AN ENDOCRINE CELL CARCINOMA WITH GASTRIC‐AND‐INTESTINAL MIXED PHENOTYPE ADENOCARCINOMA COMPONENT IN THE STOMACH

A 77‐year‐old man complained of bodyweight loss, and a Borrmann 3 type lesion was observed endoscopically in the anterior wall of angular region of the stomach. The endocrine cell carcinoma (ECC) having the cytoplasmic staining of chromogranin A (CgA) was detected pathologically in the biopsy samples. The patient underwent distal gastrectomy plus systemic lymph node (LN) dissection (D2 LN dissection), and pathological examination revealed ECC invading the subserosa, and no LN metastasis (pT2N0M0). None of the gastric and intestinal endocrine cell marker expression was apparent in the ECC cells. The lesion also contained a moderately differentiated type tubular adenocarcinoma component, which was judged to be gastric‐and‐intestinal mixed (GI type) phenotype, using gastric and intestinal exocrine cell markers. After the surgery, he left the hospital and started oral doxifluridine (600 mg/day). The patient now (March 2008, about 19 months since the surgery) continues this chemotherapy with no recurrence. In conclusion, we experienced ECC with a GI type adenocarcinoma component. The ECC cases with the GI type adenocarcinoma component may have a relatively good prognosis, being similar to the results of advanced gastric cancers from the viewpoint of gastric and intestinal phenotypic expression.     

Factors affecting corneal hysteresis in normal eyes

BACKGROUND: To evaluate factors affecting corneal hysteresis (CH) in normal eyes. METHODS: We examined 86 normal eyes of 43 healthy volunteers (age, 39.1 +/- 14.5 years (mean +/- standard deviation); range, 19 to 68 years; gender, 26 men, 60 women; manifest refraction, -2.25 +/- 2.89 diopters (D); range, -9.13 to 3.88 D). We quantitatively assessed the value of CH using an Ocular Response Analyzertrade mark (Reichert Ophthalmic Instruments). We carried out this measurement three times, and the average value was used for statistical analysis. Multiple regression analysis was used to assess the relevant factors of the CH. RESULTS: The mean CH was 10.2 +/- 1.3 mmHg. Explanatory variables relevant to the CH were, in order of magnitude of influence, the central corneal thickness (CCT) (partial regression coefficient B = 0.022, p < 0.0001), and the intraocular pressure (IOP) (B = -0.119, p = 0.04). No significant correlation was seen with other clinical factors such as age, gender, manifest refraction, or mean keratometric readings. CONCLUSIONS: Eyes with thinner CCT and eyes with higher IOP are more predisposed to have lower CH. Refractive surgeons should, from a biomechanical viewpoint, take not only CCT but also IOP into consideration before performing keratorefractive surgery.     

Von Hippel-Lindau-coupled and transcription-coupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin

PURPOSE: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. Experimental Design and RESULTS: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. CONCLUSION: These results suggest that both TC-NER-induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.     

Structural and functional diversity in the PAR1b/MARK2‐binding region of Helicobacter pylori CagA

Helicobacter pylori (H. pylori) cagA‐positive strains are associated with gastritis, peptic ulcerations, and gastric adenocarcinoma. Upon delivery into gastric epithelial cells, the cagA‐encoded CagA protein specifically binds and aberrantly activates SHP‐2 oncoprotein in a manner that is dependent on CagA tyrosine phosphorylation. CagA‐deregulated SHP‐2 then elicits aberrant Erk activation while causing an elongated cell shape known as the hummingbird phenotype. In polarized epithelial cells, CagA also binds to PAR1b/MARK2 and inhibits the PAR1b kinase activity, thereby disrupting tight junctions and epithelial cell polarity independent of CagA tyrosine phosphorylation. We show here that the CagA‐multimerization (CM) sequence that mediates interaction of CagA with PAR1b is not only essential for the CagA‐triggered junctional defects but also plays an important role in induction of the hummingbird phenotype by potentiating CagA‐SHP‐2 complex formation. We also show that the CM sequence of CagA isolated from East Asian H. pylori (referred to as the E‐CM sequence) binds PAR1b more strongly than that of CagA isolated from Western H. pylori (referred to as the W‐CM sequence). Within Western CagA species, the ability to bind PAR1b is proportional to the number of W‐CM sequences. Furthermore, the level of PAR1b‐binding activity of CagA correlates with the magnitude of junctional defects and the degree of hummingbird phenotype induction. Our findings reveal that structural diversity in the CM sequence is an important determinant for the degree of virulence of CagA, a bacterial oncoprotein that is associated with gastric carcinogenesis. (Cancer Sci 2008; 99: 2004–2011)     

Serum Anti-PT and Anti-FHA Antibody Levels, and Agglutinin Titers after Administration of Accellular Pertussis Vaccines

Simultaneous evaluation of acellular pertussis vaccines from three manufacturers (Takeda, Biken, and Chiba) was performed. After receiving two doses of acellular pertussis vaccine in the form of DPT (diphtheria pertussis tetanus), both infants and children showed high serum anti-PT (pertussis toxin) and anti-FHA (fdamentous hemagglutinin) antibody levels. These levels were equivalent to those observed in children in the convalescent stage of natural pertussis infection. Children who received 2 doses of Biken vaccine showed higher anti-PT and anti-FHA antibody levels than those who received Takeda or Chiba vaccine. Elevation of agglutinin titers was observed in children who received either Takeda or Chiba vaccine. ( Acta Paediatr Jpn 1989; 31: 120–126)     

