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Pollen exine is essential for protection from the environment of the male gametes of seed-producing plants, but its assembly and composition remain poorly understood. We previously characterized Arabidopsis (Arabidopsis thaliana) mutants with abnormal pollen exine structure and morphology that we named kaonashi (kns). Here we describe the identification of the causal gene of kns4 that was found to be a member of the CAZy glycosyltransferase 31 gene family, identical to UNEVEN PATTERN OF EXINE1, and the biochemical characterization of the encoded protein. The characteristic exine phenotype in the kns4 mutant is related to an abnormality of the primexine matrix laid on the surface of developing microspores. Using light microscopy with a combination of type II arabinogalactan (AG) antibodies and staining with the arabinogalactan-protein (AGP)-specific β-Glc Yariv reagent, we show that the levels of AGPs in the kns4 microspore primexine are considerably diminished, and their location differs from that of wild type, as does the distribution of pectin labeling. Furthermore, kns4 mutants exhibit reduced fertility as indicated by shorter fruit lengths and lower seed set compared to the wild type, confirming that KNS4 is critical for pollen viability and development. KNS4 was heterologously expressed in Nicotiana benthamiana, and was shown to possess β-(1,3)-galactosyltransferase activity responsible for the synthesis of AG glycans that are present on both AGPs and/or the pectic polysaccharide rhamnogalacturonan I. These data demonstrate that defects in AGP/pectic glycans, caused by disruption of KNS4 function, impact pollen development and viability in Arabidopsis.

The purpose of the present trial was to clarify the efficacy of postoperative adjuvant chemotherapy including an oral fluoropyrimidine anticancer drug, the 1-hexylcarbamoyl-5-fluorouracil (HCFU), for the treatment of colon cancer. Patients with clinical stage Dukes’ B and C colon cancer, who had been treated surgically, were assigned to a chemotherapy group treated with mitomycin C, 5-fluorouracil (5-FU), and HCFU and to a control group that received no postoperative adjuvant chemotherapy. Of the 1,001 patients registered for the study, 17 (1.7%) were ineligible. The incidence of toxicity was significantly higher in the chemotherapy group than in the control group. However, there were few severe side effects and no deaths related to the treatment. Overall survival showed no significant difference between the groups. The disease-free survival or the recurrence-free intervals was significantly higher in the chemotherapy group than in the control group. The incidence of hepatic recurrence was significantly (P=0.003) lower in the chemotherapy group than in the control group. The results of this study demonstrated the efficacy of adjuvant chemotherapy for colon cancer, i.e., combined chemotherapy that included the 5-FU oral anticancer drug HCFU.

To evaluate the long-term functional outcome of colonic J-pouch reconstruction after low anterior resection (LAR) for rectal cancer in a prospective study. We compared the functional outcome of 46 patients who underwent J-pouch reconstruction (J-group) and 49 patients who underwent straight anastomosis (S-group) after LAR for rectal cancer. We evaluated clinical function using a 17-item questionnaire about different aspects of bowel function. Physiologic reservoir function was evaluated by manovolumetry. Among the patients with an ultralow anastomosis (≤4 cm from the anal verge), those in the J-group had fewer bowel movements during the day and at night, and less urgency, soiling, protective pad use, incontinence, and dissatisfaction with bowel function than those in the S-group. Among the patients with a low anastomosis (5–8 cm from the verge), those in the J-group had fewer bowel movements at night, and less urgency and soiling than those in the S-group. Moreover, reservoir function (reflected by the maximum tolerable volume, threshold volume, and compliance) was better in the J-group than in the S-group in both the ultralow and low anastomosis groups. J-pouch reconstruction after low anterior resection creates a better stool reservoir than straight anastomosis, especially when the anastomosis is less than 4 cm from the anal verge, resulting in a better quality of life 3 years after rectal cancer resection.

In colon cancer surgery, it is recommended that en bloc resection involving extended lymphadenectomy, characterized as a hemicolectomy, be performed by ligating the primary feeding artery at a high position and resecting proximal and distal with 5-cm to 10-cm bowel margins. However, there is little evidence to unequivocally support such extensive lymphovascular resection. The distribution of nodal metastases was obtained by the clearing method in 164 patients with colon cancer. For pericolic spread, for pT1 tumors, the distance from the primary tumor to a diseased node was 2.5 cm; for pT2, the distance was less than 5 cm; for 97.0 percent of pT3 tumors and 93.3 percent of pT4 tumors with nodes involved, the distance was less than 7 cm. For central spread, for pT1 tumors, the rate of spread to central nodes was 0 percent; for pT2, the rate of spread was 20.0 percent to intermediate nodes (for tumors more than 5 cm from the feeding artery, the rate for central nodes was 0 percent); for pT3, the rate was 30.6 percent to intermediate nodes and 15.3 percent to main nodes; for pT4, the rate was 44.4 percent to intermediate nodes and 22.2 percent to main nodes. For curative resection cases with pT3 tumors more than 7 cm from the feeding artery, the rate to central nodes was 0 percent. In T1 tumors, central node dissection is not required, but resection with proximal and distal 3-cm margins are required; in T2, central node dissection that includes the intermediate node should be performed in addition to resection with proximal and distal 5-cm margins. In T3 and T4, central node dissection that includes the main node should be performed in addition to resection with proximal and distal 7-cm margins. However, for T2 more than 5 cm from the primary feeding artery, and for T3 more than 7 cm from the primary feeding artery, proximal and distal resection alone may be adequate.

