET/CT imaging with co-registration of anatomic and functional imaging data is useful in the initial lymph node staging of patients with operable esophageal cancer compared with PET alone.

Adult intussusceptions induced by a terminal ileum diverticulum: a case report.

We herein report a case of adult intussusceptions induced by a terminal ileum diverticulum. Histological examination confirmed a terminal ileum diverticulum full of feces, and it was considered an infiltrated region. The clinical characteristics of previously reported adult intussusceptions are also discussed, including jejunoileal diverticulum and surgical management.

[Cancer stem cell].

Recently it is considered that there is a small population of cells with stem cell property not only in leukemia but also in solid cancer.These cells show the ability of self-renewal and multi-potential differentiation, and can initiate and maintain a tumor. The origin of cancer stem cells might be their normal stem cells, progenitor cells, or bone marrow-derived cells. It is still difficult to isolate cancer stem cells in solid cancer. There are three possible methodologies to isolate or identify cancer stem cells; the use of a surface marker, use of cells cultured in a specific condition (sphere), or the use of side population cells identified by FACS. The gold standard assay that fulfills the definition of cancer stem cell may be serial transplantation in animal models. Cancer stem cells are likely to be responsible for disease relapse or metastasis, and also for resistance to radiation or conventional chemotherapy. The stem cell niche plays an important role on maintaining cancer stem cells. The novel promising therapies against cancer stem cells are considered, including antibody-based therapy, signal inhibitors, overcoming radiation and drug resistance, or differentiation therapy. Another interesting therapy targeting the niche may also be considered.

Phase I/II study of docetaxel, cisplatin, and 5-fluorouracil combination chemoradiotherapy in patients with advanced esophageal cancer.

PURPOSE: This phase I/II study was aimed to determine the recommended dose (RD) of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for patients with esophageal cancer and to evaluate the efficacy and safety of this protocol. METHODS: Fourteen patients with esophageal cancer enrolled in this dose escalation study to determine the RD for a phase III trial. Efficacy and toxicity in DCF-RT of RD were evaluated in 37 patients with esophageal cancer. RESULTS: The RD for DCF-RT for esophageal cancer in the present study was 50 mg/m(2) docetaxel plus 60 mg/m(2) cisplatin on day 1 and day 29 plus 600 mg/m(2) 5-FU on days 1-4 and days 29-32 and concurrent radiation of 60 Gy/30 fractions/6 weeks. The main toxicities were myelotoxicity and radiation esophagitis. In this phase I/II study, we could have safety and feasibility by RD, because there was low mortality and most toxicities were manageable level. The complete response (CR) rate and response rate were 54.1 and 83.8 %, respectively, in the phase II study. In patients with a classification of clinical T4, the CR rate and response rate were 47.6 and 85.7 %, respectively. The 2-year overall survival rate, 2-year progression-free survival rate, and median survival time (MST) were 52.9, 50.0 %, and 24.7 months, respectively. In patients with clinical T4 classification, the 2-year overall survival rate, 2-year progression-free survival rate, and MST were 43.5, 44.9 %, and 21.6 months respectively. CONCLUSIONS: DCF-RT keeps safety and feasibility by management of myelotoxicity adequately in RD. This protocol might produce a high CR rate and favorable prognosis compared with standard chemoradiotherapy for advanced esophageal cancer.

A case of chondromatous tumor of the breast.

This report describes an exceedingly rare case of a benign cartilage-containing breast tumor that developed in the right breast of a 52-year-old woman. She found the mass on self examination. Physical examination revealed a 1.5 x 1.4 cm, firm, smooth and mobile lump in the lower medial quadrant close to the nipple of the right breast. Mammography revealed a slightly indistinct margined, oval-shaped, and high density nodule without microcalcifications. On ultrasonography, the lesion was a hypoechoic, oval-shaped mass with an echogenic spot. The border was slightly rough. Fine needle aspiration cytology revealed some giant cells and necrotic tissue. Excisional biopsy was then performed. Histopathologically, the lesion consisted of islands of mature hyaline cartilage with intervening strands of fibrous stroma. Mammary lobules and ducts were lacking within the mass. Fat and muscular components were not present. Therefore chondromatous tumor of the breast was diagnosed.