Comparison of Incorporation and Extension of Nucleotides in vitro opposite 8-Hydroxyguanine (7,8-Dihydro-8-oxoguanine) in Hot Spots of the c-Ha-ras Gene

DNA templates with 8-hydroxyguanine (7,8-dihydro-8-oxoguanine, oh⁸Gua) at a site corresponding to the first or second position of codon 12 of the c-Ha-ras gene were prepared, and the nucleotides inserted opposite the modified base were compared. The Klenow fragment (KF) of Escherichia coli DNA polymerase I inserted C opposite oh⁸Gua at both positions. Taq DNA polymerase incorporated C and A opposite oh⁸Gua, and the ratio of C to A was higher at the first position than at the second position. DNA polymerase α (pol α) inserted A and C at the first position, and A at the second position of codon 12, indicating that the ratio of C to A was higher at the first position. Moreover, we studied the extensions of bases paired with oh⁸Gua by DNA polymerases with or without 3'-5'exonuclease activity. G and T opposite oh⁸Gua were removed, and subsequently C was inserted by KF. We found that an oh⁸Gua:A pair was recognized by the exonuclease activity of the enzyme and that A was partially subsituted by C. On the other hand, pol α extended only C and A opposite oh⁸Gua. No difference was observed with oh⁸Gua at the two positions. These results indicate that the ratio of nucleotides incorporated opposite oh⁸Gua depends on the sequence context, while there is no particular difference in the extension of base pairs involving oh⁸Gua by DNA polymerases.     

Antimicrobial Chemotherapy for Children with Malignancy

Infection is the major complication occurring in children with cancer and is often fatal. Since the clinical manifestations of infection are slight, except for fever, a definitive diagnosis is difficult in the early phase of infection, but using laboratory parameters, the differentiation of bacterial infections may be possible to some extent. The infection cannot be treated only by antimicrobial chemotherapy, but supportive measures such as neutrophil transfusion, and other biological medications should be given in consideration of the deficiency of the immune defense mechanisms of the patient. Anticancer treatment is also needed, along with antimicrobial treatment. The prophylactic use of antimicrobial drugs is still controversial but it is effective, depending on the type of infection for which it is used, and on the status of the defective defense mechanism in the patient who is on cancer chemotherapy.     

Development of autologous specific reactivity to human neuroblastoma

Antigenic analysis of neuroblastoma cells was performed by autologous typing and indirect immunofluorescent test combined with absorption tests. Serum of a patient with neuroblastoma before treatment showed weak reactivity with cultured autologous neuroblastoma cells, while serum obtained from the same patient 3 months after chemotherapy exhibited strong reactivity with the same indicator cells. This reactivity was absorbed with neither cultured autologous fibroblasts nor allogeneic tumor cells from seven neuroblastoma and two melanoma patients. In addition, cultured hematopoietic cells from two subjects, normal fetal and adult tissues also failed to remove the reactivity. This reactivity, however, was completely removed by the absorption with the cultured autologous neuroblastoma cells and the homogenate, suggesting that these neuroblastoma cells may express tumor specific antigen(s), located on neither normal cells in any stage of the development nor other malignant cells, although the cells and tissues we tested may not be adequate to confirm this.     

Superior efficacy of MMCP regimen compared with VMCP and MMPP regimens in the treatment of multiple myeloma

OBJECTIVE: A newly designed combination chemotherapy for multiple myeloma, MMCP [ranimustine (MCNU), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL)], was analyzed and compared with the results of our previous randomized trial of VMCP [vincristine, MPH, CPM and PSL] and MMPP [MCNU, MPH, procarbazine and PSL]. METHODS: MCNU (33.3 mg/m2, div) on day 1 and MPH (4 mg/m2, po), CPM (66.7 mg/m2, po) and PSL (30 mg/m2, po) from day 1 to 4, were administered. Each cycle was repeated every 3 weeks. PATIENTS OR MATERIALS: From January 1991 until August 1995, 104 patients with multiple myeloma diagnosed at 10 hospitals of Nagoya Cooperative Study Group were enrolled. RESULTS: Of the 87 evaluable patients, partial response rate for MMCP was 65.5% and was significantly higher than that of VMCP (13/47=27.7%, p<0.0001) and that of MMPP (21/47=44.7%, p=0.0196). A plateau attainment was observed in 49.4%. The percentage of the patients who attained plateau was significantly increased in the MMCP arm than in the VMCP arm (19.1 %, p=0.0017) but was not in comparison with that of MMPP arm (42.6%, p=0.6790). Patients treated with MMCP survived significantly longer than those treated with VMCP or MMPP (p=0.0009 by generalized Wilcoxon test, p=0.0023 by log-rank test) with median survival for MMCP being 31.6 months, for VMCP 22.5 months, and for MMPP 22.9 months. No significant differences were observed with respect to adverse effects among the three regimens. CONCLUSION: The newly designed MMCP is a candidate as an induction chemotherapy for multiple myeloma.