Few reports on the long-term functional outcome of colonic J-pouch reconstruction have been published, and data comparing J-pouch and straight reconstruction are contradictory. This prospective study compares the functional outcome of colonic J-pouch and straight anastomosis five years after low anterior resection for rectal cancer. Functional outcome was compared in 46 patients with J-pouch reconstruction (J-group) and 48 patients with straight anastomosis (S-group). Clinical status was evaluated with a 17-item questionnaire inquiring about different aspects of bowel function. Reservoir function was evaluated by manovolumetry. The Fisher’s exact test and Wilcoxon’s rank-sum test were used to compare categoric and quantitative data, respectively. Among patients with an ultralow anastomosis (≤4 cm from the anal verge), the number of bowel movements during the day (≥5, 4.3 vs. 29.2 percent; P = 0.028) and at night (>1/week, 4.3 vs. 33.3 percent; P = 0.013) and urgency (4.3 vs. 33.3 percent; P = 0.013) and soiling (21.7 vs. 50.0 percent; P = 0.043) were less in the J-group than in the S-group. Among patients with a low anastomosis (5 to 8 cm from the verge), patients in the J-group had fewer bowel movements at night (>1/week, 0 vs. 20.8 percent; P = 0.028) and less urgency (0 vs. 20.8 percent; P = 0.028). Reservoir function was better in the J-group than in the S-group in both the ultralow (maximum tolerable volume (mean), 101.7 vs. 76.3 ml; P = 0.004; threshold volume (mean), 46.5 vs. 30.4 ml; P < 0.001; compliance (mean), 4.9 vs. 2.5 ml/cm H2O; P < 0.001) and low-anastomosis (maximum tolerable volume, 120.4 vs. 97.9 ml; P < 0.001; threshold volume, 58.3 vs. 40.8 ml; P < 0.001; compliance, 5.2 vs. 3.1 ml/cm H2O; P < 0.001) groups. J-pouch reconstruction increased reservoir function and provided better functional outcome than straight anastomosis, even five years after surgery, especially in patients whose anastomosis is less than 4 cm from the anal verge.

症例は47歳,女性.平成9年5月市民検診で便潜血反応陽性を指摘された.注腸X線造影検査にて下部直腸後壁に粘膜面不整像を認めた.大腸内視鏡検査では肛門縁より10cmの部位に壁外性圧迫,粘膜下腫瘍を認めた.生検を施行したが再生上皮に覆われたびらん状の大腸粘膜組織であった.経過観察とし2カ月後再検査を施行した.同部位に前回より増大する壁外性圧迫,粘膜下腫瘍を認めた.悪性疾患を否定できず, 11月18日直腸粘膜下腫瘍の診断で低位前方切除術+左卵巣合併切除術を施行した.病理組織学的には粘膜下層から筋層に子宮内膜間質細胞が認められた.直腸間膜リンパ節内にも子宮内膜組織を認めた.腸管子宮内膜症で所属リンパ節に病変を伴うものは極めて稀な疾患である.腸管子宮内膜症のなかには比較的短期間に腫瘤が増大し,所属リンパ節迷入をきたして,悪性腫瘍との鑑別が困難である症例が存在することを若干の文献的考察を加えて報告した.

The pathology and prognosis of hepatitis B surface antigen (HBsAg)-positive hepatocellular carcinoma (HCC) and hepatitis C virus antibody (HCVAb)-positive HCC is well documented. However, patients with HBsAg-negative/hepatitis B core antibody (HBcAb)-positive HCC are included with non-B non-C disease and have been characterized independently. A series of 125 patients who had undergone hepatectomy for HCC were divided into three groups and compared. The HBsAg group comprised 25 HBsAg-positive patients, the HCV group comprised 70 HCVAb-positive patients, and the HBcAb group comprised 22 HBcAb-positive/HBsAg-negative patients. Eight patients of negative virus markers were excluded in this study. Tumors were larger in the HBcAb group (6.2 cm) than in the HBsAg (4.4 cm) and HCV (3.7 cm) groups. Disease-free 1-, 3-, and 5-year survival rates were, respectively, 75.0%, 57.1%, and 57.1% in the HBcAb group; 60.9%, 41.8%, and 41.8% in the HBsAg group; and 88.0%, 54.0%, and 37.8% in the HCV group. HBcAb-positive HCC patients had larger tumors, but their prognosis was relatively good. Although HBsAg and HCVAb are used for conventional screening of patients with hepatic disorders, we believe that screening is also necessary in patients with positive HBcAb titers for early detection of HCC.

Hepatocellular adenoma sometimes causes intraperitoneal hemorrhage. It is, however, rare for small hepatocellular adenoma to cause intrahepatic huge hemorrhage without intraperitoneal bleeding. Here we describe such a rare case of hepatocellular adenoma with huge intrahepatic hemorrhage in a 25-year-old female, who had taken oral contraceptives for the last 2 weeks. She was admitted to our hospital with a sudden onset of right-upper-quadrant abdominal pain and temporally fell in shock state. Plain CT depicted low density area measuring more than 13 cm in diameter in the right lobe of the liver. Huge tumor was also suggested by abdominal ultrasound, contrast enhanced CT, magnetic resonance imaging (MRI) and angiography. The patient was diagnosed as intrahepatic rupture of hepatic tumor. Because of the risk of re-hemorrhage and malignancy, she underwent right hepatic lobectomy. Histopathologial examination of the resected specimen showed a typical small hepatocellular adenoma with the surrounding huge hematoma in the liver. The case presented here is very rare but seems to be suggestive to the natural course and management of hepatocellular adenoma.

BACKGROUND: The presence of non-tumor cells inside cancer tissue is one of the causes of errors in cell cycle analysis by DNA flow cytometry. The recent establishment of bivariate cytokeratin and DNA flow cytometry has made feasible the accurate assessment of tumor proliferative activity. METHODS: Bivariate flow cytometry and immunohistochemistry examinations of paraffin-embedded specimens were performed in 92 patients with non-small cell lung cancer (NSCLC). Determination of the S-phase fraction by flow cytometry, with cytokeratin gating (CK-gated SPF) and without gating (ungated SPF), and the expression of proliferating cell nuclear antigen by immunohistochemistry (PCNA labeling index), were used to assess cancer cell proliferation. RESULTS: Two tumors had DNA histograms with a coefficient of variation of more than 8.0% and were excluded from the flow cytometric analysis. In DNA diploid tumors (n = 25), the ungated SPFs (8.7 +/- 3.6%) showed a lower distribution than the CK-gated SPFs (14.3 +/- 4.7%) (P < 0.0001). In DNA aneuploid tumors (n = 65), there was no difference in distribution between the ungated SPFs (15.0 +/- 8.3%) and the CK-gated SPFs (15.1 +/- 7.1%) (P = 0.94). The CK-gated SPF and the PCNA labeling index of an individual tumor had a good correlation (P < 0.0001), and this agreed with the result showing that DNA diploid and aneuploid tumors had equal proliferative activity (P = 0.64 and P = 0.63, respectively). CONCLUSION: The technique using CK-gating markedly improved the SPF measurement in DNA diploid tumors. This assessment showed no difference in proliferative activity between DNA diploid and aneuploid tumors in NSCLC. Bivariate cytokeratin and DNA flow cytometry is an accurate and objective method for cancer-specific analysis, and will surely be informative in clinical oncology.

