Search

Introduction Bcl-2 and Bcl-xL confer resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We examined the relationship between the expression of Bcl-2 and Bcl-xL and chemosensitivity of breast cancer cells, with the aim of developing specific targeted therapy. Methods Four human breast cancer cell lines were examined, and the effects of antisense (AS) Bcl-2 and AS Bcl-xL phosphorothioate oligodeoxynucleotides (ODNs) on chemosensitivity were tested in vitro and in vivo. Chemosensitivity was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, and the antitumor effect was assessed in vivo by the success of xenograft transplantation into athymic mice. Results Treatment with AS Bcl-2 and Bcl-xL ODNs resulted in a sequence-specific decrease in protein expression, compared with controls. Treatment of BT-474, ZR-75-1, and MDA-MB-231 cells with AS Bcl-2 increased chemosensitivity to doxorubicin (DOX), mitomycin C (MMC), paclitaxel (TXL), and docetaxel (TXT). Transfection of the Bcl-2 gene into MDA-MB-453 cells decreased sensitivity to DOX and MMC. Treatment of MDA-MB-231, BT-474, and ZR-75-1 cells with AS Bcl-xL increased chemosensitivity to DOX, MMC and taxanes to a smaller extent than AS Bcl-2. This occurred in the setting of increased Bax and cleaved poly(ADP-ribose) polymerase, as well as decreased Bcl-2 and pAkt. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, which was attenuated by methylation of the CpG motifs of AS Bcl-2; however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Bcl-2 and Bcl-xL, to a smaller extent, are major determinants of chemosensitivity in breast cancer cells. Conclusion Targeted therapy against Bcl-2 protein with the use of AS ODNs might enhance the effects of chemotherapy in patients with breast cancer.

Using 4 human cancer cell lines, 4 tumors xenografted into nude mice, and 11 fresh tumor specimens removed at surgery, we investigated the relevance of NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD) activity (nmoles/min/mg protein) to mitomycin C (MMC)-induced cytotoxicity. In culture cell lines, KB cells had significantly higher levels of DTD activity (8260) than PH101 (1934), SH101 (1805) or K562 (1796), and the highest sensitivity to MMC. In contrast, the higher the DTD activity of xenografts, the greater their resistance to MMC, while the inhibition rate of relative tumor growth for MMC, as evaluated by the NCI protocol, was highest in SH-6, high in CH-5, lower in CH-4 and lowest in EH-6. The investigation using 11 fresh tumor specimens also showed an inverse relationship between IC50 values after a 30-min MMC treatment, as evaluated by ATP assay and DTD activities. Moreover, a non-toxic DTD inhibitor, dicoumarol (DIC), or flavin adenine dinucleotide (FAD), suppressed the efficacy of MMC in culture cells, but enhanced it in xenografts. Thus, we suggest that DTD may play an important role in MMC-induced cytotoxicity but MMC metabolism by DTD in solid tumors may differ from that in culture cells.

Recent observations have demonstrated that the reduced expression of p27Kip1 (p27) is correlated with progression and poor prognosis of breast, colon, and gastric carcinomas. These observations led us to examine the expression of p27 and cyclin D1 and E protein in six esophageal carcinoma cell lines and 81 esophageal carcinoma tissues by Western blot analysis and immunohistochemistry. The expression levels of cyclin D1 and p27 were correlated clearly in esophageal carcinoma cell lines by Western blot analysis. Immunohistochemical analysis revealed that the high-grade expression of p27 protein was detected in 61% of esophageal carcinomas, and it was correlated with tumor invasion, lymph node metastasis, and poor patient prognosis. This observation was different from the results reported in other organs. Cell cycle regulation is a very complicated process. Homeostatic feedback mechanisms against the overexpression of cyclin D1 may exist in esophageal carcinomas, and there can be organ-specific regulations in the progression of carcinomas.

BACKGROUND Methods for identifying sentinel lymph nodes (SNs) and their clinical significance have been established. Recent advances in molecular immunology have enabled the analysis of precise immune responses. The objective of the current study was to clarify the dendritic cell (DC) maturation, T-helper type 1 (Th-1) and Th-2 responses, and regulatory T-cell responses of SNs in patients with breast carcinoma. METHODS SNs and non-SNs were identified by radioguided and blue dye-guided methods in 70 consecutive patients with clinically lymph node negative (N0) breast carcinoma. Lymphocytes were collected from SNs and non-SNs and were subjected to flow cytometric analysis (FCM) using antibodies of CD83-fluorescein isothiocyanate (FITC), CD80-phycoerythrin (PE), CD86-PE, CD40-PE, human leukemic D-related antigen (HLA-DR)-FITC, CD4-FITC, and CD25-PE. Total RNA was extracted from SNs and non-SNs, and the expression of CD83, interleukin 12p40 (IL-12p40), interferon γ (IFN-γ), IL-4, IL-10, and Foxp3 was evaluated by using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The immunologic status of SNs was analyzed further with regard to micrometastases, which were identified as negative microscopically but positive according to an RT-PCR analysis that was specific for mammaglobin. RESULTS SNs were detectable in 70 of 71 consecutive patients (98.6%) with clinically N0 breast carcinoma. Fourteen of 70 patients (20.0%) had positive metastasis in SNs. When SNs were compared with non-SNs in 56 metastasis-negative patients, FCM revealed that HLA-DR-positive, CD80-positive, CD86-positive, and CD40-positive cell populations were decreased significantly in SNs. RT-PCR analysis demonstrated that, among 44 patients with metastasis-negative SNs, the expression levels of CD83 and IFN-γ mRNA were significantly lower in SNs compared with non-SNs. Immunologic parameters also were compared between 44 metastasis-negative SNs and 14 metastasis-positive SNs. The metastasis-positive SNs demonstrated significantly higher expression of CD83, IL-12p40, IFN-γ, IL-10, and Foxp3 mRNA than the metastasis-negative SNs. Correction of micrometastasis detected by mammaglobin enhanced these differences consistently. CONCLUSIONS In patients with breast carcinoma, cellular immune responses, from DC maturation to Th-1 responses, appeared to be less active in SNs compared with non-SNs before metastasis developed. Once metastasis was established in SNs, DC maturation was triggered and was followed by the up-regulation of Th-1 responses, which may reflect antigen-specific immune responses in SNs. Unlike DC maturation and Th-1 responses after metastasis in SNs, up-regulation of Th-2 and regulatory T-cell responses developed in parallel. Cancer 2006. © 2006 American Cancer Society.

