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Transposable element (TE) marker system was developed considering the useful properties of the transposable elements such as their large number in the animal and plant genomes, high rate of insertion polymorphism, and ease of detection. Various methods have been employed for developing a large number of TE markers in several crop plants for genomics studies. Here we describe some of these methods including the recent whole genome search. We also review the application of TE markers in molecular breeding.

BACKGROUNDFor patients with non-small cell lung cancer the TNM staging system and other conventional prognostic factors fail to predict accurately the outcome of treatment and survival. This study attempts to determine the prognostic value for survival of the proportions of CD4+ lymphocytes in the pleural cavity (PLY) of patients with resectable non-small cell lung cancer.METHODSLymphocytes in the pleural cavity separated from 51 patients with non-small cell lung cancer were examined by flow cytometry to measure the proportions of CD4+ PLY. Univariate and multivariate analyses were performed to assess the association between the proportion of CD4+ PLY and survival.RESULTSThe 5 year survival rate of patients with percentage CD4+ PLY of ⩽30% was 84% whereas that of patients with %CD4+ PLY >30% was 26.9%. The difference in survival between the %CD4+ PLY ⩽30% and %CD4+ PLY >30% groups was significant (p30% was also significant (p =0.015). Multivariate analysis showed that the proportion of CD4+ PLY (hazard ratio=6.9, 95% CI 0.045 to 0.47) and nodal status (hazard ratio=22.7, 95% CI 0.006 to 1.806) are significant and independent prognostic factors for the survival of patients with lung cancer.CONCLUSIONSThe proportion of CD4+ PLY may help to select patients who are likely to have a poorer prognosis after surgery and therefore may be suitable for consideration of adjuvant treatments. These results need confirmation in a larger prospective study.

Under a Just-In-Time (JIT) pull system the sequencing of products requires the satisfaction of two main goals: (1) keeping a constant rate of usage of parts, and (2) smoothing the workload at work stations to avoid line stoppages. By using a practical observation related to JIT delivery systems we propose a two-step approach, where in the first step we consider only goal (1) by applying a benchmark heuristic. In the second step we focus on goal (2), by investigating the effectiveness of a spacing-constraint based approach, commonly used in the automotive industry, in comparison with a more general time-based one. We designed and conducted a simulation experiment based on the practical situation of final assembly lines and we found that the benchmark heuristic represents an appropriate choice for step one (based on a new performance measure that represents a lower bound on variation in parts utilization). For the second step, related to workload smoothing, the spacing-constraint based method presents bette...

The sequencing of products for final assembly in JIT mixed-model manufacturing systems is sometimes based on multiple criteria. The two main criteria that have been discussed in the literature are: the smoothing of parts utilization and the smoothing of the product load. Product rate variation smoothing and sub-assembly load variation smoothing may also be considered. One procedure for treating these multiple criteria is by the use of a weighted multi-attribute cost function, which is an aggregation of the respective objective functions. However, one difficulty which may be associated with this approach is in obtaining proper estimates for the weights. In this paper, we propose an alternative approach (a parametric procedure), which utilizes only the relative preference information for the criteria. A numerical example is presented to illustrate the procedure.

Toyota's goal-chasing method has proved effective for dealing with practical-sized sequencing problems for mixed-model assembly lines in just-in-time (JIT) production systems. Miltenburg introduced the multi-level concept to JIT assembly line sequencing, and his remark about Toyota's neglect of product ‘usage’ smoothing (PUS) when determining the assembly-line product sequence, primarily gave impetus to this study. We note that for most JIT systems, PUS would only be of practical significance, if it helps to achieve sub-assemblies and parts usage smoothing (SUS). In this paper, we conduct a simulation experiment for two-level sequence scheduling for JIT assembly lines. Using the SUS objective value as the metric, the results show that in a comparatively higher percentage of cases (relative to single-level SUS objective scheduling), which can be reasonably considered as statistically significant, better sequences are produced, This phenomenon is found to apply to Toyota's SUS objective as well as Miltenburg's.

Late airway changes are frequently observed in long-term surviving rat lung allografts. In this present study, we investigate this problem using the mixed lymphocyte reaction, graft-versus-host assay (popliteal lymph node assay), skin grafting from the donor strain to the lung allograft recipient, and histology to evaluate this problem. The results show that spleen cells from recipient rats with long-term surviving lung allografts possessed alloreactivity in mixed lymphocyte reaction against both donor and third-party ACI antigens. Suppressor cell activity was not detected in spleen cells from these recipient rats. The popliteal lymph node assay showed that the response to recipient spleen cells was detectable but weaker than that of naive spleen cells from the same strain. Mean survival time of skin grafts from the donor strain to long-term allograft survivors was significantly longer than that between donor and recipient strains. Chest roentgenograms revealed opacification of long-term surviving lung allografts at 2 to 3 wk after skin transplantation that was coincident with the rejection of the skin grafts, and histologic examination of the lung allografts revealed changes compatible with acute rejection. We conclude that alloreactivity can be demonstrated in rats with long-term surviving lung allografts and suggest that late airway changes in these lungs are immunologically mediated.

We study the nonlinear interaction of laser light with vacuum for a large angular aperture at electromagnetic field strengths far below the Schwinger limit. The polarization and magnetization in vacuum irradiated by a focused laser beam clearly differ from those in matter. This is due to the dependence on the Lorentz invariant, which results in a ring-shaped radiation distribution in vacuum. The number of the radiated photons increases nonlinearly with increasing angular aperture.