PURPOSE: We examined the usability of a newly developed, compact-sized DNA array filter for studying the gene expression pattern of individual colorectal cancer. METHODS: Complementary DNA probes were prepared from mRNA extracted from colonic cancer specimens and adjacent normal mucosa and then were labeled with chemiluminescence. These labeled probes were allowed to bind to the gene fragments on the filter. A specialized scanning charge-coupled device camera measured the intensity of each chemiluminescent spot, which is an indicator of the degree to which a specific gene is expressed. Gene expression image was quantified into intensity of signals by using computer software. RESULTS: Characteristic gene expression patterns were obtained from the colonic cancer cell line, RPMI4788, and the leukemia cell line, HL60, by using this compact-sized DNA array filter in the preliminary experiment. Up-regulation of nm23, TIMP1, VEGF, and cyclin E and down-regulation of some tumor suppressor genes (p53, TOSO, and SIVA),β-catenin, and metallothionein were observed in colonic cancer specimen when compared with those of normal mucosa. CONCLUSIONS: We have obtained unique gene expression patterns from colorectal cancer and normal tissue by using a newly developed compact-sized DNA array filter system. Collecting, storing, and analyzing of gene expression data from many samples of colorectal cancer will enable us to identify distinct subsets of patients based on molecular characteristics in the near future.

To identify the genetic prognostic markers for breast cancer, we analyzed loss of heterozygosity (LOH) at 11p, 16q, 17p, 17q, and 18q, as well as amplification of the ERBB2, INT2, and MYC genes, in 131 patients with breast carcinoma, 49 of whom had lymph node involvement, but none of whom had distant metastases. Among the several chromosome arms tested, LOH at 17q was correlated with lymph node metastasis. Amplification of the ERBB2, MYC, and INT2 genes was found more frequently in tumors from patients with lymph node metastases than in tumors from those without lymph node metastases. Univariate analysis demonstrated that LOH at 17q and INT2 amplification were factors influencing disease-free survival (DFS). A multivariate analysis was performed on 89 tumors that were able to be evaluated for both LOH at 17q and INT2 amplification, and the results showed that patients who had tumors with these genetic changes were more likely to have a poor prognosis. The findings of this study suggest that investigating genetic changes, in addition to conventional clinicopathologic factors, may contribute to defining groups of breast cancer patients with differences in prognosis.

目的:大腸癌術後補助療法について施行された臨床比較対照試験(RCT)を精査し,そのメタアナリシスの結果をレビューすることによって欧米およびわが国で行われている標準治療の評価,検討を行う.方法:RCTはMEDLINE,学会報告,Trialistとのコンタクト等によって検索を行い,図表・データの解析,また可能な症例では症例個別データを集積したメタアナリシスを行い,すでに発表されているメタアナリシスの結果との整合性を検討する.結果:欧米における研究ではNSABPによるC-01～06,R-01,02,またIMPACTグループによるRCTとそれらのメタアナリシスによって5-FU/Leucovorinが標準治療として認められた.わが国の大腸癌補助療法臨床試験の検討では経ロフッ化ピリミジン製剤の有用性が示唆された.結論:RCTとそれらの試験のメタアナリシスはEBMによる大腸癌補助療法の正確な評価を可能とし,標準治療の確立に有用と考えられる.

妊娠反応偽陽性にて発見されたhCG産生肺大細胞癌を経験したので報告する.症例は27歳, 女性. 高hCG血症, 胸部異常陰影を主訴に婦人科に入院し. 腹腔鏡下に妊娠ならびに原発巣は確認されなかったが, 肺転移をともなう絨毛癌の診断でMAC療法による化学療法を4コース施行された. hCG値は低下し腫瘍は縮小したが, hCG産生原発性肺癌の疑いで当科にて肺葉切除および縦隔リンパ節郭清を施行した. 病理組織診断は肺大細胞癌, p-T2N0M0, stageIBであった. 抗hCG抗体による免疫組織染色では細胞質が染色され, hCG産生肺大細胞癌と診断された. 術後54ヵ月経過した現在も再発なく生存中である.

Background: For hepatic resection, intraoperative bleeding is reduced by clamping the afferent blood flow. Selective clamping at the hepatic hilum can be accomplished using the standard controlled method or Glisson's pedicle transection method. The safety and efficacy of these two methods have not previously been compared. Study Design: The intraoperative findings and complications were retrospectively reviewed in 90 patients who underwent major hepatectomy with selective inflow clamping between 1988 and 1997. Results: Blood loss and operative time did not differ between the two groups. Bile leakage was observed in 3 of 43 patients (7.0%) in the standard controlled method group and 11 of 47 patients (23.4%) in the Glisson's pedicle transection method group (p = 0.031). In the Glisson's pedicle transection method group, bile leakage occurred more frequently in patients who underwent left lobectomy than in those who underwent right lobectomy (p = 0.023). Conclusions: There were no differences in intraoperative findings and postoperative complications analyzed between the standard controlled method and Glisson's pedicle transection method for major hepatectomy except for the rate of bile leakage. In particular, attention must be paid to the bile duct injuries when the Glisson's pedicle is dissected.

Thomsen-Friedenreich antigen (TF; Galbeta1-3GalNAcalpha1-) is expressed on many human carcinomas. Evidence suggests that TF-carrying tumor cells specifically bind asialoglycoprotein receptors on hepatocytes resulting in metastasis formation in the liver. We used an animal model to examine the feasibility of preventing metastasis formation by an antibody to TF. Treatment of Colon 26 cells with neuraminidase led to the exposure of TF, and consequently to a higher frequency of liver metastases in syngeneic Balb/c mice. This could be prevented by an antibody to TF (A78-G/A7), but not by a control antibody. The results may open up a new strategy for the prophylaxis of metastatic spread to the liver.