Neoadjuvant chemotherapy was initially used only as treatment for locally advanced breast cancer. However, because breast cancer is considered to be a systemic disease in which distant micrometastases are already present at the time of the initial diagnosis, primary systemic therapy may be beneficial in the eradication of these micrometastatic lesions. Despite the fact that no survival benefit of neoadjuvant chemotherapy over adjuvant chemotherapy has yet been demonstrated, the clinical indication for neoadjuvant chemotherapy is being extended not only to stage T3/4 tumors but also to some stage T1/2 operable breast cancers. The current clinical benefits of the use of neoadjuvant chemotherapy are that (1) the safety of neoadjuvant chemotherapy is comparable with that of adjuvant chemotherapy, (2) neoadjuvant chemotherapy increases the possibility of the use of breast-conserving surgery, and (3) pathologic complete response may be a predictive indicator of better survival. Importantly, the response to neoadjuvant chemotherapy in vivo could provide a useful prediction of prognosis and help define strategies for an individual patient's future treatment with alternative chemotherapy regimens or molecular-targeting agents. Furthermore, the discovery of predictive markers for tumor response to neoadjuvant chemotherapy through the analysis of complementary DNA microarrays and proteomics may also help facilitate individualized chemotherapy, particularly by improving survival in patients with breast cancer with a poor prognosis. Herein we review the current status and future role of neoadjuvant chemotherapy in operable breast cancer in terms of its survival benefit and the potential for the individualization of adjuvant therapy for these patients.

This study aimed to evaluate the tolerability and pharmacokinetics of capecitabine, given twice daily for 6 weeks without interruption, and to identify the maximum tolerated dose (MTD) and the suggested phase II schedule.The initial dose of capecitabine was 251 mg/m2 twice daily, without interruption, and a dose escalation schedule was planned according to a modified Fibonacci scheme. Patients received oral capecitabine twice daily for at least 6 weeks unless grade 3 or 4 toxicity was observed. Blood and urine samples were collected for pharmocokinetic analysis on days 1 and 15.Sixteen patients with malignant solid tumors (seven breast, seven colorectal, and two gastric) were enrolled, all of whom were evaluable. Among 4 patients treated with capecitabine 1255 mg/m2 twice daily, one experienced grade 4 hemorrhagic gastric ulcer and one experienced grade 3 skin toxicity. Consequently, this dose was defined as the MTD, and gastrointestinal and cutaneous effects were identified as dose-limiting toxicities. There was no grade 3/4 diarrhea at any dose level. There was also no grade 4 hematologic toxicity at doses below the MTD, and there were no treatment-related deaths. Two patients with breast cancer had partial responses, at capecitabine doses of 502 mg/m2 and 1255 mg/m2, twice daily. Pharmacokinetic data show that high concentrations of doxifluridine (5'-DFUR) occur in tumor cells within 2 h after administration of capecitabine.The MTD of continuous oral capecitabine over 6 weeks was 1255 mg/m2 twice daily. Because of the higher occurrence of skin disorders reported in this study with a continuous treatment regimen, an intermittent treatment regimen of 828 mg/m2, administered twice daily for 3 weeks, followed by a 1-week rest period, was recommended for phase II studies. This regimen is being evaluated in phase II studies in Japanese patients with gastric, colorectal, and breast cancers.

Dihydropyrimidine dehydrogenase is the most extensively investigated predictive marker for individual response to 5-fluorouracil. Clinical responses to the anticancer agent, along with various reports, have clearly shown that dihydropyrimidine dehydrogenase activity is closely correlated to its mRNA levels, but the regulatory mechanisms of its expression have remained unclear. We attempted to clarify the mechanisms and found that activator protein (AP-1) is probably one of the key factors in the transcriptional regulation of DPYD in cancer cells, and that phorbol 12-myristate 13-acetate (PMA) plus ionomycin treatment enhances transcription of DPYD via AP-1 activation. In this study, we characterized our previously subcloned 5′ region of human DPYD, an ∼3.0-kb fragment (accession no. AB162145). Luciferase reporter assay showed that the clone showed strong promoter activities in 293T and HSC42 cells, and comparative analysis using 5′ deletion mutants suggested the existence of several positive and negative regulatory regions, including putative binding sites for AP-1, SP-1, and nuclear factor-κB. PMA/ionomycin treatment increased the mRNA level of DPYD in HSC42 cells, and electrophoretic gel mobility shift assay showed that the complex on the putative AP-1 binding site was drastically induced by PMA/ionomycin treatment. The complexes formed were competed out by preincubation with the cold-consensus AP-1 binding site, and the DNA binding complex formed on the site contained c-Jun and c-Fos, which are components of AP-1 transcription factor. We further identified the functional AP-1 binding site (nucleotide positions from −290 to −280), whose nucleotide mutations abolished PMA/ionomycin-induced DPYD promoter activation.