In designing control systems, it is important to make exact mathematical model of the controlled object. In particular, it is difficult to obtain the mathematical model for nonlinear systems. Therefore, lots of design schemes of nonlinear models have been proposed. As one of them, the group method of data handling (GMDH) network has been proposed as a method to represent such systems. It is a kind of multi-layered networks with a structure which is determined through training, and has a feature that the nonlinear dynamics are expressed as a mathematical model. However, since the mathematical model generated by the GMDH network includes several needless terms, they give unsuitable effects on the estimation accuracy. In this paper, a nonlinear model is identified by using a real data set of an atmospheric distillation process system. Finally, the proposed modeling scheme is evaluated on a simulation example.

This paper elucidates the correspondence between the Schur-Cohn (SC) test and the Routh-Hurwitz (RH) test by showing that the latter is obtained as a limit of the former. The argument is developed in a stochastic framework, where stochastic interpretations of the tests are used. The interpretation of the SC test can be derived from its equivalency to the Levinson-Durbin algorithm, while that of the RH test is newly presented here.

In Brown Norway to Lewis rat lung transplantation, short-term administration of cyclosporine produces permanent adoption of allografts; however, the adopted grafts show symptoms of chronic rejection. To clarify the difference in cytokine production in acute an chronic rejection of the allografts, an immunohistochemical study was performed. In acute rejection, positive cells for respective cytokines were observed in infiltrating cells, increasing in number as the days after transplantation passed, and reaching a maximum on the fifth day. The strongest reactivity was observed perivenously. In chronic rejection, TNF-alpha positive cells were observed in the perivascular and peribronchial regions, especially around class II positive epithelia. The number of positive cells was, however, less than that in the vascular phase of acute rejection. Few cells were positive for IL-1 beta, IFN-gamma and, unexpectedly, for IL-4. These facts indicate the functional difference of infiltrating cells between acute and chronic rejection.

In process industries, PID control schemes have been widely used due to their simple structure and ease of comprehending the physical meanings of control parameters. However, since most processes are considered as nonlinear multivariable systems with mutual interactions, good control performance can not be obtained by simply using PID control schemes. In this paper, a design method for neural-net based PID controllers is proposed for a nonlinear multivariable system with mutual interactions. The proposed method consists of a decoupler generated by the sum of a static decoupler and a neural-net based decoupler, and multiloop PID controllers. Finally, the effectiveness of the proposed control scheme is evaluated for a simulation example.

The effects of deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced aberrant crypt foci (ACF) in the rat colon were examined. The effect of these bile acids on DNA adduct formation by PhIP in the colon was then analyzed, since the main action of PhIP is the formation of DNA adducts and subsequent gene mutations. For the ACF study, male F344 rats were administered PhIP-HCl (75 mg/kg, 10 doses) by gavage, and a diet containing bile acid (0.4% DCA or UDCA) was provided from 3 days before the first dose of PhIP for 8 weeks. The mean number of ACF per colon of DCA, UDCA and controls were 9.9, 2.4 and 5.5, respectively. The ACF number was significantly increased by DCA and decreased by UDCA (P0.001). To examine the effect of bile acids on DNA adduct formation, male F344 rats were fed a diet supplemented with bile acids (0.1 or 0.4% of DCA and UDCA) 7 days prior to the PhIP administration. All rats were administered a single dose of PhIP-HCl (50 mg/kg) by gavage and sacrificed 48 hours later. DNA adduct levels of the 0.1% UDCA, 0.1% DCA and controls were 2.93 (adducts/10(7) nucleotides), 2.65 and 1.10, respectively. Those of 0.4% UDCA, 0.4% DCA and controls were 1.64, 1.30 and 1.00, respectively. The PhIP-DNA adduct level was significantly increased by administration of 0.1% UDCA, 0.1% DCA (P0.05) and 0.4% UDCA (P0.01). The increasing effect of both DCA and UDCA on PhIP-induced DNA adduct formation was unexpected, and was not directly associated with ACF formation.

The importance of reinterpreting the Schur-Cohn test as a lossless bounded realness criterion for rational transfer functions on the unit disk is discussed, and a concept of their lossless bounded real (LBR) realization is introduced. A LBR realizability condition is shown to be equivalent to a lossless bounded realness criterion and then is extended to a bounded real one, which will play a crucial role not only in the realization problem, but also in the inverse scattering problem, digital filter design, and numerical analysis. >

Thymic epithelial tumors are mainly consisted of thymoma, thymic carcinoma, and thymic carcinoid. And thymic carcinoma is very rare neoplasm. The classification of thymic carcinoma has remained a subject of controversy for many years. The outline of thymic carcinoma has been clarified by "Atlas of Tumor Pathology: Tumors of the Mediastium (AFIP)" and "Histrogical Typing of Tumours of the Thymus (WHO)" published recently. Squamous cell carcinoma is by far the most common in Japan. Thymic carcinoma is a predilection for male. The peak of age was 40-60 years. Thymic carcinoma already had contiguous invasion around neighbor organs, dissemination, and lymph node metastases or distant metastases at diagnosis. Two third of patients with thymic carcinoma performed surgery, and most of them performed adjuvant radiotherapy or chemotherapy. 5-year survival of thymic carcinoma was 33-50%. Histologic tumor type, type of tumor margin, growth pattern, nuclear atypia, necrosis and mitotic activity were correlated with survival. In this paper thymic carcinoma is reviewed mainly based on recently literatures and results obtained from a questionnaire on thymic epithelial tumors in Japan.