症例は56歳の女性. 発熱と腹痛を主訴に来院した. 前医で, 下部胆管癌に幽門輪温存膵頭十二指腸切除術が今永式 (I型再建法) で再建され, 術後繰り返す胆管炎と肝膿瘍に膿瘍ドレナージが行われていた. 血清ALPなどの胆道酵素や上部消化管造影検査では異常を認めず, 99mTc-PMT胆道シンチグラフィーからも胆管空腸の吻合部狭窄や胆汁うっ滞所見はなかった. 食事摂取で発熱などの胆管炎症状が現れ, 抗生剤動注療法も奏効しなかった. 胆管炎の原因が食物の胆道内への逆流と考えられ再開腹後, 再建法をI型からII型に変更した. 術後, 6か月経過した現在, 胆管炎の再燃は認めない.

Background. This study was conducted to evaluate the significance of postoperative adjuvant chemotherapy using mitomycin C (MMC) and UFT (tegafur; uracil at 1:4 molar ratio) in combination for rectal cancer.

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary disease characterized by hamartomatous polyposis involving the entire bowel. Recently STK11, a gene bearing a mutation responsible for PJS, was isolated. We investigated the entire coding region of STK11 in 15 unrelated PJS families by the PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) method and PCR-direct sequence analysis, and found nine different, novel mutations among ten of those families. One nonsense mutation and five different frameshift mutations (two families carried the same mutation), all of which would cause truncation of the gene product, were found in seven families; mutations found in five families were clustered within exon 6. Among these five mutations, three occurred at the mononucleotide-repeat region (CCCCCC) of codons 279-281, suggesting that this region is likely to be a mutational hotspot of this gene. One of the remaining three families carried a 3-bp in-frame deletion that would eliminate an asparagine residue within a kinase domain of the product; the other two carried intronic mutations at or adjacent to the consensus dinucleotide sequences of splice-acceptor or -donor sites, which were likely to lead to aberrant splicing.

Background: Our previous study of hepatic arterial infusion of interleukin-2 (IL-2)–based immunochemotherapy demonstrated a high response rate of patients with unresectable liver metastases. In this study, we applied this therapy to the prevention of liver recurrence in patients who underwent potentially curative resection of liver metastases. Study Design: A pilot study was conducted of 18 patients with liver metastases from primary colorectal cancer who underwent potentially curative liver resection followed by adjuvant immunochemotherapy. The regimen consisted of a weekly hepatic arterial infusion of IL-2 (1.4–2.1 × 10 6 U) and 5-fluorouracil (250 mg) and a bolus of mitomycin C (2–4 mg) for 6 months. Results: Among 18 patients, 14 are still alive with a median postoperative survival of 52 months (as of April 1998). The 5-year overall survival rate was 75%. Although recurrent cancer developed in 6 of the 18 patients, no patients had recurrence in the residual liver. This complete prevention of liver recurrence is believed to have contributed to the high 5-year survival rate (75%) as compared with the survival rate of patients treated with surgery alone (average, 30%–40%) or with several other forms of adjuvant therapy. Conclusions: Interleukin-2–based immunochemotherapy is useful in combination with liver resection for the prevention of liver recurrence in colorectal cancer patients with liver metastases. A multicenter randomized trial is recommended.

It is well known that the operative results for esophageal cancer, especially thoracic esophageal cancer, are not favorable. We analyzed the relationship between neural invasion (NI) and histopathologic factors and recurrence types in 104 patients who underwent resection of esophageal cancers with T2 or greater depth of invasion of the esophageal wall. The implications of NI as a prognostic indicator were also examined. Of the 104 patients, 48 (46.2%) were NI-positive (NI(1)) and 56 (53.8%) were NI-negative (NI(−)). The NI(1) patients had a higher ratio of type 3 cancer. Concerning the histopathologic factors, there was a significant relationship between NI and lymph node metastasis (N) and between NI and lymphatic vessel invasion (ly) (P

The invasion and metastasis of carcinoma cells require the action of tumor-associated proteases and their inhibitors, which may also may be involved in the stages of carcinogenesis. In the present study, we evaluated the levels of fibrinolytic factors, urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), type-1 plasminogen activator inhibitor (PAI-1), and u-PA specific receptor (u-PAR) as well as matrix metalloprotease-1 (MMP-1) and its tissue inhibitor of metalloprotease-1 (TIMP-1) in extracts of human gastric carcinoma tissues and their corresponding normal mucosas. The antigen levels of u-PA, PAI-1, and TIMP-1 were significantly higher in carcinomas than normal mucosas, while those of u-PAR were not changed as much. Thus, the increase of u-PAR ligand u-PA and its inhibitor PAI-1 may be important in carcinoma tissues. In addition, the amidolytic activity with S-2444 of carcinomas was significantly higher than that of normal tissue indicating that u-PA but not t-PA was involved in the fibrinolytic activity of carcinoma tissues. However, the relationships between any two factors among these components were not clear. From these findings, it is also confirmed that u-PA and PAI-1 are the major regulators of human gastric cancer cells. In addition, since both MMP-1 and TIMP-1 were found to be higher in the carcinomas than the normal mucosas, it is suggested that this matrix enzyme and inhibitor are also up-regulated in carcinomas, the pathway of which is independently linked to fibrinolytic system.

Purpose: The aim of this study was to identify the route of administration of 5-FU with the greatest pharmacological advantage in a rat model using noninvasive in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. Methods: 5-FU (50 mg/kg) was administered to anesthetized Wistar rats cannulated into the hepatic artery, portal vein or tail vein and 11 NMR spectra were acquired from the liver region to 60.5 min every 5.5 min. Results: With systemic i.v. (tail vein) infusion, the 19F-NMR signal for 5-FU from the liver region peaked in the first spectrum (0–5.5 min), and then gradually decreased. The signal for the 5-FU catabolite α-fluoro-β-alanine (FBAL) gradually increased to the sixth spectrum (0–33.0 min) and then plateaued. Following portal vein infusion the intensity of the first 5-FU spectrum was twice as high as that following i.v. infusion, but the intensity decreased and the FBAL signal increased gradually in the sixth spectrum as systemic i.v. infusion. In contrast, the intensity of the 5-FU signal following hepatic artery infusion was the same as that following portal vein infusion in the first spectrum, and maintained a strong intensity to the final spectrum (60.5 min). The FBAL signal was detected from the second spectrum following hepatic artery infusion, but its intensity was significantly weaker than that following i.v. or portal vein infusion. Conclusions: Hepatic arterial infusion resulted in the active form of 5-FU being present for a longer time and its degradation in the liver being suppressed compared with the results following portal vein infusion. This catabolic advantage of hepatic areterial infusion could lead to a more potent anti-tumor activity against liver metastases, but could also lead to significant host toxicity including biliary toxicity. We recommend that the dose/schedule of 5-FU administered via the hepatic artery should be adjusted carefully.

