Nuclear Localization of Immunoreactive β-Catenin Is Specific to Familial Adenomatous Polyposis in Papillary Thyroid Carcinoma

Thyroid carcinoma is the first symptom in some patients with familial adenomatous polyposis (FAP). We evaluated the cellular localization of β-catenin in thyroid carcinomas associated (n=4) or not associated (n=173) with FAP, since loss of functional protein of the adenomatous polyposis coli (APC) gene leads to nuclear accumulation of β-catenin in adenomas and carcinomas of the FAP colon. Immunoreactive β-catenin was demonstrated at the cell membrane of glandular cells of the non-neoplastic thyroid and non-FAP carcinomas. On the other hand, cytoplasmic and nuclear accumulation of β-catenin is specific to FAP-associated papillary carcinomas. The abnormality in the APC/β-catenin pathway is thus also important in FAP-associated thyroid carcinoma, and β-catenin immunohistochemistry is a feasible screening method to identify occult FAP in young patients with thyroid tumors.     

Expression of SART3 Tumor-rejection Antigen in Gastric Cancers

We previously reported SART3 as a tumor-rejection antigen recognized by histocompatibility leukocyte antigen (HLA)-A24-restricted cytotoxic T lymphocytes (CTLs). In this study, we investigated the expression of the SART3 antigen in gastric cancers, as a candidate for use in specific immunotherapy. The SART3 antigen was detected in 9 of 10 (90%) gastric cancer cell lines, 35 of 52 (67.3%) gastric cancer tissues, and 0 of 20 non-tumorous gastric tissues. SART3-derived peptides corresponding to positions 109–118 and 315–323 induced HLA-A24-restricted and tumorspecific CTLs from peripheral blood mononuclear cells (PBMCs) of gastric cancer patients. These peptide-induced CTLs recognized HLA-A24⁺ SART3⁺ gastric cancer cells, but not HLA-A24⁺ SART3⁻ or HLA-A24⁻ SART3⁺ gastric cancer cells. Therefore, the SART3 peptides could be useful in specific immunotherapy of gastric cancer patients.     

Bone Marrow Transplantation for Hematologicai Diseases in Hokkaido--June 1985 to December 1991

Bone marrow transplantation (BMT) was started in Hokkaido in1985. In the present report we have reviewed the clinical outcomeof patients treated with BMT for hematologicai diseases in Hokkaido.Fifty-eight allogeneic and 19 autologous transplants were registeredby December 1991. The underlying diseases consisted of 47 leukemias,14 lymphomas, 10 aplastic anemias and six myelodysplastic syndromes.Among the allogeneic BMT cases, 55 were human leuhocyte antigen(HLA) identical and three were mismatched. Among the autologousBMT patiets, two recieved their marrow purged with 4-hydroperoxycyclophosphamideand five, with monoclonal antibodies and complements. The conditioningregimens used for malignancies were chiefly cyclophosphamide(CY) plus total body irradiation, or busulfan plus CY. In manycases, cytokines were used for rapid recovery of decreased leukocytes.Engraftment was observed in 50 out of 52 evaluated allogeneicand 18 out of 19 autologous transplants. Ten allogeneic patientssuffered from severe acute graft-versus-host diseases (GVHD),and extensive chronic GVHD appeared in 16 patients. Relapseswere observed in four cases of allogeneic BMT and six of autologous.BMT. The major complications were interstitial pneumonitis (IP)and severe infections. Long-term, survival rates were almost60% in both allogeneic and autologous transplants. Mild acuteGVHD and limited chronic GVHD increased the survival rates.The results indicated that substantial problems such as GVHD,IP and relapses must be controlled in the near future for animproved outcome to be made possible.     

Administration schedule of daunorubicin for elderly patients with acute myelogenous leukemia: a single-institute experience

We evaluated the efficacy of daunorubicin (40 mg/m(2)/day for 5 days, 200 mg/m(2)/cycle) combined with standard dose of cytarabine (100 mg/m(2)/day for 7 days) for acute myelogenous leukemia patients aged 65-74 years as induction therapy. Complete remission (81.3%) was achieved in 13 of 16 patients following the therapeutic program. The median duration of recovering absolute neutolophilic counts over 1000/μl and platelet counts over 100 000/μl were 33 days and 27 days, respectively. None of the patients had any adverse cardiac complications or died during administration of the induction therapy. Patients achieving complete remission received post-remission therapy consisting of two regimens other than induction therapy. The 3-year disease-free and overall survival rates were 36.9 and 50.0%, respectively. Extending the total period of the daunorubicin therapy might be an alternative to increasing the daily dose of daunorubicin in the induction therapy for elderly patients who were candidates for receiving intensified chemotherapy.     

Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats

In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia.     

BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer

Background

Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes.

Methods

Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed.

Results

BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values ≥3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352–5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549–7.422; P = 0.002).

Conclusions

BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.

     

YM-201627: an orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation

We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC50s of 0.0039-0.12 microM), that would not be expected to have any direct antiproliferative effect on other cell types. YM-201627 inhibited angiogenesis in vitro at a concentration of 0.01 microM. In the in vivo studies, it inhibited microvessel formation induced by human melanoma A375 cells suspended in Matrigel (86% with twice-daily doses of 30 mg/kg). Moreover, once-daily oral dosing of YM-201627 to mice bearing A375 xenografts elicited significant antitumor activity (73% with daily doses of 10 mg/kg). These results suggest that YM-201627 is a selective growth inhibitor of endothelial cells, which may be useful for treatment of solid tumors.     

The association between vascular endothelial growth factor-C, its corresponding receptor, VEGFR-3, and prognosis in primary breast cancer: a study with 193 cases

Lymphangiogenesis plays an important role in several normal and pathological conditions, such as wound healing, pathogen infection, inflammation or the metastasis formation of endothelial malignancies. Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are important and specific regulatory factors for lymphatic endothelial proliferation and lymphangiogenesis. Both growth factors mediate their biological activity mainly by VEGF receptor-3 (VEGFR-3, Flt-4). In this study, we measured intratumoral levels of VEGF-C and VEGFR-3 through enzyme-linked immunosorbent assay (ELISA) in 193 primary breast cancer tissues and examined their prognostic values. A significant correlation was found between the VEGF-C and VEGFR-3 protein levels. High VEGF-C levels were associated with low-grade tumors and a smaller size. Univariate analysis showed that high VEGF-C was significantly associated with a favourable prognosis for disease-free survival (DFS) and overall survival (OS). No significant prognostic value of VEGFR-3 was detected. Multivariate analysis confirmed the independent prognostic value of VEGF-C. The intratumoral VEGF-C level is a significant prognostic indicator of primary breast cancer. An investigation of the mechanisms of VEGF-C protein processing in human cancer tissue should be carried out in the future.     

Four new bioactive pyrrole-derived alkaloids from the marine sponge Axinella brevistyla.

Four new alkaloids (1-4) were isolated from the marine sponge Axinella brevistyla, and their structures were determined on the basis of spectroscopic analysis. The alkaloids 1-4 were antifungal against the yeast Saccharomyces cerevisiae at <1.0, <1.0, 30, and 100 microg/disk, respectively. Compounds 1-3 also exhibited cytotoxicity against L1210 cells with IC(50) values of 1.1, 0.66, and 2.5 microg/mL, respectively.