Objective: Epidermal growth factor (EGF) has many biological functions and plays an important role in the progression of various tumors including gastric cancer. An A-G single nucleotide polymorphism (SNP) at position 61 in the 5′-untranslated region (UTR) of the EGF gene has recently been reported to be associated with different levels of EGF production. We examined whether this polymorphism is correlated with the development and malignant phenotypes of gastric cancer. Methods: The study population included 200 gastric cancer patients and 230 healthy control subjects. The SNP in the 5′-UTR of the EGF gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Results: The A allele was significantly less frequent in patients than in controls (p = 0.01). Individuals with the A/A or A/G genotype showed a significantly lower risk of gastric cancer than those with the G/G genotype [adjusted odds ratio (OR) = 0.56], whereas the same genotypes were associated with malignant progression of this cancer, e.g. deeper tumor invasion, increased lymph node metastasis and advanced clinical stage, and histological classification in gastric cancer patients (adjusted OR = 1.80, 1.98, 2.26 and 1.89, respectively). Conclusions: Our findings suggest that the A-G polymorphism of EGF is involved not only in the occurrence but also in the malignant progression of gastric cancer.

BACKGROUND Because the overexpression of HER-2 and Bcl-2 is associated with resistance to tamoxifen (TAM), the authors examined the effect of antisense (AS) Bcl-2 on sensitivity to TAM compared with the effect of trastuzumab on sensitivity to TAM in breast carcinoma cell lines. METHODS Drug sensitivity was assessed in vitro using a [3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay with the breast carcinoma cell lines ZR-75-1, MDA-MB-453, and BT-474. AS Bcl-2 18-mer phosphorothioate oligonucleotide was applied. Apoptotic cell death was assessed with the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling method, and gene expression was evaluated with Western blot analysis. RESULTS The expression of Bcl-2 was identified in ZR-75-1 and BT-474 cells and, to a lesser extent, in MDA-MB-453 cells. Overexpression of HER-2 was identified in BT-474 cells, and moderate expression was identified in MDA-MB-453 and ZR-75-1 cells. Combination treatment with trastuzumab or AS Bcl-2 enhanced TAM sensitivity in ZR-75-1 cells, which showed 50% inhibitory concentration (IC50) values of 0.9 μM (7.2-fold increase) and 0.5 μM (13.0-fold), respectively. Combination treatment with trastuzumab or AS Bcl-2 slightly enhanced TAM sensitivity of BT-474 cells, with IC50 values of 3.0 μM (1.3-fold) and 1.5 μM (2.6-fold), respectively. The sensitivity of MDA-MB-453 cells to TAM was not enhanced by combination with trastuzumab or AS Bcl-2. Modulation of TAM sensitivity by AS Bcl-2 was superior to modulation by trastuzumab in HER-2-expressing and Bcl-2-expressing breast carcinoma cells. Enhanced sensitivity in combination with AS Bcl-2 was associated with down-regulation of Bcl-2 and pAkt, which was correlated with the induction of Bax and caspase-3, leading to apoptosis. CONCLUSIONS AS Bcl-2 appeared to be superior to trastuzumab with respect to regulating the signal-transduction pathways involved in breast carcinoma cells. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Autocrine and paracrine growth mediated by the platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR)-signaling pathway plays an important role in the progression of solid tumors. The authors assessed the effect of STI571 on the tumor growth of gastric carcinoma in combination with 5-fluorouracil (5-FU) or paclitaxel targeting the PDGF/PDGFR-signaling pathway. METHODS In MKN-45 gastric carcinoma cells, the cytotoxic effect was evaluated by 3-(4,5 dimethiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and the in vivo antitumor effect was evaluated in a nude mouse xenograft. Both STI571 and an antitumor drug were administered intraperitoneally. Gene expression was assessed by Western blot analysis and immunohistochemical staining. Apoptotic cell death was evaluated by the terminal deoxyuridine triphosphate-biotin nick-end labeling assay, and tumor angiogenesis was evaluated by microvessel density analysis. RESULTS Treatment with STI571 alone was not effective in vitro, as assessed by a 50% inhibitory concentration value of 24.3 μM. Combination treatment with STI571 and 5-FU or paclitaxel enhanced the cytotoxic effect somewhat when the concentration of STI571 was increased to 10 μM. Combination treatment with STI571 and 5-FU or paclitaxel enhanced the antitumor effect of the antitumor drug significantly in vivo. The enhanced antitumor effect was associated with increased apoptotic cell death and inhibition of tumor angiogenesis. Treatment with STI571 down-regulated the expression of PDGF-BB and PDGFR-β in tumor cells and decreased the production of phosphorylated PDGFR-β and phosphorylated Akt. Furthermore, treatment with STI571 inhibited the expression of PDGFR-β in stromal cells. CONCLUSIONS STI571 was an effective chemosensitizer of antitumor drugs, such as 5-FU and paclitaxel for gastric carcinoma, targeting the PDGF/PDGFR-signaling pathway of tumor cells and stromal cells in disease progression and angiogenesis. Cancer 2005. © 2005 American Cancer Society.

A randomized phase II clinical trial has been designed and started in the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) to select the better regimen between tailored CPT-11 + S-1 and the standard S-1 treatment for advanced or recurrent gastric cancer as the first line chemotherapy. Selection of the better treatment for general clinical practice in this clinical trial will lead to a more precise assignment of a promising regimen for a future phase III randomized trial, placing continuous 5-FU infusion as the reference arm. In this trial, subsidiary pharmacokinetic analysis for the tailored dose arm is also proposed. In order to continue chemotherapy for a long time and to obtain longer survival, our study design for the tailored therapy could be exploited, especially in the field of general clinical practice.