Recurrent spontaneous esophageal rupture.

Spontaneous rupture of the esophagus is a relatively uncommon event, and recurrent rupture is extremely rare. We present a patient who experienced and survived 2 spontaneous perforations of the esophagus, occurring 6 years apart. A 43-year-old man was admitted to our hospital with upper abdominal pain after vomiting. Esophagoscopy, esophagogram, and computed tomography were suggestive of esophageal rupture. Emergency left thoracolaparotomy revealed a 20-mm perforation of the left lower esophageal wall that had been previously repaired. After the perforation was repaired with a single-layer closure, the mediastinum and pleural cavity were drained. The patient recovered well and was discharged from the hospital on postoperative day 29. To the best of our knowledge, only 7 previous cases of recurrent spontaneous esophageal perforation have been reported in the literature.

Phase I dose-escalation study of docetaxel, nedaplatin, and 5-fluorouracil combination chemotherapy in patients with advanced esophageal cancer.

More effective protocols are needed for unresectable and recurrent esophageal cancer. Therefore, we conducted a phase I trial to establish the recommended dose of docetaxel, nedaplatin, and 5-fluorouracil (DNF) as combination chemotherapy. Fourteen patients with esophageal cancer were enrolled and received DNF combination therapy at different dose levels according to the treatment and examination plan. Dose-limiting toxicities (DLTs) included febrile neutropenia. DLTs occurred in 3/5 patients at level 4. The recommended doses (level 3) of DNF were 60 mg/m(2) (day 1), 70 mg/m(2) (day 1), and 700 mg/m(2) (days 1-5), respectively, given at 3-week intervals. In conclusion, DNF combined chemotherapy for advanced esophageal cancer was associated with relatively minor adverse events and was safely administered at the recommended dose. A phase II study is now underway.

Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression.

This study consisted of 2 aims: (i) to determine genes associated with hepatocellular carcinoma (HCC) by microarray analysis; and (ii) to evaluate the clinicopathological significance of human ubiquitin-conjugating enzyme E2C (Ube2c) found to be overexpressed in HCC from microarray analysis. Laser microdissection and cDNA-microarray were performed to identify genes associated with HCC. We then focused on the Ube2c gene. Using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR), Ube2c expression status and clinicopathological significance were studied in 65 clinical HCC samples. A number of genes upregulated in HCC cells compared to noncancerous liver cells were identified, one of which was the Ube2c gene. Ube2c gene expression in the cancer tissue was higher than in the corresponding noncancerous tissue in 62 of the 65 cases (95.4%, p < 0.01). Tumors with high Ube2c expression showed higher frequencies of tumor invasion to capsular formation (fc-inf), invasion to portal vein (vp) and tumor de-differentiation (p < 0.05). Patients with high Ube2c expression also showed significantly worse disease-free survival rates than those with low Ube2c expression (p < 0.01). In addition, Ube2c expression was found to be an independent prognostic factor for disease-free survival rate in multivariate analysis. We identified differentially expressed genes between HCC and normal liver tissues. Of those, the Ube2c gene appeared to be associated with HCC progression, and may be useful as a prognostic indicator for HCC patients.

Opa interacting protein 5 (OIP5) is a novel cancer-testis specific gene in gastric cancer.