The extent of lymphatic metastasis is the most important factor in the prognosis for non-small cell lung cancer (NSCLC). Therefore, suppression of lymphatic metastasis provides an improvement in survival time in lung cancer patients. We established a new patient-like model for lung cancer metastasis by orthotopic implantation in severe combined immunodeficiency (SCID) mice and demonstrated the lymphogenous spread histologically using human NSCLC cell lines. The cardinal features of this model are a simple procedure and a similarity to the metastatic form of human lung cancer. The purpose of this study is to assess the inhibitory action of uracil-tegafur (UFT) and cis-diamminedichloroplatinum(II) (CDDP) on lymphatic metastasis and life span prolongation in our lymphogenous metastatic model system using SCID mice.The inhibition ratios of mediastinal lymph node metastasis were 86.2, 94, and 92.1% for 12 mg/kg body UFT, 17 mg/kg body UFT, and 10 mg/kg body CDDP, respectively. The administration of anticancer drugs prolonged the life span by 4.6 days (17 mg/kg body UFT) and 8 days (10 mg/kg body CDDP) in MST.We demonstrated that UFT alone and CDDP alone suppressed mediastinal metastasis and prolonged the life span in our lymphogenous metastatic model. Regardless of the administration route and characteristics of anticancer drugs, cytostatic or cytotoxic, our model is capable of evaluating the inhibitory effect of drugs on lymphatic metastasis. This model should make an important contribution to our understanding of the mechanism and selection of drugs for antilymphatic metastasis in lung cancer.

A food-born carcinogen, 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) induces cancer in the rat colon. The mechanism for colonic DNA adduct formation leading to cancer by IQ was studied using a colostomized F344 rat model. In this model, the transverse colon of the rat was colostomized, which produced a fecal stream-positive proximal colon and a negative distal colon were produced. When IQ (50 mg/kg) was administered into the distal colon of the colostomized rats (n = 5), the ratio of the DNA adduct level of the distal colonic mucosa to the paired muscular layer 24 hr after dosage was 2.02, whereas that was 1.51 and 1.37 when IQ was administered into the stomach (n = 6) and the vein (n = 5), respectively. This suggested that luminal exposure of IQ induced DNA adduct formation. Since IQ (an amine form) has no reactivity toward DNA, these findings suggested that IQ was immediately activated in the absorbed mucosal cells and reacted with DNA. However, most of the IQ absorbed was metabolically activated in the liver, distributed by blood circulation, and formed DNA adducts in the colonic mucosa and muscular layer.

The purpose of this study was to evaluate the possibility of differential diagnosis of tumors, such as breast cancer, by measuring the mammary electrical bioimpedance via the skin surface noninvasively and by examining the relationship between the tissue structure of the breast and electrical bioimpedance. The mammary electrical bioimpedance was measured in 24 patients with breast cancer. Taking into account the measurement results and the distribution of the mammary glands and fatty tissue, a breast model with tumors was proposed. Based on this model, the distributions of the electric potential and electric field in the tissue were theoretically analyzed by the three-dimensional finite element method. In clinical cases, the Re values of the diseased breast were significantly larger than those of the contralateral healthy breast. In theoretical analysis based on the breast model, the Re value of mammary electrical bioimpedance varied due to the structure of the breast, that is, the ratio of fatty tissue to mammary gland and the presence of mammary tumors. The results of the measurement agreed with the theoretical analyses. These results suggest that differential diagnosis of breast tumors is possible by measuring the mammary electrical bioimpedance using noninvasive electrodes on the skin.

Rare subtypes of lung cancer, that is, carcinoid, adenoid cystic carcinoma, muco-epidermoid carcinoma and adenosquamous carcinoma, were described. These tumors except adenosquamous carcinoma, are generally low malignant and slow growing and arise from upper airway. Complete surgical resection is the best treatment. Sometime tracheobronchoplastic surgery is recommended. Adenosquamous carcinoma is more malignant than adenocarcinoma or squamous carcinoma.

An animal model of metastasis with features similar to those of lung cancer metastasis in humans is required for an understanding of the cellular and molecular mechanisms of human lung cancer metastasis. Ma-44 cell lines derived from human squamous cell lung cancer were percutaneously injected (2-3 x 10(4)) into the left lung of SCID mice. After orthotopic implantation, Ma-44 cell lines formed tumors in the left lung at a high rate (17/25, 68%), and many of those metastasized to mediastinal lymph nodes (13/17, 76%) by the 14th day, but not to other organs. After the ectopic implantation, the Ma-44 cell line inoculated subcutaneously (2-3 x 10(5)) formed a tumor at the inoculation site by the 28th day (all mice), but did not metastasize to any organs. The Ma-44 cell line inoculated intravenously (2-3 x 10(5)) formed metastases in the lungs (37/50, 74%), and these pulmonary metastases metastasized to the mediastinal lymph nodes at low rate (3/37, 8%) by the 14th day. The orthotopic sites of implantation are critical for the metastatic ability of transplanted tumors in SCID mice. Since non-small cell lung cancer (NSCLC) grows at the primary site in humans, lymphogenous metastasis occurs frequently, and blood-born metastasis occurs at moderate rate, our orthotopic SCID mice model was similar to the metastatic behavior of NSCLC in humans. Thus, this model may be useful for elucidating the mechanism of lymphogenous metastasis in human lung cancer, and testing the anti-metastatic efficacy of therapeutic agents in vivo.