Matrix metalloproteinase-1 (MMP-1) plays a key role in cancer invasion and metastasis by degradation of extracellular matrix (ECM) and basement membrane barriers. The 1G/2G single nucleotide polymorphism (SNP) in the MMP-1 promoter at position –1607 bp has been reported to affect the transcriptional activity. In the light of these findings, we investigated whether this SNP in the MMP-1 promoter is associated with the development, differentiation, and progression of gastric cancer. The 215 gastric cancer patients and 166 controls were used in this study. The SNP of the MMP-1 promoter was analyzed by PCR-RFLP and sequencing. The genotype frequency was compared between cases and controls, and the association with clinicopathological parameters among cases was studied. The frequency of 1G/2G genotypes in gastric cancer patients was similar to those in controls (p=0.57). The degree of tumor invasion, the presence of lymph node metastasis, and clinical stage showed no significant association with the SNP. On the other hand, we found a significant association with histological differentiation and gender among gastric cancer patients (p

末梢型の原発性肺癌を想定し, ブタの肺の末梢に蛍光ビーズ (Fluorescent polystyrene latex microspheres, Polyscience Inc.) を注入して, リンパ管, リンパ節の描出を試みた.右上葉へ注入した際には右気管気管支リンパ節が, 右下葉へは2回のうち1回は右主気管支周囲リンパ節が, 左上葉へは大動脈下の主気管支周囲リンパ節が, 注入後30分以内に蛍光を発した.検討した7回のうち6回 (86%) において所属リンパ節の1個から数個が標識可能であった.その特長としては, 数分後にセンチネルリンパ節に向かう輸入リンパ管が描出された後に, 蛍光ビーズはリンパ節に集積した.anthracosisをきたしたリンパ節の割面においても明瞭に斑点状に認められたが, リンパ節の線維性被膜の表面からは集積しているかの判定に難渋することがあった.投与した蛍光ビーズのほとんどは摘出標本内に残存しているものと考えられた.

83歳,女性で,胃癌から単独に脳転移をきたした症例を報告した. 3型胃癌の診断にて,幽門側胃切除術が施行された.開腹時診断はsT3sP0sH0sN3 (stage IV)で,組織学的診断はpoorly differentiated adeno carcinoma, Se, ly3, v2, n3: pT3pP0pH0pN3 (stage IV)であった.免疫組織化学的検査ではp53の異常蓄積, cycline E, integrinlinked kinase (ILK), VEGF-Cの発現増強とhMLH1, p27, E-cadherineの発現減弱が認められた.術後2カ月目に痙攣,意識混濁を認めたため,頭部CT検査を施行した結果,胃癌からの脳転移が疑われた.症例は術後4カ月目に永眠された.

The SWI/SNF proteins are ATP-dependent chromatin remodeling enzymes that have been implicated in the regulation of gene expression. Recent studies have shown that members of the SWI/SNF superfamily can function as tumor suppressor genes. DNA methylation and transcriptional inactivation of the HLTF gene, which is a homologue to the SWI/SNF genes, have been observed in colon cancer. In the present study, we studied the DNA methylation status of the HLTF gene by methylation-specific PCR in 50 gastric carcinoma tissues, and seven gastric carcinoma cell lines and compared the methylation status with the levels of HLTF mRNA expression. DNA methylation of the HLTF gene was found in 25 (50%) of 50 gastric carcinomas, and levels of HLTF mRNA were associated with methylation status of HLTF (P = 0.027; Mann-Whitney U test). No correlations were found between HLTF mRNA levels and DNA methylation and T grade, N grade, tumor stage, or histological type. In corresponding non-neoplastic mucosae, DNA methylation of the HLTF gene was found in 1 (7%) of 15 samples. The methylated allele was not detected in any of 10 normal gastric mucosae from 10 healthy volunteers. Among seven gastric carcinoma cell lines, the KATO-III cell line showed loss of HLTF mRNA expression associated with DNA methylation. This loss was rectified by treatment with both Aza-2'-deoxycytidine, a demethylating agent, and trichostatin A, a histone deacetylase inhibitor. Chromatin immunoprecipitation assay revealed that the acetylation levels of histones H3 and H4 in the 5' CpG island of the HLTF gene were inversely associated with DNA methylation status. These results suggest that transcriptional inactivation of HLTF by aberrant DNA methylation and histone deacetylation may be involved in stomach carcinogenesis through down-regulation of HLTF expression.

Enhancing effect on liver metastasis of surgical stress of thoraco-laparotomy and its regulation with a radical scavenger were examined in rat model. The rats were divided into three groups: those given thoraco-laparotomy (TL group), laparotomy alone (L group) and a short laparotomy (C group). The liver content of the lipid peroxide (LPO) and the ability of granulocytes to produce active oxygen were highest in the TL group. The numbers of metastatic liver nodules were 40.6±29.7, 15.0±15.8 and 13.7±9.4 in the TL, L and C groups, respectively. When EPC-K1, a powerful hydroxyl radical scavenger, was administered to the TL group, the LPO level of the liver decreased and the number of metastatic liver nodules decreased from 27.2±30.0 to 8.9±12.7 in parallel. The findings of this study suggested that the excessive surgical stress produced by thoraco-laparotomy enhanced liver metastasis in parallel with an increase in LPO levels. These enhancing effect for tumor metastasis caused by surgery might be termed “surgical oncotaxis”. However, the radical scavenger EPC-K1 could aid in reversing the effect.

In the present study, in order to evaluate the feasibility of personalized chemotherapy, a prospective randomized pilot study was performed in 30 advanced or recurrent gastric cancer patients. As we have demonstrated previously, the expressions of mRNA from tumor biopsy samples for seven molecular markers, i.e., dihydropyrimidine dehydrogenase (DPD), glutathione S-transferase (GST)-pi, beta-tubulin (tub), O6-methylguanine-DNA methyltransferase (MGMT), multiple drug-resistant protein (MRP)-1, NADPH/quinone oxidoreductase (NQO)-1, and cytochrome p450 (P450), were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis and therapy was recommended in a flow chart that depended on the level of expression of these predictive molecular markers. We chose 12 therapeutic plans, including best supportive care (BSC). We treated 15 patients according to the gene expression profiles, and the remaining 15 patients (controls) were treated without recommended regimens, and the therapy was continued after the expression profiles were checked. Interestingly, 11 of 26 lesions (42.3%) responded after treatment given according to gene expression analysis; however, no clinical response was detected in the control group. The prediction of the response, including resistance, was successful in 75.9% by the gene expression profiles. Moreover, the survival of the patients with the recommended treatment was better than that of patients without a recommended protocol. These results indicate that personalized treatment may be beneficial for gastric cancer chemotherapy and further randomized trials should be carried out in the future.

