A case of granulocyte-colony stimulating factor producing gastric cancer]

We report a case of granulocyte-colony stimulating factor producing gastric cancer with multiple liver metastases. A 68-year-old woman who complained of epigastralgia visited our hospital. Upper gastrointestinal endoscopic examination revealed a type-2 gastric cancer. The laboratory data at admission indicated leukocytosis (35,900/microl) and a high level of serum granulocyte-colony stimulating factor (61 pg/mg). Granulocyte-colony stimulating factor producing gastric cancer was diagnosed by immunohistochemistry of biopsy specimen. Since we detected multiple liver metastases, chemotherapy was performed. Granulocyte-colony stimulating factor-producing gastric cancer is relatively rare and we summarize previous reports.     

Hepatocellular carcinoma: Efficacy of transcatheter oily chemoembolization in relation to macroscopic and microscopic patterns of tumor growth among 100 patients with partial hepatectomy

Purpose: To evaluate the efficacy of transcatheter oily chemoembolization (TOCE) for hepatoceliular carcinoma (HCC) on the basis of microscopic and macroscopic findings postembolization. Methods: HCCs ranging in size from 0.5 to 13 cm (mean 3.6 cm) were obtained from partial hepatectomies of 100 consecutive patients who had undergone TOCE between 20 and 246 days (mean 59.5 days) prior to surgery. The efficacy of TOCE was assessed on the basis of the necrotic to live cell ratio of the tumors. The microscopic pattern of tumor growth was grouped into expanding type (complete capsule formation) and replacing type (incomplete or no capsule). There were five types of macroscopic groupings: single nodule, single nodule with extranodular growth (SNE), contiguous and noncontiguous multinodular, and massive growth type. Results: Among 79 cases with the expanding type, 29 (37%) had 100% HCC necrosis, but none with 100% necrosis were in the replacing type. By macroscopic grouping, the efficacy of TOCE decreased from the single nodule type (50% of patients had 100% necrosis) to the SNE type (21%), and the other types (9%).     

Ultrastructure of primary squamous cell carcinoma of the submandibular gland

Primary squamous cell carcinoma of the submandibular gland is a rare tumor. In this report, the histological and ultrastructural features of a case of primary squamous cell carcinoma arising in the left submandibular gland is presented. Light microscopically, the tumor consisted of well differentiated keratinizing squamous cell nests. Ultrastructurally, the tumor cells were oval or spindle-shaped, and several tumor cells had intracytoplasmic desmosome-like structures, resembling intercellular desmosomes. The majority of the tumor cells contained a large number of intermediate filaments (tonofilaments). Intercellular desmosomes were well developed. No secretory granules were found. These ultrastructural features may enable us to distinguish primary squamous cell carcinoma from mucoepidermoid carcinoma which is often misdiagnosed as squamous cell carcinoma.     

Nucleotide mutations associated with hepatitis B e antigen negativity

One hundred and forty four patients with chronic hepatitis B were tested to identify new mutations associated with hepatitis B e antigen (HBeAg) negativity, using a full genome sequence analysis. All the patients were Chinese and had hepatitis B virus infection of genotype C. Patients with none of the pre-core or core promoter mutations were significantly (P < 0.001) less common in the group with anti-HBe (13%) than in the group with HBeAg (56%). The complete nucleotide sequence was determined in four anti-HBe-positive patients who had neither pre-core nor core promoter mutations and in five HBeAg-positive patients who also had neither of these mutations (the groups were matched for age and sex). Six mutations were found to be significantly more common in the former group than in the latter: G529A (3/4 vs. 0/5), C934A (4/4 vs. 1/5), A1053G (4/4 vs. 1/5), G1915T/A (4/4 vs. 0/5), T2005C/A (4/4 vs. 0/5), and C3026T (3/4 vs. 0/5). Three of the six mutations were significantly more common in the four anti-HBe-positive patients who had neither pre-core nor core promoter mutations, compared to 11 HBeAg-positive patients who had pre-core and core promoter mutations, and also compared to 15 anti-HBe-positive patients who had pre-core and core promoter mutations, suggesting further the specificity of these mutations. Of the six mutations, two resulted in amino acid substitution in the polymerase protein, and one is located near the enhancer I region. The results suggest that the six newly discovered mutations are associated with HBeAg negativity.     