BACKGROUND: Identification of novel cancer-specific antigens is important for the advancement of immunotherapy. Our aim was to identify cancer-specific genes in gastric cancer. METHODS: Using cDNA microarray analysis, we detected genes overexpressed specifically in gastric cancer cells. The expression levels of selected genes, including OIP5, was confirmed by real time RT-PCR analysis in tumor/normal paired bulk samples of 58 clinical cases. The expression levels of selected genes in normal tissues were also determined with a human total RNA master panel. We also compared the expression status of OIP5 with that of the other known cancer-testis specific genes. RESULTS: Twenty-two genes were determined to be upregulated in gastric cancer cells. Among these, three genes (CDC6, Exo1, and OIP5) were selected and confirmed to be upregulated in the tumor tissue compared to normal tissue. A human total RNA master panel demonstrated that OIP5, but not Exo1 or CDC6, showed high specificity in testis. Thus OIP5 may be considered a cancer-testis specific gene. In 58 clinical cases of gastric cancer examined, we found OIP5 gene expression in 27 cases (47%). Thirteen of these 27 cases showed no expression of the known cancer specific genes such as MAGE-1, MAGE-3 or NY-ESO-1. CONCLUSIONS: Using a combination of LMD and microarray, we identified OIP5 as a cancer-testis specific gene. Further expression analysis in a set of clinical cases revealed that OIP5 may be a novel immunotherapy target for patients with gastric cancer.

Loss of MAL expression in precancerous lesions of the esophagus.

BACKGROUND: We have identified a novel function of MAL (T-cell differentiation-related gene) as a candidate suppressor gene in esophageal cancer. As the role of MAL expression in esophageal carcinogenesis is as yet undetermined, MAL expression in a rat multi-step carcinogenic model and in precancerous lesions of the human esophagus was investigated. Microarray analysis between MAL-transfectant and control cells was also carried out to clarify how MAL confers its anti-tumor effects. MATERIALS AND METHODS: (1) In the rat model, MAL expression levels in laser microdissected normal esophageal epithelium, dysplastic tissues and carcinoma tissues were examined by reverse transcription (RT)-PCR. (2) Immunostaining with MAL antibody was performed in 10 dysplastic lesions adjacent to cancer in six cases of esophageal cancer. (3) We established a MAL transfectant using a Tet-off vector in esophageal cancer cells and performed microarray analysis under MAL-positive and MAL-negative conditions. RESULTS: (1) In the rat model, MAL mRNA expression was observed only in the normal samples. (2) MAL expression was observed distinctively in differentiated or keratinized normal tissues and was not observed in either dysplastic lesions or carcinoma tissue. (3) Up-regulated genes in MAL-positive cells included keratin 18 (transfectant/control = 2.94) and keratin 10 (t/c = 2.82). CONCLUSION: MAL expression was lost in dysplastic lesions of the rat carcinoma model as well as the human esophagus. The up-regulated keratins revealed by microarray analysis and the strong staining of the differentiated normal tissues in immunohistochemical study support the role of MAL as a regulator of differentiation in esophageal epithelium.

Pilot study of the effects of ONO-5046 in patients with acute respiratory distress syndrome.

Evidence has linked neutrophil elastase to acute respiratory distress syndrome (ARDS), suggesting that inhibiting the activity of this enzyme could prevent the development and progression of ARDS. However, few clinical trials have examined this notion. We therefore examined the effects of ONO-5046 (sivelestat, a specific inhibitor of neutrophil elastase; sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylaminobenzoyl]amino-acetate tetrahydrate]) in a randomized, double-blinded trial in patients with ARDS. We randomly assigned 24 patients with ARDS to groups that received conventional therapy without or with sivelestat (0.2 mg. kg(-1). h(-1)) for 14 days. The variables of interest associated with clinical outcome were the duration of mechanical ventilation; changes in oxygenation from baseline; changes in cytokine levels from baseline; number of patients alive at 30 days who did not need mechanical ventilation; and mortality rate. The length of intensive care unit stay, number of ventilation days, and mortality rates did not statistically differ between groups. ARDS was more persistent in the control than in the sivelestat group (control, 19.5 +/- 7.4 days; sivelestat, 13.5 +/- 5.9 days; P = 0.039). Neutrophil elastase activity significantly differed between groups at 72 h after treatment. Levels of interleukin-6 were lower in the sivelestat group than in the controls at 24, 48, and 72 h after treatment. ONO-5046 apparently did not affect survival or the duration of mechanical ventilation.