〈目的〉胃癌手術において上腹部横切開法が上腹部正中切開法に比べ術後イレウスの発生頻度を低下させうるかどうかretrospectiveに検討した. 〈対象〉 1994年より2001年までの胃癌切除症例576例を対象とした.開腹方法は1998年までは正中切開,それ以降は横切開が選択され469例, 107例であった.両群間の背景として術式に差は認めなかったが,進行度はやや正中切開群に高い傾向があった. 〈結果〉術後イレウスは27例(4.7%)で8例に手術が施行された.発生頻度は横切開6.5%,正中切開4.3%と差がなく,術式では胃全摘6.9%,幽門側胃切除3.3%と有意差はないものの胃全摘が高率であった.横切開では手術時間の延長を,また早期癌に限ると手術時間の延長,出血量の増加を認めた. 〈結語〉上腹部横切開法では,術後イレウスの発生頻度は減少せず,開腹方法が術後イレウス発生の防止に与える影響は少ないものと考えられた.

巨大な虫垂粘液嚢腫が虫垂根部で捻転し,急性腹症として開腹手術を施行した極めて稀な症例を経験したので報告する.症例は33歳,女性.主訴は腹痛.以前より時折腹痛があったが,放置していた. 1ヵ月前に当院にて妊娠中絶手術施行.突然腹痛出現したため,当院産婦人科受診.下腹部に圧痛と筋性防御を認め,経膣超音波検査にてダグラス窩に8×3 cmの嚢胞性病変および腹水を認めたため,右付属器炎,卵管膿腫による腹膜炎の疑いで緊急手術となった.開腹時,右付属器は正常であったが,腸詰様に腫大した虫垂がその根部を軸として時計方向に2と1/4回転(810度)捻転していた.捻転を解除後,虫垂切除し,手術終了した.摘出した虫垂は, 3×10cm大,内部はゼリー状物質で満たされていた.病理診断は非腫瘍性の貯留嚢胞で,悪性の所見は認めなかった.患者は術後8日目に軽快退院した.

感染を契機に発見され, 胸腔鏡補助下に切除した先天性気管支のう胞の症例を経験したので報告する.症例は, 24歳, 女性.2001年5月5日より咳嗽, 前胸部痛を自覚, 近医受診し, 胸写にて左下肺野に異常陰影を指摘され入院した.胸部CTにて左肺下葉に多房性空洞を認めた.気管支鏡, 食道透視にて著変を認めなかった.CTガイド下肺針生検にても悪性所見は認められず, 結核, アスペルギルス等の感染も認められなかった.抗生剤投与にて症状がいったん軽快したが, 再度出現したため, 6月13日精査加療目的に当科に転院し, 気管支のう胞を疑い, 6月25日, 胸腔鏡補助下肺部分切除を施行した.病変は左肺下葉に5cm大の腫瘤として認められ周囲に線維性に癒着していた.病変部を自動縫合器にて切離した.のう胞の表面は暗赤色調で厚い被膜に覆われ, 内部には大小の隔壁を認め, 血性膿が貯留していた.病理所見は気管支のう胞でみられる気管支軟骨が認められず, 肺分画症でみられる大循環との交通もないことから, 多房性のう胞と診断された.臨床所見からは先天性気管支のう胞と診断した.

We have reported that the percutaneous low output microwave coagulation therapy (PLMCT) as a minimal invasive therapy was useful for the treatment for small hepatocellular carcinoma (HCC). But this time, peritoneal dissemination as the complications after PLMCT for HCC was experienced. As there is no effective systemic chemotherapy to HCC at all, these rare complications after PMCT must be avoided. We should be aware of possible peritoneal dissemination after PLMCT for HCC. Every effort should be made to prevent this serious complication, particulary in cases of superficial and less differentiated HCCs.

手術侵襲が腫瘍の転移を促進し, その主因であるサイトカイン・ストームの制御が臓器障害にみならず癌患者の予後の向上にも重要であることを報告してきた. 今回ラットを用いてEPC-K1とmethylprednisolone (MP) が, 手術侵襲後の血清中の各種反応物質にどのように影響を与えるかについて検討した. 手術侵襲後のIL-6値は開胸開腹 (TL) 後に有意に上昇した. Endotoxin値は同様に上昇したが有意ではなかった. LPOおよびcorticosterone値は手術直後値が上昇した. IL-6およびendotoxin値はEPC-K1およびMPで抑制された. LPO値はEPC-K1でのみ抑制された. 血清corticosterone値は両者で抑制されず, MP群でより高値であった. さらに, 開胸開腹術後にsecond attackを負荷すると血清IL-6値およびNO値, 肝LPO値は著明に上昇し, EPC-K1およびMPはこれを抑制する傾向は示したがその効果は不十分であった. 以上の結果より, EPC-K1はMPよりも術後反応物質を効率よく抑制したが, second attackがかかった場合にはその抑制効果は不十分であることが判明した.

The possible use of percutaneous low output microwave tissue coagulation therapy (PLMCT) using ultra-sonography under local anesthesia for small solitary recurrent or metastatic liver cancer was studied.The subjects were 15 patients having recurrent or metastatic liver cancer with solitary liver tumor less than 4 cm in diameter.Consisting of 7 recurrent hepatocellular carcinoma and 8 metastatic liver cancers. PLMCT was performed at the output of 30 watt for 90 seconds at a time. Tumors less than 3 cm in diameter were completely coagulated by irradiation from 2 to 6 times judged by enhanced CT.No tumor recurrence was recognized in the coagulation area. Thus, the results suggested that PLMCT is a useful therapy for small solitary liver cancer especially, recurrence of hepatocellular carcinoma as a local control.