Acinic cell carcinoma of the salivary glands is a rare cancer representing a low grade malignancy. The recurrence of a tumor is sometimes encountered, usually within 5 years of initial operation. We describe an unusual recurrence after a long interval following primary surgery. In 1987, a 60-year-old woman underwent excision of a mass in the superficial lobe of the right parotid gland under the preoperative diagnosis of a benign tumor. A histologic diagnosis of acinic cell carcinoma was made by examining sections from the resected mass. The patient noted several small nodules in the right parotid region in 1995, but she did not visit our clinic until 1998 when tenderness developed. A locally recurrent tumor and cervical lymph nodes containing metastases were resected and postoperative radiotherapy was given 11 years after the first operation. At least 10 years of follow-up may be necessary for patients with acinic cell carcinoma because of slow-tumor growth.

The latest revision of the International System for Staging Lung Cancer was published in June 1997. We discuss the following 4 major items in the new TNM staging system. 1) The fact that stage I was divided into stage IA (T1N0M0) and IB (T2N0M0) is reasonable, as the survival prospects for the subsets differ significantly. 2) The fact that stage II was divided into stage IIA (T1N1M0) and IIB (T2N1M0) is not appropriate, However, there is no significant survival difference between the T1N1M0 subset and the T2N1M0 subset, because there are fewer T1N1M0 cases. 3) The fact that the T3N0M0 subset was shifted into stage IIB is reasonable. Patients who undergo resection of tumors invading the parietal pleura, neighboring lobe, and main bronchus within 2 cm of the carina in the T3N0M0 group have a good prognosis, but those who undergo resection of tumors invading the rib, intercostal muscle, and diaphragm in the T3N0M0 group have a poor prognosis. 4) The decision to designate satellite lesions within the lobe of the primary tumor as T4 is controversial, because it is very difficult to determine whether satellite lesions are metastases from other lesions or if they are primary synchronous neoplasms.

The effectiveness of combining mitomycin C (MMC), tamoxifen (TAM), and 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) was evident in patients with estrogen receptor-positive (ER+) breast cancers. UFT, an oral preparation of tegafur and uracil at a molar ratio of 1:4, was reported to have higher antitumor effects than tegafur alone for patients with breast cancer. Therefore, the combined chemotherapy of MMC, TAM and UFT may possibly be effective for breast cancer. From 1988 to 1991. we studied the effects of postoperative adjuvant therapy for Japanese women with stage 11 breast cancer, all seen at 71 institutions in western areas of Japan. Five hundred and ninety four patients with stage II primary breast cancer who had undergone curative surgery, including total mastectomy and axillary lymph node dissection, were enrolled. On the day of surgery, each patient was given 13 mg/m2 of MMC intravenously. Patients with ER+ tumors were then assigned to group A or group B. Group A received 30 mg/day of TAM given orally from postoperative 2 weeks, for 2 years. Group B was additionally given an oral dose of 300 mg/day of UFT for 2 years, given concomitantly with 30 mg/day of TAM. Patients with ER- tumors were assigned to group C or group D. Group C were prescribed 300 mg/day of UFT, orally, from postoperative 2 weeks for 2 years, and group D were additionally given an oral dose of 30 mg/day of TAM together with 300 mg/day of UFT. There were no differences among the groups regarding prognostic factors or doses of MMC and TAM in ER+ patients and MMC and UFT in ER- patients. Toxicity rates for leukopenia, anorexia, and nausea/vomiting were higher in group B than in group A patients. There were no statistical differences in the overall survival and disease-free survival times between groups A and B, or groups C and D, for all eligible cases. In a retrospective subgroup analysis using Bonferroni's adjustments, the additional effect of UFT on the combined treatment of MMC and TAM lengthened the disease-free survival time for patients with premenopausal ER+ cancers (corrected P value by Bonferroni's adjustments0.05). Multivariate analysis showed that effects of the combined treatment of MMC, TAM, and UFT was significantly related to the menopausal status (P0.01). Our findings show that postoperative ingestion of MMC, TAM, and UFT was effective for patients with premenopausal ER+ stage II breast cancer.

DNA adduct formation is assumed to be a major carcinogenic event, leading to the development of endometrial cancer in breast cancer patients taking tamoxifen and healthy women enrolled in a tamoxifen chemopreventive trial. To determine whether DNA adducts were formed by tamoxifen, trans- and cis-alpha-acetoxytamoxifen N-oxides were synthesized as model-activated forms via major tamoxifen metabolites, tamoxifen N-oxide and alpha-hydroxytamoxifen N-oxide. When alpha-acetoxytamoxifen N-oxide was reacted with human DNA, at least three DNA adducts were detected by (32)P-postlabeling coupled with HPLC. The total amount of DNA adducts formed by trans-alpha-hydroxytamoxifen N-oxide was 1.5-fold higher than that formed by the cis form. Both trans- and cis-alpha-acetoxytamoxifen N-oxide reacted with 2'-deoxyguanosine, resulting in the formation of three adducts (fr-1, fr-2-1, and fr-2-2). These products were studied using mass spectroscopy and proton magnetic resonance spectroscopy. fr-1 was identified as a mixture of the epimers of trans-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide. fr-2-1 and fr-2-2 were determined to be epimers of cis-alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.