PURPOSE: In surgery for rectal cancer, it is unclear whether the inferior mesenteric artery should be ligated at a high or low position. The study contained herein was undertaken to clarify the indications for high ligation of the inferior mesenteric artery. METHODS: Subjects included 198 patients with rectal cancer who underwent resection with high ligation of the inferior mesenteric artery. Nodal metastases were examined by the clearing method. RESULTS: The incidence of metastases to the lymph nodes surrounding the origin of the inferior mesenteric artery (root nodes) was 8.6 percent. Inferior mesenteric artery root nodal metastases occurred more frequently with pT3 and pT4 cancer. The five-year survival rate in patients with inferior mesenteric artery root nodal metastases was 38.5 percent; this rate was significantly lower than in those without inferior mesenteric artery root nodal metastases (73.4 percent). CONCLUSIONS: Although the five-year survival rate in patients with inferior mesenteric artery root nodal metastases was lower than in those without metastases, inferior mesenteric artery root nodal dissection should be performed after high ligation of the inferior mesenteric artery for patients with pT3 and pT4 cancers.

BACKGROUND Tumor procoagulant is one of the factors responsible for disseminated intravascular coagulation and metastasis. The authors found procoagulant activity in LK52 human squamous cell carcinoma cells, which they designated cancer cell-derived blood coagulating activity 1 (CCA-1). A monoclonal antibody (MoAb) was generated to characterize this CCA-1 procoagulant activity. To date, antibodies that show an inhibitory effect on procoagulant activity as well as high reactivity in cancer cells are well known for their tissue factor specificity. METHODS Characterization of the procoagulant activity of CCA-1 was performed and an anti-CCA-1 MoAb, FS01, was generated. CCA-1 expression on the cancer cell surface was examined by flow cytometry. Procoagulant activity of various cancer cell lines and the inhibitory effect of the FS01 MoAb on this procoagulant activity was monitored by a clot timer. RESULTS The enzymologic character differed from that of cancer procoagulant (CP). The FS01 MoAb inhibited the procoagulant activity of CCA-1, but did not inhibit that of tissue factor. A positive correlation was observed between the expression intensity of CCA-1 and the inhibitory effect of the FS01 MoAb on the procoagulant activity of cancer cell lines. Expression of CCA-l was observed more frequently than that of tissue factor in human cancer cell lines. CONCLUSIONS The FS01 MoAb generated in the current study is a new antibody that reacts with various cancer cell lines, but not with normal cells. FS01 inhibits cancer cell-derived procoagulant activity and does not react with tissue factor and CP. CCA-1, which is recognized by the FS01 MoAb, appears to play a major role in cancer cell-derived procoagulant activity. Cancer 1998;82:1563-9. © 1998 American Cancer Society.

Patients with Peutz-Jeghers syndrome (PJS), an autosomal dominant disease characterized by hamartomatous polyposis of the gastrointestinal tract, are thought to be predisposed to malignancies of the digestive tract, genital tract, and other organs. Using microsatellite markers on chromosome 19p, we have closely defined the region containing the gene responsible for this disorder through linkage analysis in seven affected families. The lack of obligate recombinants at two of these loci, D19S883 and D19S878, with maximum LOD scores of 2.88 and 3.75, confirmed the localization of the PJS locus to chromosome 19. Furthermore, haplotype analysis placed the PJS locus within a 6-cM telomeric region of chromosome 19p, between D19S886 and D19S565.

PURPOSE: We examined the survival benefit of pelvic exenteration for locally advanced colorectal cancer with lymph node metastases, because this issue remains controversial. METHODS: Medical records of 50 patients who underwent curative pelvic exenteration for colorectal cancer were reviewed retrospectively. Nodal metastases were examined by the clearing method in 29 patients and by the conventional manual method in 21 patients. RESULTS: Invasion to contiguous pelvic organs was present in 40 patients (80 percent) and absent in 10 patients (20 percent). Node metastases were present in 33 patients (66 percent). Operative morbidity and mortality rates were 22 percent (11 patients) and 6 percent (3 patients), respectively. Respective five-year survival rates were 60 and 80 percent in the groups with and without organ invasion (no significant difference). Five-year survival rates in patients with nodal metastases was 54.6 percent but was significantly higher, 82.4 percent, in patients without nodal metastases. Five-year survival in 28 patients with both organ invasion and nodal metastases was 53.6 percent. CONCLUSIONS: Long-term survival was afforded by pelvic exenteration for locally advanced colorectal cancer with nodal metastases.

大腸癌肺転移の経過と予後の解析におけるDNA ploidy pattern, S phase fraction (SPF) の有用性を検討した.大腸癌術後肺転移23例の原発巣と肺転移巣の核DNA量をHow cytometerを用いて測定した.DNA diploidyを示した癌のSPFは原発巣 (7例), 肺転移巣 (6例) で各々10.5±5.7%, 9.4±5.5%であり, DNA aneuploidyを示した癌のSPFは原発巣 (11例), 肺転移巣 (17例) で各々24.0±8.3%, 23.9±8.3%であった.SPFからみた増殖活性は原発巣, 肺転移巣の間で有意差はなかった.原発巣と肺転移巣のDNA ploidy patternは18例中15例で一致し, SPFは直線的相関関係を示した.DNA aneuploidyでは原発巣と肺転移巣のSPFは肺再発までのdisease-free interval (DFI) と逆相関関係を示し, SPFはDFIと関係する有用な指標である.肺転移巣切除後の予後は, 原発巣リンパ節転移, 肺転移個数, 肺門縦隔リンパ節転移と有意な関係を認めたが, DNAploidypattern, SPFと関係しなかった.