症例は70歳,男性.咳嗽を主訴に受診し,精査にて左上葉原発の扁平上皮癌と診断された.術前精査にて左主肺動脈根部に浸潤を認めたため治癒切除は困難と判断し,シスプラチン,ビンデシンによる術前化学療法を2コース施行した.左肺動脈根部への浸潤が消失し同部での切離が可能となったため左肺摘除術により完全切除となった.摘出標本の組織学的検索では, B1+2区域気管支周囲リンパ節に低分化型扁平上皮癌の転移が認められ一部は肺動脈外膜に浸潤していたが,腫瘍中心部原発巣には腫瘍細胞は認められなかった.術前化学療法の組織学的効果はEf. 2であった.術後3年が経過した現在,再発を認めていない.術前化学療法が局所制御に有効であり,微小転移巣の制御に有効であったと推察される.

症例は69歳, 女性.検診にて右肺に異常陰影を指摘され, 当科へ紹介された.胸部CTにて右肺S3b, 肺門部に2cm大の腫瘍を認め, 画像上肺癌 (cT1N0M0) を疑ったが, 術前に気管支鏡下に施行された細胞診・組織診では確定診断を得ることはできなかった.そのため診断および治療目的にて外科的生検を先行する手術を施行した.開胸下に腫瘍を露出したが肺門にありexcisional biopsyは不可能であり, cutting biopsy形式の18ゲージ針を用いてueedle biopsyを行った.迅速病理にて悪性の診断を得て右上葉切除術を施行した (sT1N0M0).永久病理にてadenocarcinoma, pT1N0M0, p0であったが, 閉胸前に行った胸腔内洗浄細胞診にて腫瘍細胞とともに気管支上皮細胞が確認され, needle biopsyによる腫瘍細胞の胸腔内脱落と判断した.術前の経皮針生検による腫瘍細胞の散布が問題になっているが, 今回のように術中の針生検でも同様の問題が起こりうる.熟練した術者により, fine needleを用いて, 出血させ癌細胞を流出させることなく, 1回の穿刺で診断をつけることが重要と考えられる.

成人の先天性食道気管支瘻の稀な1例を経験した.症例は44歳,女性.幼少時より飲水時の咳漱を, 14歳時より左肺下葉の肺炎・肺化膿症を4回繰り返していた.検診の食道胃透視にてバリウムの気管支への漏出を指摘され,精査の結果下部食道に正常粘膜に覆われた径2mm大の瘻孔を認め左B10に交通していた.瘻孔径が2mmと小さいこともあり内視鏡的に瘻孔縫縮術を施行したが完治せず,根治手術を施行した.組織学的に瘻管は食道粘膜上皮から気管支粘膜上皮への移行像が認められ,先天性食道気管支瘻と診断した.

悪性胸膜中皮腫は手術, 化学療法, 放射線療法, 等の治療に抵抗性で, 予後不良である. 再発または手術不可と判定された8症例 (平均59.6歳, 男/女: 6/2, epithelial 5, sarcomatous 2, biphasic 1) に対し, 局所免疫療法, 特に活性化自己リンパ球移入療法を施行した. 4例の胸水, 2例の腹水の貯留は, OK-432, Interleukin-2 (IL-2), lymphokine-activated killer (LAK), tumor infiltrating killer (TIL) の胸腔内または腹腔内投与によりコントロ-ルが可能であった. 48歳女性は腫瘍内局注により腫瘍は一時縮小し, 社会復帰しつつ4年を超える余命を得た. 右胸膜肺摘除術, 横隔膜合併切除後に腹膜播種性再発した60歳男性はイレウス症状が改善し, 他病死するまでの10カ月の間外来通院した. 61歳男性はIL-2の腫瘍内局注後に胸腔内出血から呼吸不全をきたし, 本療法の問題点を提起した. 悪性胸膜中皮腫に対し, 活性化自己リンパ球移入療法により予後の延長は確認できなかったが, 腔水症はほぼ完全にコントロ-ルされた. 本療法はquality of life (QOL) を維持しつつ治療が可能であり有用な治療法となりうることが期待される.

乳癌根治術後の末梢肺野の孤立性腫瘤陰影に対しては診断や治療に難渋することがある.症例は肺手術の2から4年前に原発性乳癌に対する根治的乳房切除術の既往のある4例である.肺腫瘍は全て末梢肺野の孤立性であり,長径2.0から4.5cmであった.画像上の特徴は全例とも原発性肺腺癌を想起させるものであった.そのうち1例は術前の気管支鏡検査では診断しえず,肺葉切除を前提とした開胸下の生検となり, 4例中2例ではすでに所属リンパ節転移を有しており原発性肺癌として標準的肺葉切除術が施行された.乳癌肺転移は時に高分化型肺腺癌の画像所見に酷似し,所属リンパ節転移を伴うことがある.術前に病理組織学的確診が得られなければ,外科的生検術の際には乳癌の病理組織をreviewする必要があり,乳癌肺転移として適切な外科治療が施されることが望まれる.

Summary Background: Alkaline oesophagitis attributable to duodenal mechanisms may induce oesophageal carcinogenesis in a rat reflux model. Aim: To investigate the mechanism of the regurgitation after distal partial gastrectomy. Methods: Oesophageal manometry was used in 16 patients before and after distal partial gastrectomy with reconstruction by Bilroth methods. Serum concentrations of four gastrointestinal hormones were measured by radioimmunoassay in 10 gastrectomy patients and nine healthy volunteers before and after a standardized meal. Results: The lower oesophageal sphincter pressure was reduced to 83% after surgery. The amplitude and duration of the peristaltic waves tended to be increased, and the velocity tended to be less after surgery (amplitude 120%, duration 114%, velocity 88%). Interrupted waves appeared more frequently after surgery. The manometric changes in gastrectomized patients are considered to be disadvantageous relative to regurgitation. After surgery, gastrin and pancreatic polypeptide were completely abolished postprandially, whereas cholecystokinin and neurotensin were significantly increased. Conclusion: The hormonal changes should have a suppressive effect on the lower oesophageal sphincter. Both the manometric and the hormonal changes may exacerbate reflux oesophagitis after distal partial gastrectomy.