We examined the effect of recombinant IFN-alpha and IFN-gamma on induction of LAK cells from peripheral blood mononuclear cells (PBMNCs) in 7 pre-operative breast cancer patients and 4 healthy volunteers. Significant LAK activity was developed from PBMNCs of pre-operative breast cancer patients and healthy volunteers after incubation for 4 days with IL-2 (presence of IL-2 vs. absence of IL-2). Incubation of PBMNCs of pre-operative breast cancer patients with 1000 U/ml of IFN-alpha for 4 days suppressed the LAK activity significantly (P0.05). By contrast, incubation of PBMNCs of pre-operative patients with 1000 U/ml of IFN-gamma for 4 days increased the LAK activity significantly (P0.05). Significant cytotoxicity against MCF-7 cells (estrogen receptor positive human breast cancer cell line) was developed from PBMNCs of pre-operative breast cancer patients at 20:1 and 40:1 E/T ratios after incubation for 4 days with IL-2 (absence of IL-2 vs. 20:1 or 40:1, P0.05, P0.05), whereas PBMNCs of healthy volunteers did not. Stimulation of LAK cells with IFN-gamma produced a significant augmentation of cytotoxic activity against MCF-7 (P0.05), while IFN-alpha suppressed the cytotoxicity significantly (P0.05). These findings suggested that combined stimulation by IFN-gamma and IL-2 might be a reasonable treatment for breast cancer patients.

We examined the effect of OK-432 on induction of cytotoxic T lymphocytes (CTL) directed against autologous tumor cells (ATC) and lymphokine-activated killer (LAK) cells from mononuclear cells separated from regional lymph node cells (RLMNCs) of 49 lung cancer patients. We also examined the phenotypic changes of RLMNCs during incubation with or without OK-432. Significant CTL activity and LAK activity against ATC developed from RLMNCs after stimulation with OK-432 or IL-2. Sequential treatment with OK-432 plus IL-2 or IL-2 plus OK-432 also developed significant CTL activity and LAK activity from RLMNCs. The CTL activity produced by OK-432 alone was as high as the CTL activity developed by IL-2 alone, OK-432 plus IL-2, or IL-2 plus OK-432. There was no significant difference in the CTL activities achieved by these four treatments. The proportion of CD25+ cells in RLMNCs after incubation with OK-432 was twice that before incubation. Although OK-432 increased IL-2 receptor expression on RLMNCs, it showed no synergistic effect with IL-2 in developing CTL and LAK activity. After incubation with OK-432, the proportion of HLA-DR + cells was also increased significantly. Moreover, the proportions of HLA-ABC+ and HLA-DR+ (class I and class II major histocompatibility complex antigens) cells in ATC were significantly larger than in Daudi cells. OK-432 alone could develop CTL activity against ATC from the RLMNCs of lung cancer patients that was as high as that developed by IL-2 alone or by sequential treatment with OK-432 plus IL-2 or IL-2 plus OK-432. The CTL developed from the RLMNCs of lung cancer patients may recognize class I and/or II antigens on the surface of ATC. These results indicated that treatment with OK-432 might be therapeutically useful for lung cancer patients as a CTL inducer rather than a LAK inducer.

Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility has been discussed that chemoendocrine therapy combined with endocrine agents is more effective.In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breast cancer, we ran a pilot study during the period from July 1994 to July 1996.Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m2) i.v. and 5-fluorouracil (500 mg/body) i.v. on day 1 (repeated every 3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10%), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response rate was 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity and hematological toxicity, but these were clinically well tolerated. No serious cardiac, liver or renal symptom was seen.Based on these results, we consider the addition of high-dose toremifene to the CAF therapy to be useful in the treatment of advanced and recurrent breast cancer.

Surgery is the first-line therapy for thymoma. Postoperative radiotherapy should be given for all invasive thymomas, followed by chemotherapy in some cases. Even if the resection is not complete, surgery is effective therapy because most thymomas are local and slow growing. Multidrug chemotherapy including cisplatin is effective against thymoma. Thymic cancer is histologically varied. Surgery is only one effective therapy for thymic cancer. Although no definitive chemotherapy regimen for thymic cancer has yet been established, we feel that the cisplatin, doxorubicin, cyclophosphamide, vincristine 4-drug combination regimen is effective in thymic cancer patients. Seminoma out of mediastinal germ cell tumor (GCT) is expected to have a good prognosis after surgery and radio-/chemotherapy. Although the prognosis for those with nonseminomatous GCT has recently improved due to chemotherapy and surgery, it is still poor.

Azatyrosine is known to convert ras, raf or c-erbB-2-transformed NIH3T3 cells to a normal phenotype. We attempted to identify the signal-transduction process triggered by oncogenic c-ErbB-2 that was inhibited by azatyrosine. Azatyrosine did not suppress activation of Ras induced by introduction of c-ErbB-2. However, it inhibited increases in phosphorylation of c-Raf-1 induced by oncogenic c-ErbB-2. Furthermore, azatyrosine inhibited activation of the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element in response to stimulation by oncogenic c-ErbB-2. These results suggest that this agent acts downstream of Ras in signal transduction from oncogenic c-ErbB-2 to nuclear factors. Moreover, we found that azatyrosine was incorporated into proteins instead of tyrosine. The simultaneous presence of a high concentration of tyrosine inhibited the conversion to a normal phenotype of transformed cells by azatyrosine. These results strongly suggest that incorporation of azatyrosine into proteins might convert the transformed cells in to cells with a normal phenotype.