Recently PTEN/MMAC1, a candidate tumor suppressor gene, was isolated from chromosome 10q23‐24 and somatic mutations of this gene were detected in several malignancies including brain, prostate, and breast tumors. To investigate further the potential role of this gene in mammary carcinogenesis, we examined 69 primary breast cancers for mutations in PTEN/MMAC1 by means of polymerase chain reaction single‐strand conformation polymorphism and sequencing analysis. We detected only one somatic missense mutation, a change from T to C at codon 59 (TCA to CCA) resulting in substitution of Pro for Ser in the predicted protein. This site is located outside of phosphatase or phosphate‐acceptor motifs, but this codon encodes a residue that is conserved in homologous proteins, tensin and auxilin and is likely to be crucial for normal function of PTEN/MMAC1. Among the 69 tumors examined, three low‐frequency polymorphisms were found as well, one in the non‐coding region of exon 1 and one each in introns 2 and 7. Our results suggested that mutation of the PTEN/MMAC1 gene is not a major factor in the development of most primary breast cancers.

We have generated a monoclonal antibody (MAb), FS01, which inhibits the procoagulant activity (CCA-1) produced by a human squamous cell carcinoma cell line, LK52. Expression of the antigen recognized by FS01 MAb in various cancer cell lines correlated well with the procoagulant activities of the expressing cell lines. Our objective was to characterize the molecule reacting with FS01 MAb and to analyze its involvement in the CCA-1 procoagulant activity. The molecule was identified as a glycolipid and found to be involved in the procoagulant activity because both procoagulant activity and reactivity to FS01 MAb were lost after endoglycoceramidase treatment of CCA-1. Furthermore, FS01 MAb recognized the Lewis Y (Le y ) antigen. To confirm the involvement of a glycolipid incorporating the Ley antigen in the procoagulant activity, we attempted to purify CCA-1 from LK52 culture supernatant. In one of the purification steps, a fraction containing low procoagulant activity (CCA-1p) separated from the Le y -positive fraction (CCA-1c). Although CCA-1c alone did not show procoagulant activity, the procoagulant activity of CCA-1p was augmented by CCA-1c and this augmentation was inhibited by FS01 MAb. Furthermore, CCA-1c enhanced the procoagulant activity of 33 cell lines tested as well as CCA-1p. In addition, purified Ley glycolipid from canine intestine augmented the procoagulant activity of CCA-1p, and this augmentation also could be inhibited by FS01 MAb. We conclude that Ley glycolipid is a co-factor for the procoagulant activity derived from cancer cells. Int. J. Cancer 73:903‐909, 1997. r 1997 Wiley-Liss, Inc.

The functional outcome after low anterior resection (LAR) using the colonic J-pouch was compared with that after LAR using straight anastomosis. Colonic J-pouch construction was performed in 58 patients who underwent resection of tumors located 5–10 cm from the anal verge (J-pouch group). Functional assessment was performed 1 year postoperatively. Clinical function was evaluated using a scoring system, while physiologic sphincter and reservoir function were evaluated by anorectal manometry. The historical control group consisted of 20 patients who underwent LAR with straight anastomoses (straight group). The functional score of the J-pouch group was significantly better than that of the straight group. Although sphincter function was similar in the two groups, reservoir function was significantly better in the J-pouch group than in the straight group. These results demonstrated that the functional outcome following LAR for rectal cancer is improved by the colonic J-pouch construction.

A review of advancement of rectal cancer surgery in Japan is presented. The standard operation for rectal cancer was altered in the 1960s from abdominoperineal resection to the pull-through technique and the handsewn anterior resection in the 1970s, and it became the stapled anterior resection in the 1980s. Today, more than 75 percent of rectal cancers are treated with sphincter-preserving anterior resections, and the remaining 20 percent by abdominoperineal resections. Colonic J-pouch is used with anastomoses involving very low anterior rectal resection for cancers. In the late 1970s, a method of dissecting extended pelvic nodes was adopted to decrease local recurrence. However, extended dissection has been applied to only T3 and T4 cancers of the lower rectum because of postoperative dysfunction of pelvic organs. This was caused by injury to the pelvic nerve plexus, thus lowering the quality of life of the patients. Since the middle of the 1980s, the autonomic nerve-preserving operation attracted surgeons' attention because it prevented these dysfunctions from occurring as a result of the treatment of cancer in the upper rectum and for T1 or T2 cancers in the lower rectum. In this article, recent advances in rectal cancer surgery in Japan are reviewed.

BACKGROUND The surgeon is no longer able to palpate the mesocolon for lymph node metastases during laparoscopic colectomy. The extent of lymph node dissection should be determined beforehand for cancer control. METHODS The distribution of lymph node metastases was obtained by the clearing method on colon carcinomas for 164 patients. RESULTS For pericolic spread: for pT1 tumors, the distance from the primary tumor to a metastatic lymph node was 2.5 cm; for pT2, the distance was within 5 cm; for 97.0 % of pT3 tumors with lymph node metastases, the distance was within 7 cm; for 93.3 % of pT4 tumors with lymph node metastases, the distance was within 7 cm. For central spread: for pT1 tumors, the rate of metastasis to central lymph nodes was 0 %; for pT2, the rate of metastasis was 20.0 % to intermediate lymph nodes; for pT3, the rate of metastasis was 30.6 % to intermediate lymph nodes and 15.3 % to main lymph nodes; for pT4, the rate of metastasis was 44.4 % to intermediate lymph nodes and 22.2 % to main lymph nodes. CONCLUSIONS Central lymph node dissection is not required for patients with T1 carcinomas, but proximal and distal 3-cm margins of resection are required. For T2, central lymph node dissection that includes the intermediate lymph node should be performed, as well as 5-cm proximal and distal margins of resection. For T3 and T4, central lymph node dissection including the main lymph node should be performed, as well as 7-cm proximal and distal margins of resection. [See editorial on pages 177-8, this issue.] Cancer 1997; 80:188-92. © 1997 American Cancer Society.

直腸癌神経浸潤の同定,判定に基底膜の構成成分であるlamininを用いた免疫組織学的染色を行った.Laminin染色では神経線維束や神経周膜が明瞭に染色され,従来の染色法では観察が不可能であった微小な神経浸潤が正確に判定できた.神経浸潤陽性率は47.8%であった.神経浸潤は壁深達度,静脈侵襲およびリンパ節転移と強い関係を認めた.直腸癌局所再発は157例中26例(16.6%)に認め,神経浸潤陽性では75例中20例(26.7%)であり,陰性では82例中6例(7.3%)であった.7年生存は神経浸潤陽性39%,陰性77%であり有意差を認あた.さらに神経浸潤は局所再発や予後に重要な影響を与え,とくに神経周囲間隙型が予後を左右する重要な浸潤形式であることが明らかになった.Laminin染色を用いて神経浸潤を詳細に検討することは,術前術後の補助療法や自律神経温存手術の適応を決定するうえで意義があると考えられた.