To analyze the clinical efficacy of a protracted infusion of low-dose 5-fluorouracil (5-FU) and cisplatin (CDDP), a phase II study was performed in 36 patients with advanced gastric cancer. The treatment schedule of the low-dose administration of 5-FU and CDDP (FP) was a continuous infusion of 5-FU (250 mg/m2) for 28 consecutive days and a drip infusion of CDDP (3.5 mg/m2) for 5 consecutive days, followed by a 2-day interval each week in one cycle. The overall response rate was 47.2%. Of importance, the improvement in quality of life assessed by performance status (PS) and oral intake was 13.9% and 33.3%, respectively. The toxicity in low-dose FP treatment was less than grade 2, including gastrointestinal toxicities and bone marrow suppression, and this was tolerable during the treatment. The median survival time (MST) and 1-year survival rate were 8 months and 36.2%, respectively. In a pharmacokinetic analysis following the protracted infusion of low-dose FP, the plasma concentrations of 5-FU and CDDP were increased to about 120-130 ng/ml and 0.3-0.5 microg/ml on day 21 after the treatment, respectively. The plasma concentrations of 5-FU and CDDP were not significantly different between responders and non-responders. The tumor response to low-dose FP treatment was associated with the induction of apoptotic cell death and with the overexpression of apoptosis-related genes, such as Bax and Bcl-Xs, in cancer cells. These results indicate that the protracted infusion of low-dose FP could be a useful regimen for patients with advanced gastric cancer, in terms of the high response rate and low toxicity, possibly leading to the prolongation of survival and improvement in the quality of life.

The possible use of percutaneous low output microwave tissue coagulation therapy (PLMCT) using ultra-sonography under local anesthesia for small solitary liver cancer was studied.The subjects were 19 patients having primary or metastatic liver cancer with solitary liver tumor less than 4 cm in diameter. Consisting of 5 primary, 7 reccurent hepatocellular carcinoma and 7 metastatic liver cancers. PLMCT was performed continuously 3 times at the output of 30 watts for 30 seconds at a time. Tumors less than 3 cm in diameter were completely coagulated by irradiation from 2 to 6 times judged by enhanced CT.No tumor recurrence was recognized in the coagulation area. Thus, the results suggest that PLMCT is a useful therapy for small solitary liver cancer especially, recurrence of hepatocellular carcinoma as a minimal invasive surgery.

Bowel obstruction, in the setting of palliative care, is an important problem associated with advanced gastrointestinal malignancies, because it causes distressing symptoms such as abdominal pain, bloating, nausea and vomiting. Not all patients are fit for surgery because of their limited prognosis. Decompression with prolonged nasogastic suction is not recommended, which may worsen their quality of life. We report here a patient with terminal cancer associated with malignant bowel obstruction whose symptom was effectively controlled by administration of octreotide, a somatostatin analogue. A 76-year-old woman underwent an enbloc resection of extrahepatic bile ducts and Roux-en-Y hepaticojejunostomy for perihilar bile duct cancer. One year after the operation, intrahepatic metastatic lesions were found and hepatic arterial infusion with leucovorin and 5-FU was performed. Thereafter she developed symptoms such as abdominal colicky pain, nausea and vomiting due to bowel obstructions. The conventional therapy including morphine and haloperidol was started for this situation, however, vomiting persisted and therefore administration of octreotide was started. Vomiting was ceased within several days after the start of the treatment, and the symptomatic relief lasted until her death without nasogastric suction.

ACTH産生胸腺カルチノイドの1例を経験した.本症例は切除術後大陰唇に転移を来すという特異な経過をたどった.症例は26歳, 女性.Cushing症候群を疑われ精査したところ前縦隔に腫瘤を指摘された.異所性ACTH産生腫瘍として手術を施行し, 病理組織所見にてatypical carcinoidと診断された.切除により症状は軽快したが1年3ヵ月後に再増悪を来し, 外陰部 (右大陰唇) の硬結の生検より, 胸腺カルチノイドの外陰部転移と診断した.現在, 臨床症状は外来にてmitotaneの投与によりコントロールでき, 良好なQOLを維持している.ACTH産生胸腺カルチノイドの文献での本邦報告例15例について, 主に本疾患の転移・再発形式およびその治療について検討を加え報告する.

A 27-year-old man was admitted to the hospital because of chronic onset of right lower abdominal pain. Colonoscopy was performed, because pain and tenderness were present over the right lower quadrant and a mass 2cm in size was palpable at the same region. An elevated lesion was observed at the orifice of appendix by a colonoscopy. Inflammatory disease in the cecum or chronic appendicitis was suspected. However, diffuse wall thickness of the appendix especially submucosal layer was observed but no elevated lesion was seen at the orifice of appendix by a ultrasonography of the abdomen. Chronic appendicitis was diagnosed but to make differential diagnosis from other diseases, an appendectomy and a partial resection of the cecum were performed. It was chronic inflammtion and no change of neoplasm was observed in histological examinations. We consider that the elevated lesion on the colonoscopy was formed by inflating the colon due to sclerosing change of the appendix and the fixation with the abdominal wall.

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.