Recently, it was suggested that splice variants of the surface glycoprotein CD44 (CD44v) were associated with tumor metastasis in some cancers. We examined the expression of variant forms of CD44 in 31 non-small cell lung carcinomas (NSCLCs) and in 8 normal lung tissue samples by reverse transcription-PCR (RT-PCR). CD44v3, CD44v5, CD44v6, and CD44v7 were not expressed or were weakly expressed in normal lung tissue (0 of 8). In contrast, CD44v3, CD44v5, CD44v6, or CD44v7 was expressed in 28 of 31 (90.3%) NSCLCs. Additionally, we examined the expression of CD44v6, which has been shown to be related to metastasis, in 5 normal lungs and 30 NSCLCs by RT-PCR and immunohistochemical analysis to clarify which cells express CD44v6 in NSCLC specimens. Thirty-six of 61 (59%) NSCLCs variably expressed CD44v6 by RT-PCR, and cancer cells were selectively immunostained by anti-CD44v6 antibodies in 23 of 30 (76.7%) NSCLCs. The results of immunohistochemical analysis almost correlated with those of RT-PCR. NSCLCs with lymph node metastasis expressed significantly more v6 exon than did those without lymph node metastasis [23 of 29 (79.3%) versus 13 of 32 (40.6%); P0.01]. There was a significant association between the intensity of v6 expression by RT-PCR and the frequency of cases showing lymph node metastasis (Cochran-Armitage's test, P0.002). In conclusion, this study demonstrated that in NSCLC, a number of variant forms of CD44 are frequently expressed, although these variants are infrequently expressed in normal lung tissue, and that the expression of CD44v6 is particularly associated with lymph node metastasis in NSCLC.

Total calcium is routinely measured after thyroidectomy in a clinical setting, while the measurement or calculation of the free calcium level is not generally performed. We reviewed total and free calcium levels in patients who underwent lobectomy (n = 15), subtotal thyroidectomy (n = 15) and total thyroidectomy (n = 15). Postoperative total calcium levels decreased significantly in comparison to preoperative levels in all thyroidectomies (p0.01), and this fall was significantly related to the extent of surgery (p0.01). In contrast, there was no significant difference between preoperative and postoperative free calcium levels in patients undergoing lobectomy, although we found a decrease in free calcium levels after both subtotal and total thyroidectomy. Total protein levels decreased regardless of the type of operation. Serum total calcium levels were thought to be altered by serum protein levels through the change of protein-bound calcium levels. When examined for free calcium levels, some patients were administered unnecessary calcium supplementation because hypocalcemia had been judged from the total calcium level. Since the wrong diagnosis may be given with regard to hypoparathyroidism by measurement of total calcium levels alone, we propose that free calcium levels should be routinely measured or calculated after thyroidectomy.

Comparison of acquired mutations in the p53 tumor suppressor gene can illuminate factors contributing to carcinogenesis among cancer cohorts. Japan has an ethnically homogeneous population with a low incidence of breast cancer. Previously we reported an unusual frequency, allelic status, and clustering of mutations in breast cancers from the northern part of the main Japanese island. To extend these findings, exons 2-11 and adjacent intronic sequences were analysed in tumors of women from northern (Hokkaido) and southern (Tokushima) Japan. The frequency of breast cancers with p53 gene mutations in the Hokkaido group is the highest reported (81%) while that in Tokushima (28%) is similar to most other populations. Thirteen of the 19 mutations (68.4%) in the Hokkaido cohort were heterozygous, an unusually high frequency for p53 mutations in any tumor type. There were three missense mutations at codon 175, a known hotspot for alterations in the p53 gene, and three missense mutations at codon 179, a rare site for p53 changes. In addition, the patterns of p53 gene mutation differed between the two Japanese cohorts (P=0.04). The multiple differences in acquired p53 mutations suggest unsuspected biological differences among breast cancers in northern and southern Japan. In addition, the high frequency of p53 mutations in breast cancers from Hokkaido predicted a poorer prognosis for this population which was confirmed on examination of mortality data.

We reported recently that azatyrosine inhibits the growth of c-Ha-ras, c-raf or c-erbB-2-transformed NIH3T3 cells and converts the transformed cells to cells with a normal phenotype. To analyze the mode of action of azatyrosine, we examined the effects of azatyrosine on the synthesis of macromolecules. Azatyrosine had no obvious inhibitory effects on the synthesis of DNA, RNA and protein in c-erbB-2-transformed cells. Furthermore, azatyrosine inhibited cell growth but did not interrupt the cell cycle at any specific stage. Thus, the mode of action of azatyrosine appeared to be different from that of typical anticancer drugs. Moreover, we found that azatyrosine was incorporated into proteins instead of tyrosine. The simultaneous presence of a high concentration of tyrosine inhibited the conversion to a normal phenotype of transformed cells by azatyrosine. These results strongly suggest that incorporation of azatyrosine into proteins might convert the transformed cells to cells with a normal phenotype. The analysis of azatyrosine-containing proteins by two-dimensional electrophoresis revealed that the mobilities of some proteins differed from those of the corresponding tyrosine-containing proteins. An alteration in molecular structure of the proteins that include azatyrosine residues might be associated with the ability of azatyrosine to convert transformed cells to cells with a normal phenotype.

Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)alanine] is known to convert ras- or raf- transformed NIH3T3 cells to a normal phenotype. We report herein that azatyrosine also inhibits the growth of c-erbB-2-transformed cells and induces normal morphology. We attempted to identify the signal-transduction process triggered by oncogenic c-ErbB-2 that was inhibited by azatyrosine. Azatyrosine neither affected the phosphorylation of the introduced oncogenic c-ErbB-2 nor did it suppress activation of Ras induced by introduction of c-ErbB-2. Thus, azatyrosine did not inhibit the signal transduction from oncogenic c-ErbB-2 to Ras. However, azatyrosine inhibited increases in phosphorylation of c-Raf-1 and c-Jun induced by oncogenic c-ErbB-2. Furthermore, azatyrosine inhibited activation of the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element in response to stimulation by oncogenic c-ErbB-2. These results suggest that azatyrosine acts downstream of Ras in signal transduction from oncogenic c-ErbB-2 to nuclear factors.

The mechanism of mucosa-specific formation of DNA adducts, which was found recently in human intestines, was studied in male F344 rats treated with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). There are three conceivable pathways for p.o. administered IQ to reach the target colonic mucosal cells: pathway 1, through the digestive canal which exposes from the lumenal direction; pathway 2, following enterohepatic circulation re-expose from the lumenal direction; and pathway 3, exposure via blood circulation. To investigate these possible pathways, the following surgical procedures were performed: (a) portal catheterization for IQ administration to eliminate pathway 1 and (b) choledochal catheterization for bile drainage to eliminate pathway 2. When both procedures are combined, only pathway 3 is active. Four types of IQ-DNA adducts were commonly observed in the colons of all experimental groups, with no qualitative difference between the mucosal and muscular layers. When IQ-HCl was administered by p.o. gavage at a dose of 100 mumol/kg body weight, approximately 70% of the IQ-DNA adducts in the colonic mucosa (13.1 +/- 4.3 adducts/10(7) nucleotides) was induced through pathway 1. Pathway 3 induced the remaining 30% of mucosal adducts, producing equal adduct levels in both layers. Pathway 2 did not work for adduct formation. The DNA adduct formation was unaffected in the presence of intestinal flora, indicating that detoxified IQ does not reactivate by floral enzymes. In conclusion, mucosa-specific DNA adduct formation in the colon is caused most likely by the absorption of carcinogens through the lumen.

The patient was a 38-year-old woman who was diagnosed as having right breast cancer (T1aN1bM0, stage II) at the age of 36 when she underwent right mastectomy. Postoperative adjuvant therapy was performed using UFT and tamoxifen. After 2 years and 4 months, pulmonary metastasis was diagnosed from elevated tumor markers and chest X-P. After the relapse, treatment with goserelin acetate (Zoladex) and CPA was started. After 2 months of this treatment, the tumor in the lung had shrunk in size, and after 5 months partial remission (PR) was evaluated from improvements in chest X-P and normalization of tumor markers, This PR condition continues at present. A case report is presented of a patient with premenopausal recurrent breast cancer in whom good results were obtained by concomitant administration of Zoladex and CPA.

During screening for inhibitors of ras-mediated differentiation of PC12 cells, trichostatin A (TSA) was isolated from the metabolites of Streptomyces as a potent inhibitor. TSA blocked both oncogenic ras- and NGF-induced neurite outgrowth from PC12 cells. However, addition of TSA 1 h after NGF-stimulation did not inhibit neuronal differentiation, suggesting that TSA affects an early step in the NGF-signaling pathway mediated by ras. Northern blotting analysis showed that TSA prolonged the maximum expression period of c=fos mRNA triggered by NGF and delayed its return to the basal level. TSA reduced c-jun mRNA induction by NGF but greatly enhanced c-myc mRNA induced by NGF. Yoshida et al. (J. Biol. Chem, 265, 17174-17179, 1990) showed that TSA inhibits histone deacetylation, which might influence the gene expression involved in cellular differentiation. In this study, we also found that TSA prevents histone deacetylation in PC12 cells as well as other cell lines, suggesting that inhibition of histone deacetylation by TSA might affect the expression of early-response genes. We also demonstrated that TSA induced reversion of oncogenic ras-transformed NIH3T3 cells to a normal morphology, suggesting that inhibitors of ras-mediated differentiation of PC12 cells may be effective as anticancer agents.

At age 35, the patient was diagnosed with left breast carcinoma (T4bN0M0, Stage IIIb) during her first pregnancy, and underwent mastectomy of the left breast and bilateral oophorectomy. Although CPA was administered as adjuvant chemotherapy after the operation, left pelvic pain developed about a year after the operation, and bone metastasis was detected from the imaging diagnosis. Then, the therapy was switched to UFT (600 mg/day) and tamoxifen (20 mg/day), which markedly relieved the pain along with bone scintiscan (NC) and simple X-P (NC). Five years have passed since the operation, and the progress is excellent. There is neither increase of pain nor adverse reactions to drugs. Furthermore, the patient received breast reconstruction operation at her strong insistence in the third year after operation, and has achieved a high quality of life (QOL).