Kinetics of hepatic transport of 4-methylumbelliferone in rats. Analysis by multiple indicator dilution method

Hepatic elimination of 4-methylumbelliferone (4MU), which has been used as a model compound for conjugative metabolism, was studied by means of a multiple indicator dilution (MID) method in the isolated perfused rat liver. Using this method, three intrinsic hepatic clearances, CL _int,inf , CL _{int,eff, and} CL _{int,seq, which represent the influx, efflux, and sequestration processes, respectively, were obtained. When the dose was increased from a low dose (50 g/rat liver) to a high dose (3000 g/rat liver), the hepatic availability of 4MU increased from 0.11 to 0.73. With increasing dose, the} CL _{int,eff value increased approximately two times, while the} CL _{int,seq value decreased to approximately one-third. The remarkable dose dependence of hepatic availability was due to nonlinearity in both} CL _{int,eff and} CL _{int,seq values. However, the} CL_int,inf value was almost independent of dose. The dose-dependent change in CL_int,seq might be explained by the saturation of conjugative metabolism of 4-MU, while the increase in the CL _{int,eff value with increasing dose might be partly explained by the nonlinear tissue binding of 4-MU, since the tissue unbound fraction determined by an ultrafiltration method using liver homogenate increased approximately 1.5 times at higher concentration of 4-MU compared to that at lower concentrations. In addition, based on a comparison of the individual intrinsic clearances, i.e.}, CL _int,inf , CL _{int,eff, and} CL _{int,seq, the major determining process of the apparent hepatic intrinsic clearance of 4MU is thought to be the sequestration process at the high dose. However, at the low dose, the membrane transport process (influx and efflux processes) as well as the sequestration process also determine the apparent hepatic intrinsic clearance}.     

beta-Catenin and ras oncogenes detect most human colorectal cancer.

PURPOSE AND STUDY DESIGN: Recent studies have shown that beta-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the beta-catenin oncogenic signaling cascade along with its twin, the K-ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we analyzed oncogenic beta-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those of mutational activation of K-ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact. RESULTS: We found two distinct patterns of beta-catenin activation, i.e., diffuse NA in 20 cases (27%) and selective NA at the tumor invasion front (NAinv) in 19 cases (26%). The presence of the NAinv pattern was significantly correlated with advanced Dukes' stage tumor (P = 0.0005) and the presence of distant metastases (P = 0.0064). K-ras proto-oncogene was mutated in the tumors of 31 cases (42%). Activated beta-catenin or K-ras was detected in most (78%) colorectal cancers analyzed, although a weak inverse correlation was found between the activities of the two oncogenes in the tumors. Importantly, most (7 of 8) patients with tumor showing both K-ras activation and the NAinv pattern of beta-catenin activation were in Dukes' stage C at surgery, and half of them developed distant metastases to the liver and lungs. CONCLUSION: The results suggest that although oncogenic activation of beta-catenin and K-ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes. Consequently, activation of either or both of these oncogenes may serve as a genetic marker for molecular diagnosis.     

Truncated midkine as a marker of diagnosis and detection of nodal metastases in gastrointestinal carcinomas.

Midkine (MK) is a growth factor identified as a product of a retinoic acid-responsive gene. A truncated form of MK mRNA, which lacks a sequence encoding the N-terminally located domain, was recently found in cancer cells. We investigated the expression of the truncated MK mRNA in specimens of 47 surgically removed human gastrointestinal organs using polymerase chain reaction. Truncated MK was not detected in all of the 46 corresponding non-cancerous regions. On the other hand, this short MK mRNA was expressed in the primary tumours in 12 of 16 gastric cancers, 8 of 13 colorectal carcinomas, five of nine hepatocellular carcinomas, two of two oesophageal carcinomas and one ampullary duodenal cancer. In addition, truncated MK was detectable in all of the 14 lymph node metastases but in none of three metastatic sites in the liver, suggesting that truncated MK mRNA could become a good marker of nodal metastases in gastrointestinal tract.     

Quantification of N-acetyl-seryl-aspartyl-lysyl-proline in hemodialysis patients administered angiotensin-converting enzyme inhibitors by stable isotope dilution liquid chromatography-tandem mass spectrometry

We developed a sensitive, selective and accurate method based on liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine N-terminal thymosin-β peptides of Ac-SDKP and Ac-ADKP in human plasma samples. Quantification of Ac-SDKP and Ac-ADKP was performed using solid phase extraction (SPE) based on C(18), reversed phase LC separation, and stable isotope dilution electrospray ionization-MS/MS in multiple reaction-monitoring (MRM) mode. The Ac-SDKP-(13)C(6), (15)N(2) and Ac-ADKP-d(7) were synthesized for the internal standards. These MRM monitoring ions were m/z 488→129 (quantitative ion)/226 for Ac-SDKP, m/z 496→137 for Ac-SDKP-(13)C(6), (15)N(2), m/z 472→129 (quantitative ion)/226 for Ac-ADKP, and m/z 479→129 for Ac-ADKP-d(7), respectively. Lower limit of quantitation (LLOQ) of Ac-SDKP and Ac-ADKP was 0.1ng/mL in human plasma. Recovery values were ranged from 94.7% to 106.3% for inter- (RSD: 0.6-3.5%) and intra- (RSD: 0.4-4.9%) day assays. Plasma Ac-SDKP levels were significantly higher in hemodialyzed subjects treated with angiotensin-converting enzyme inhibitors of enalapril (27.3±24.6ng/mL, n=10) and trandolapril (12.3±16.9ng/mL, n=18) than healthy (0.4±0.2ng/mL, n=7) and hemodialyzed subjects (0.6±0.2ng/mL, n=34). This analytical method would be useful to measure N-terminal thymosin-β peptides in human plasma for the clinical study.