Recently, various cell cycle regulators have been investigated as biological markers of malignant potential. These regulators might influence the survival rate and the effect of adjuvant therapies. In this study, we analyzed p53, p21(Waf1/Cip1) and cyclin D1 expression in 64 esophageal cancer patients and the relationship between clinicopathologic parameters and patient survival. The positive expression rate was 48.4%, 42.2% and 43.8% in the p53, p21 and cyclin D1 groups respectively. Multivariant analysis revealed that tumor depth, chemotherapy, p53, p21 and cyclin D1 expression showed significant values. p53- and cyclin D1-negative patients had a worse prognosis. p21-positive patients had a better prognosis. In stage 0, I and II patients, there was a significant difference between p53-positive and -negative, p21-positive and -negative, and cyclin D1-positive and -negative groups. In stage III and IV patients, there was no significant difference between any two groups. However, a significant difference was seen in the p21 group: among patients who received adjuvant chemotherapy, the p21-positive group had a 5-year survival rate of 50% compared with 13.4% in the p21-negative group (not significant).

To elucidate the necessity of pyloroplasty for the gastric tube through the posterior mediastinum in esophageal surgery, gastric emptying and duodenogastric reflux (DGR) were evaluated in 16 cases undergoing an anterior pylorectomy (group P) and in 16 cases treated by the finger bougie method (group F). First, the obstruction and reflux symptoms were examined based on a patient questionnaire using a brief scoring system. The median value of the symptom score showed the patients in P to have more symptoms than those in F; however, the difference was not significant (8.0 vs 6.0). Secondly, the swallowed Tc O4 − (85 MBq) was counted using a gamma camera at three sites on the sternal bone in the upright position based on a gastric transit scintigram. Both the descending time of the RI peak and the clearance rates were similar between the two groups. Thirdly, intragastric 24-h pH monitoring was carried out. Antimony pH sensors were anchored 5 and 15 cm below the esophagogastrostomy. We could not find any difference between the two groups in both the % time pH>4 and %time pH>7. These findings thus revealed no big difference between groups P and F. The finger bougie method to drain the vagotomized posterior mediastinal stomach was found to achieve results similar to conventional pyloroplasty, while it was also simpler and safer.

In order to elucidate the efficacy in gastric surgery, we evaluated seven resected cases of a submucosal gastric tumor in which laparoscopic techniques were used. The patients consisted of 1 man and 6 women. The tumors were located in the upper, middle, and lower third of the stomach in 4, 1, and 2 cases, respectively. Three tumors were located mainly on the anterior gastric wall, 2 were on the posterior wall, and 2 were on the lesser curvature. The resected tumor size averaged 3.2 x 2.6 cm. The tumors were classified as intraluminal type (4 cases) and the extraluminal type (3 cases) according to the classification of growth type. A histopathological examination identified 4 leiomyomas, 1 leiomyosarcoma, and 4 smooth muscle tumors of indeterminate malignant potential. After a tumor resection, no recurrence of the lesions occurred during the postoperative follow-up. An extraluminal growing tumor was easily resected by the laparoscopic method without any additional procedures, and this therefore seemed to be a good indication for the laparoscopic method. In contrast, an intraluminal tumor was found to be more difficult to resect using the laparoscopic method without a companion method, e.g., intraoperative endoscopy, because of the difficulties in the detection and resection of the tumor from the serosal side. A more efficient technique must therefore be developed for this type of tumor.

The purpose of percutaneous transhepatic low output microwave tissue coagulation therapy (PLMCT) is to locally treat using ultra-sonography under local anesthesia for small liver cancer. Usefulness of PLMCT has been described. This paper introduces special techniques which are useful to make the best use of PLMCT for liver cancer. Precautions necessary in procedure for PLMCT are as follows : 1) First of all, 16G needle aspiration biopsy of the liver tumor must be percutaneously performed under ultrasonographic guidance, and then 18G needle electrode is inserted into the 16G needle as a introducer. When this procedure is carried out, the needle electrode must not be pushed over the end of the introducer, for 18G needle electrode is weak. 2) While coagulating the tumor, the introducer had better be spun. 3) If the needle electrode is hot, cold alcohol had better be sprinkled on the needle electrode. We conclude that PLMCT is less invasive practical procedure for small liver cancer as a local control.

We generally choose transhiatal esophagectomy (THE) for patients with high risk for postoperative complications and for carcinoma of the lower thoracic esophagus, even if the tumor is in the advanced stage. In order to define indications for THE in esophageal cancer patients, we investigated 40 THE cancer patients according to the expressions of EGF/EGFR, p53 and p21. In patients with stage I, II, III and IV tumors, 5-year survival rates were 66.7%, 28.6%, 30.0% and 11.4%, respectively. The sites of first recurrence were the lymph nodes (n = 10) and single organs (n = 10). Dissemination (n = 3) and local recurrence (n = 2) were also seen as a first recurrence. According to EGF/EGFR, 5-year survival rate was 69% and 14% in the low and high EGF/EGFR groups, respectively. According to p53 expression, 5-year survival was 60% and 30% in the negative and positive groups, respectively; according to p21 expression, 5-year survival was 71% and 0% in the negative and positive groups, respectively. Significant difference was seen in EGF/EGFR and p21 groups. These data support less invasive surgery for some patients even for esophageal cancer patients. THE is a less invasive surgery, that also implies fewer curative procedure. Our results also showed that THE alone will be the only curative procedure necessary for some patients. We can determine therapeutic procedures using these new factors, and thus avoid unnecessary excess surgical stress in esophageal cancer patients.

We investigated the relationship between postoperative complications and prognosis in esophageal cancer patients. Two hundred five patients with esophageal cancer were divided into three case groups. Group A (n = 100) consisted of cases without postoperative complications. Groups B (n = 58) and C (n = 47) consisted of cases with minor and major postoperative complications. The 5-year survival rates were 41.8%, 21.3%, and 20.2% in groups A, B, and C, respectively. There was a significant difference in the prognosis between groups A and B, and also between groups A and C. Any patients who died within 5 years without a relapse their cases were excluded from the study; the 5-year survival rates were 46.7%, 32.3%, and 22.5% in groups A, B, and C, respectively, with a significant difference between groups A and B. There were no significant differences between the three groups regarding the patient characteristics. These results therefore indicate that postoperative complications might contribute to a poor prognosis in cancer patients.