Melanoma-associated antigen-A1 expression predicts resistance to docetaxel and paclitaxel in advanced and recurrent gastric cancer

Melanoma-associated antigen (MAGE) genes are cancer-testis antigen genes that serve as immunotherapy targets in several human cancers. Previous studies have revealed that the forced expression of MAGE genes induces a paclitaxel-resistant phenotype. In the present study, we examined whether the expression of MAGE-A1 could predict the response of advanced and recurrent gastric cancers (GCs) to taxan (doce-taxel or paclitaxel)-based chemotherapy. The expression of MAGE-A1 was analyzed by immunostaining in 41 primary GC samples. DNA demethylation was assessed by methylation-specific polymerase chain reaction and the effect of the forced expression of MAGE-A1 on drug resistance to taxan drugs was monitored by MTT assay. The expression of MAGE-A1 in primary GC was observed in 4 (9.8%) of 41 cases. All 4 patients with MAGE-A1-positive GC showed progressive disease, whereas MAGE-A1 expression was not detected in any of the 23 patients showing partial response (P=0.0302). There was no association between MAGE-A1 gene demethylation and response to chemotherapy (P=0.7245). The forced MAGE-A1 expression in the TMK-1 GC cell line increased the sensitivity to paclitaxel and docetaxel. These results suggest that although MAGE-A1 does not participate directly in the drug-resistant phenotype, the expression of MAGE-A1 could be a marker for the prediction of resistance to taxan-based chemotherapies in patients with GC.     

An animal model of intrinsic dental erosion caused by gastro-oesophageal reflux disease

Objectives:  To explore the association between dental erosion and gastro-oesophageal reflux disease (GORD), we used an animal model of GORD.
Materials and Methods:  We performed an operation to force gastro-duodenal contents reflux in male Wistar rats, and examined the teeth in the reflux rats at 15 or 30 weeks postoperatively. Dental erosion was evaluated based on a slightly modified index from a previous report. Estimation of pH was employed in the oesophageal and gastric contents.
Results:  Macroscopically, dental erosion was only detected in the reflux rats. Histopathologically, dentin exposure was detected in three of the seven cases after 30 weeks. Alveolar bone destruction and osteomyelitis were also noted in severe cases. The pH of the oesophageal and stomach contents was 6.93 ± 0.15 and 3.7 ± 0.39, respectively.
Conclusions:  We confirmed the relationship between dental erosion and GORD. First step of dental erosion caused by GORD is the loss of surface enamel induced by regurgitation of an acidic liquid and acidic gas. Subsequently, further destruction of dental hard tissues and tooth supporting structure is accelerated by mixed juice with gastric and duodenal contents. The reflux animal model is a useful tool to examine the mechanism of dental erosion in GORD.     

Novel anti-HIV-1 activity produced by conjugating unsulfated dextran with polyL-lysine

A conjugate of polyL-lysine (PLL) with unsulfated dextran produced by reductive amination was found to have remarkable anti-HIV-1 activity against both the macrophage-tropic R5 virus Ba-L and T-cell line tropic X4 virus IIIB strains, although neither PLL nor dextran has such activity. The conjugate is a pseudoproteoglycan (pseudoPG) that simulates the structure of a proteoglycan. Conjugation with dextran was found to produce an antiviral effect in three kinds of assay systems including a human CD4(+) T-cell line, and the pseudoPG synthesized using 10 kDa PLL and 10 kDa dextran showed EC(50) 4-40 times lower than that of sulfated dextran or heparin against Ba-L and EC(50) equal to that against IIIB, indicating that PLL-dextran (PLL-Dex) was more effective against R5 virus than sulfated polysaccharides. PLL-Dex significantly suppressed a clinically isolated R5 virus from primary peripheral blood mononuclear cells. PLL-Dex interacted with the virus during adsorption to the cell and also decreased virus entry into the cell, suggesting PLL-Dex has multiple preventive mechanisms against HIV-1.     

Dumbbell-shaped Ewing’s sarcoma family of tumor of thoracic spine in a child

An 8-year-old boy was referred due to difficulty in walking. T1-weighted MRI detected a well-marginated lesion expanding from the epidural region in the spinal canal to the paravertebral area through the Th9 and Th10 intervertebral foramen. The patient underwent a biopsy under video-assisted thoracoscopy and the tumor was diagnosed as Ewing's sarcoma family of tumor (ESFT). Imaging confirmed that the tumor completely disappeared and his neurologic functions were recovered perfectly at the end of treatment. Very few cases of skeletal ESFT of epidural extension in childhood have been documented. Video-assisted thoracoscopic surgery remains the best option for the diagnosis of endothoracic tumors in children.     