We report a case of a 60 year-old man with an umbilical polyp composed of the aberrant pancreas and small intestinal mucosa. This is an extremely rare lesion which originates in remnants of omphalomesenteric duct and is usually diagnosed in the infant period. Microscopic examination disclosed the aberrant pancreas with exocrine glands and ducts, but no islets of Langerhans. The above findings suggested that the pancreas might have been HEINRICH II in type.

We described two patients of thyroid cancer with tracheal invasion. A 54-aged female visited our hospital with complaint of the neck pain. Echography showed a tumor in the right lobe of the thyroid. In operation the thyroid tumor invaded the trachea and right recurrent nerve. A 24-aged male visited our hospital with complaint of a mass of the left side neck. Echography showed a tumor in the left lobe of the thyroid. In operation the thyroid tumor invaded the trachea, lymph node and left recurrent nerve. In these two cases we could find thyroid tumors invaded into the trachea by echography. We re-evaluated the utility of echography.

The intraarterial arm injection of freshly isolated autologous lymphocytes to a patient with upper extremity secondary lymphedema brought about a rapid and remarkable reduction in arm swelling. The protein components in the edema fluid were analyzed by two-dimensional electrophoresis before and after lymphocyte injection. We observed the appearance of a novel protein spot, with an isoelectric point of 6.5, in an electropherogram as early as 30 minutes after the lymphocyte injection. Immunoblotting using antibody against human total serum proteins suggested that the novel protein was not derived from the serum. Because incubation in vitro of the lymphedema fluid with the isolated lymphocytes produced a new protein spot, corresponding to the novel protein observed in vivo, we suspect that the novel protein originated from limited hydrolysis of a unique protein present in the arm edema fluid. Significance of the novel protein and the role of limited proteolysis after lymphocyte injection in the management of lymphedema are examined.

Among 8 patients with spontaneous esophageal rupture, mean age was 46.5 years, and there was only one female. Vomiting after drinking was the main cause of onset. In 4 patients who underwent drainage of the thoracic cavity or initial treatment by surgery within 24 hrs after onset, closure after layer-layer suture of the site of rupture was made in two patients in whom definitive diagnosis was obtained at the first medical examination and early discharge was possible. A definitive diagnosis was obtained after drainage of the thoracic cavity in the other two patients, and esophagectomy without thoracotomy was performed on the 55th day after onset in one and the other patient received only conservative treatment without surgery, both patients were discharged. Of 4 patients who underwent treatment after 24 hrs, two patients who recovered included one who received only conservative treatment and another who underwent closure by suture of the site of rupture and covering with a pedicled omental flap 12 days after onset. The other two patients died of MOF after operation. We propose the following guidelines for treatment of this condition; In patients in whom surgical treatment is possible within 24 hrs after onset, closure by layer-layer suture of the site of rupture may be indicated. In cases in which more than 24 hrs has elapsed after rupture spontaneous closure sometimes can be expected in patients with a rupture would less than 2 cm. In patients accompanied with progressing mediastinitis or pyothorax with drainage procedure surgical treatment is indicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Since taxol (NSC 125975) and tiazofurin (NSC 286193) attack at two different sites in microtubular synthetic processes, we tested the rationale that the two drugs might be synergistic in human ovarian (OVCAR-5), pancreatic (PANC-1) and lung carcinoma (H-125) cells and in rat hepatoma 3924A cells. In human OVCAR-5, PANC-1, H-125 and rat 3924A cells, for taxol the anti-proliferative IC50 was 0.05, 0.06, 0.03 and 0.04 microM, respectively; for tiazofurin IC50 = 8.3, 2.3, 1.8 and 6.9 microM. Thus, the concentrations for taxol required for IC50 for inhibiting cell proliferation were 166-, 38-, 60- and 173-fold lower than those for tiazofurin. Taxol and tiazofurin proved synergistic in all four cell lines tested. The synergism of taxol with tiazofurin should have implications in the clinical treatment of human solid tumors with particular relevance to ovarian, pancreatic, lung and hepatocellular carcinomas.

We studied the incidence of thyroid nodules in healthy adults, who had no history of thyroid disease, in Tokushima, Japan, where goiter is not considered endemic. Examination was performed by palpation and using a 10-MHz real-time sonographic scanner. Palpable thyroid nodules were present in two (0.9%) of 227 men and in four (1.8%) of 224 women. On the other hand, nodules were detected by ultrasonography in 42 men (18.5%) and 47 women (21.0%). There was no significant difference in the incidence detected by ultrasonography between men and women in any of the age groups, except in men above 60 years old. It is concluded that thyroid nodules are not an uncommon disorder even in men. Since, clinically, the incidence of nodularity appears to be higher in women than in men, there may be difference between men and women in the development of nodules until they become clinically detectable.

A 54-year-old female with incomplete type of Behçet's disease was operated on because of impending rupture of the thoracic aneurysm. There was a saccular pseudoaneurysm below the left subclavian artery, and a punched out lesion of the aorta was recognized. The defect of the aortic wall was closed with a PTFE patch. Before and after the operation, we have given prednisolone. The postoperative course was uneventful. Two years later, there was no recurrence of pseudoaneurysm near the PTFE patch. In many reports, aneurysms of Behçet's disease are saccular pseudoaneurysms, and have high incidence of complications about anastomosis postoperatively. We need a further follow-up about this patient.