過去12年間に大腸癌原発の転移性肺腫瘍31例に対して33回の肺切除術を施行したので, 術後成績および補助療法の有効性について検討した.31例中5例は肝転移に対する肝切除後の肺転移であった.全症例の平均生存期間は42.5ヵ月, 5年生存率は29.5%, 単発性, 多発性別の5年生存率はそれぞれ38.5%, と23.3%であった.手術までの無病期間が2年以上と2年未満では有意差はなかった.原発巣の組織分化度, 脈管侵襲度による差はみられなかった.肝転移先行例の3年生存率は25%と無肝転移例と差はなかったが, 5年生存は得られなかった.肺所属リンパ節転移陽性例には3年生存はなく, 陰性例の5年生存率38.1%に比し, 明らかに予後不良であった.術前後のCEA値の変動をみると, 正常値域の症例は明らかに予後が良好であった.補助療法ならびに再発例に対する治療としての化学療法は予後の改善に寄与するという証明は得られなかった.

One thousand two hundred fifty-four cases (610 colonic and 644 rectal cancers resected during 2 years from 1984 and followed up for more than 5 years) were entered from 140 institutions in Japan and analyzed by means of Cox's proportional hazards model. The analyzed pathologic variables were the size and depth of invasion, Dukes' stage, venous invasion, lymphatic permeation, and other clinical features, such as the sex and age of the patient and location of the tumor. The extent of dissection, serum carcinoembryonic antigen (CEA) level, and the presence or absence of adjuvant chemotherapy were also analyzed. Adjuvant chemotherapy consisted of three arms for both colonic and rectal cancers. For colonic cancer, arm I was a combination of i.p. (intraportal) and i.v. mitomycin C (MMC) + p.o. 5-fluorouracil (5-FU); arm II was i.v. MMC + p.o. 5-FU; and arm III was surgery only. For rectal cancer, arm IV was a combination of i.a. (inferior mesenteric artery) and i.v. MMC + p.o. 5-FU; arm V was i.v. MMC + p.o. 5-FU; and arm VI was surgery only. As for the factors affecting the disease-free survival of the patient, multivariate analysis disclosed nodal involvement, venous invasion, an elevated CEA level, and the lower part of the rectum. The effect of adjuvant chemotherapy on the patient's survival was proven for rectal cancer but not for colonic cancer. We conclude that these factors should be considered in setting the stage of tumor pre- and postoperatively.

BACKGROUND. The prognostic factors and natural history of recurrence in patients with colorectal carcinoma who underwent curative resection and no other therapy were analyzed. METHODS. The object of analysis was the potentially curative resection only subgroup in the randomized clinical trial (RCT) that we performed. Cox's proportional hazards model was used mainly to analyze recurrence rates during the first 5 years after surgery. RESULTS. The analysis was performed on a subgroup of the RCT (279 patients with colon carcinoma and 293 patients with rectal carcinoma). Five-year disease free survival rates were 76.3% and 56.5% for colon and rectal carcinomas, respectively. The prognostic factors for recurrence for colon carcinoma patients were different from those with rectal carcinoma. For colon carcinoma, only Dukes stage was significant, whereas for rectal carcinoma, Dukes stage, age, location of the tumor, and serosal and venous invasion by cancer cells were prognostic factors. Log-transformed disease free survival rates were linear in Dukes Stage B and biphasic in Dukes Stage C for both colon and rectal carcinoma. The two phases in Dukes Stage C intersected at 2.85 and 3.04 years, respectively. The annual hazard value was high for the first 3 years in both colon and rectal carcinoma. CONCLUSIONS. We conclude that follow-up of patients with colorectal carcinoma who undergo potentially curative resection is of particular importance in the first 3 years after surgery. Furthermore, the usefulness of adjuvant chemotherapy can be adequately evaluated from data yielded during this postoperative period.

BACKGROUND Epidemiologic and genetic studies suggest that cancer of the right and left sides of the bowel arise through different mechanisms. To investigate the molecular mechanisms, allelic loss of chromosome 17p, p53 mutations, and microsatellite instability were analyzed in colorectal cancer according to tumor site. METHODS Using the polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) method, mutations within exons 5–8 of the p53 gene were examined in 108 colorectal cancers including 30 right-sided and 78 left-sided colorectal cancers. Allelic loss of chromosome 17p was studied by restriction fragment length polymorphism analysis, and genetic instability was examined for replication error (RER) at three microsatellite loci on chromosomes 2p, 17p, and 17q. RESULTS Allelic loss was observed in 61% (14 of 23 informative cases) of right-sided tumors and in 60% (26 of 43 informative cases) of left-sided tumors. PCR-SSCP analysis demonstrated that 63 of 108 tumors had a mutated p53 gene in exons 5, 6, 7, or 8. When comparing the frequency of mutation in each exon based on tumor site, the frequency of mutation in exon 8 in right-sided (2 of 18 informative cases) tumors was significantly lower than that observed in left-sided (17 of 45 informative cases) tumors. RER(+) was observed in 43% of right-sided tumors, whereas 24% of left-sided tumors were RER(+). Although the difference was not statistically significant, a trend was observed between RER(+) phenotype and tumor site. CONCLUSIONS Our results suggest that the molecular mechanisms of colorectal carcinogenesis may differ between right- and left-sided tumors. Cancer 1996;77:1688-93.

A case of gas-producing liver abscess complicated with diabetes mellitus was reported. A 66-year-old woman was admitted to the hospital because of a high fever and abdominal pain in the right upper quadrant. She showed a stinking abdominal pain and Blumberg's sign, complicated with shock symptoms 3 days after the admission. Emergency operation was performed under a diagnosis of peritonitis and septic shock due to rupture of liver abscess. Operative gross finding disclosed no pus nor ascites in the abdomen. An echo free space was found in the right lobe of the liver by ultra sound examination. The echo free space of the liver was punctured, and only gas with feces's smell was discharged. Therefore, silicon pleated drain was inserted into the cavity of the liver. Klebsiella pneumoniae and E. coli were detected from the drain discharge and arterial blood. The patient was recovered from disseminated intra-vascular coagulation and adult respiratory distress syndrome which occurred after the operation. Only 29 cases of gas-producing liver abscess have been reported in Japan. Twenty three (79%) of these 29 cases were associated with diabetes mellitus. It is believed that the disease is rare and has a poor prognosis. This is a case that appropriate surgical treatment can survive such patient's life.