Pediatric thyroid cancer arising after treatment for pleuropulmonary blastoma

A 3-year-old female presented with a large tumor occupying the right thoracic space. Open biopsy revealed the pathological diagnosis of pleuropulmonary blastoma. After the first-line chemotherapy, the patient underwent surgical resection, then two courses of high-dose chemotherapy. Three years later, follicular carcinoma of the right thyroid lobe was found, so a right hemithyroidectomy was performed. Five months later, the thyroid tumor recurred. The remaining thyroid lobe was completely excised and radioiodine therapy was administered. The patient has remained tumor-free for 3 years. The etiology and treatment of the uncommon combination of pleuropulmonary blastoma and thyroid carcinoma is discussed.     

Molecular diagnosis of gastric cancer: present and future

Although histopathological diagnosis is extremely useful for the definitive as well as the supportive diagnosis of gastric cancer in clinical practice, it is limited in certain respects. Over the past 15 years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of the development and progression of gastric cancer. These abnormalities, which include telomerase activation, genetic instability, and abnormalities in oncogenes, tumor suppressor genes, cell-cycle regulators, cell adhesion molecules, and DNA repair genes, could be effective markers in the molecular diagnosis of gastric cancer. It is possible that the molecular analysis of these alterations in histopathology specimens may overcome deficiencies in diagnoses that depend only on histomorphology, and, consequently, we may be able to improve the differential diagnosis of cancer, obtain information on the grade of malignancy, and identify patients at high risk of developing multiple primary cancers. In Hiroshima, we have established a system of molecular-pathological diagnosis as a routine service; about 5000 lesions of the stomach have been subjected to this diagnosis, and much useful information has been obtained. In the near future, genetic analysis by means of DNA microarray may become routine in the diagnosis of gastric cancer. Genetic analysis of histopathology specimens may make clear the characteristics of individual cancers; indicating the common and specific features of molecular pathogenesis that may be directly connected with gene therapy or molecular-targeted therapy. By analyzing the relationship between single-nucleotide polymorphisms and cancer susceptibility, we will be able to obtain information on cancer prevention from histopathology samples. Received: May 21, 2001 / Accepted: July 3, 2001     

Hedgehog signal inhibitors suppress the invasion of human rhabdomyosarcoma cells

Purpose

In the treatment of rhabdomyosarcoma (RMS), invasion and metastasis remain the most critical determinants of resectability and survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in the invasion of RMS.

Methods

Two kinds of specific Hh signaling inhibitors, cyclopamine and forskolin, were used to suppress activated Hh signals in three RMS cell lines. The effects of the Hh signaling inhibitors on tumor cell invasion and motility were investigated using Matrigel invasion assays and wound closure assays, respectively.

Results

The number of invaded cells counted in six random microscopic fields in the Matrigel chambers was significantly decreased by both cyclopamine and forskolin in every RMS cell line. Furthermore, the wound closure assays revealed that a blockade of the Hh signaling pathway by the Hh inhibitors strongly impairs RMS cell motility, as visualized by the delayed closure of the gaps generated in the cultured cell monolayers of the three RMS cell lines.

Conclusions

Both the invasive capacity and motility of RMS cells are significantly suppressed by Hh signaling inhibitors, demonstrating that the Hh pathway plays an important role in the invasion of RMS. Hh inhibitors may provide a new paradigm for the treatment of RMS.     

A case of solitary metastasis of renal cell carcinoma to the thyroid gland

A case of solitary metastasis of renal cell carcinoma to the thyroid gland is reported. A 63-year-old-woman had been found to have an abnormal mass in the neck since April, 1986. She had a past history of right nephrectomy owing to right renal tumor 6 months earlier. Histological examination of the renal tumor revealed, common type, alveolar type, G1, INF alpha renal cell carcinoma. No metastasis was found on abdominal CT, chest tomography and bone scintigram at that time. Radical thyroidectomy was performed on June, 23, 1986. Histological examination by hematoxylin and eosin staining revealed metastasis of renal cell carcinoma, and immunohistochemical technique ruled out primary thyroid carcinoma. Postoperatively no other metastasis was found on head-chest-abdomen-CT, chest-tomography or bone scintigram. Therefore no particular adjuvant therapy was performed.