Background. Expression of oncofetal fibronectin (oncFN) and normal fibronectin (norFN) in colorectal cancer specimens was examined to investigate the correlation between fibronectin localization and histologic grade, liver metastasis, and prognosis. Methods. Immunohistochemical staining of oncFN and norFN was performed on 99 primary lesions and 12 liver metastases of colorectal cancer. The expression of norFN and oncFN was evaluated by grading the intensity of staining as negative, positive, or strongly positive. Results. Positive staining for oncFN correlated positively with increasing stage. The rate of strongly positive staining for oncFN was 53% for primary lesions with liver metastasis, significantly higher than the oncFN-positive rate of 13% for metastasis free cases (P < 0.05). Liver lesions had an oncFN-positive rate of 92%. The postoperative 5-year survival rate for 51 cases classified as Dukes Stage C was 77.8% for oncFN-negative cases, 36.5% for oncFN-positive cases, and 22.2% for oncFN-strongly positive cases; these rates were significantly different (P < 0.01). Conversely, there was no correlation between norFN and any clinical variable. Conclusion. Expression of oncFN is correlated with a poor prognosis of Dukes C colorectal cancer and may serve as a useful postoperative prognostic sign. Cancer 1995;75:2802–8.

A controlled randomized trial was conducted to compare the effectiveness of a CAF therapy including cyclophosphamide (CPA), adriamycin (ADR) and 5-fluor-ouracil (5FU) with that of CAF plus medroxyprogesterone acetate (MPA) therapy including CPA, ADR and 5FU plus MPA for the treatment of liver metastases from breast cancer. A total of 34 patients with unresectable liver metastases from breast cancer were divided into two treatment groups (CAF and CAF + MPA) with stratification for estrogen receptor status. The response rate was 13% (2 PR in 16 patients) for CAF therapy and 22% (1 CR and 3 PR in 18 patients) for CAF plus MPA therapy. There was no significant difference in response rates, median survival periods and survival rates between the two treatment groups. However, CAF therapy had significantly more toxicity than did CAF plus MPA therapy. The findings of this study suggested that CAF plus MPA therapy is a well-tolerated and effective treatment for patients with liver metastases of breast cancer.

In an attempt to improve the therapeutic efficacy against liver metastases, a hepatic arterial infusion (HAI) of interleukin-2 (IL-2)-based immunochemotherapy for anticipating the regional potentiation of hepatic lymphokine-activated killer (LAK)/tumor-infiltrating lymphocytes (TIL) was initiated. We present herein the cases of three patients with multiple liver metastases from colorectal cancer in whom complete remission was achieved by treatment with an HAI of IL-2 in combination with mitomycin C (MMC) and 5-fluorouracil (5-FU). These patients received an HAI of IL-2 at 8 x 10(5) JRU, 5-FU at 250 mg daily, and MMC at 4 mg once weekly for 3 weeks, being the induction regimen, after which they were discharged on maintenance therapy consisting of IL-2 at 2 x 10(6) JRU, 5-FU at 250 mg twice weekly, and MMC at 4 mg once weekly. It was evident from the liver CT scan taken after 2-3 months that the metastatic foci seen before therapy had clearly disappeared, while the serum carcinoembryonic antigen (CEA) had decreased to normal levels in all three patients. Pancytopenia was seen in one patient, but other laboratory studies of the hepatic and renal parameters were normal. The total lymphocyte count in the peripheral blood showed a mild decrease, while the lymphocyte phenotype study showed a notable increase in CD4+ cells and a decrease in CD8+ cells, with an elevation of a 4/8 ratio, in all cases during therapy. One patient relapsed with pelvic recurrence 14 months after the initiation of therapy, but the other two patients are still in remission 25 and 22 months after the initiation of therapy.

Activation of the Ha-ras oncogene in N-methyl-N-nitrosourea (MNU)-induced rat mammary tumors has been well documented. Such Ha-ras activation is thought to be brought about by direct action of carcinogens resulting in a G-->A transition at the second nucleotide of codon 12. However, a DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT), can specifically remove methyl groups from O6-methylguanine, which is a major mutagenic and carcinogenic DNA lesion leading to the G-->A transition. In this study, we compared the amount of MGMT mRNA in MNU-induced rat mammary tumors with and without such Ha-ras activation. A single injection of MNU into 82 female Sprague-Dawley rats induced 80 mammary carcinomas. RNase protection analysis and subsequent sequencing revealed that 42 of 65 randomly selected tumors contained Ha-ras oncogenes activated by the G-->A transition. The amount of MGMT mRNA was then measured by means of reverse transcriptase-mediated polymerase chain reaction (RT-PCR) amplification and Southern hybridization. No obvious difference in the level of MGMT mRNA was detected between the two tumor groups. In addition, in the course of our experiment, five of 42 tumors classified as containing activated Ha-ras oncogenes proved to contain low percentages of tumor cells with the Ha-ras activation. These results suggest that Ha-ras activation in MNU-induced rat mammary tumors may not necessarily be influenced by differences in MGMT activity. They also raise the possibility that activation of other oncogenes and/or inactivation of unidentified tumor suppressor gene(s) may be involved in development of a certain proportion of tumors with activated Ha-ras oncogenes, as is suspected in the case of tumors without Ha-ras activation.

大腸癌および大腸癌肝転移で切除された原発巣99例と肝転移巣12例について癌胎児性fibronectin (onc FN) および正常型fibronectin (nor FN) の免疫組織化学的染色を行い, oncFNとnor FNの局在と進行度, 肝転移および予後との関連を検討した.染色性を陰性 (-), 陽性 (+), 強陽性 (++) と3群に分け判定した.onc FNの発現形式はnorFNと異なり, carcinoembryonic antigen (CEA) などの分泌型抗原の様相を呈した.oncFN染色性は, stageの進行と正の相関を認めた.また肝転移例原発巣のonc FNの強陽性率は53%であり, 非肝転移例の13%と比較し有意に高率であった (p