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It is not well known that the correlation between HLA antigens and response to cancer therapy. To evaluate the correlation among patients' outcome, HLA antigens and therapies, we used the hierarchical clustering analysis (Ward method). We examined HLA antigens as biomarkers as well as models of gene polymorphism in 1753 gastric cancer patients followed over 25 years after treatment. Among these patients, we identified that HLA haplotypes; HLA-B54-Cw1-DQ4-DR4, might be restricting to Fluoropyrimidine drugs plus PSK therapy in gastric cancer. HLA haplotypes including HLA-B54 were candidate predictors for response to FPSK therapy in gastric cancer. HLAs will be useful biomarkers for response to therapy in Japanese patients.

Because invasion to an adjacent organ (T4) indicates highly advanced disease, and most surgeons avoid esophagectomy, the prognostic impact of clinicopathologic factors for survival of these patients after esophagectomy has rarely been analyzed.From 1960 to 2005, a total of 268 patients with esophageal squamous cell carcinoma underwent esophagectomy for pathologic T4 disease (pT4). The impact of clinicopathologic factors on survival was evaluated by univariate and multivariate analysis. Changes in surgical outcomes and longterm survival between the earlier period (1960 to 1989) and the later period (1990 to 2005) were analyzed.Overall survival rates of all patients were 25% at 1 year, 10% at 3 years, and 5% at 5 years. The survival curve of the later group was significantly better than that of the earlier group (p0.01). Multivariate analysis indicated that venous invasion (hazards ratio, 1.76; 95% CI, 1.33 to 2.33, p0.01) and presence of a postoperative complication (hazards ratio, 2.62; 95% CI, 1.96 to 3.51, p0.01) were independent risk factors for poor overall survival. Presence of residual cancer was also an independent risk factor for poor cause-specific survival (hazards ratio, 2.40; 95% CI, 1.23 to 4.69, p=0.01). Venous invasion and intramural metastasis were risk factors for residual cancer. A total of 38 (14%) patients, 15 in the early period and 23 in the later period, underwent complete resection (R0). Although overall survival after R0 resection in the later period improved slightly, cancer-related survival rates were similar in both periods.Although overall survival of patients with pT4 improved after 1990, this improvement might be mainly dependent on curability of the resection.

Although thoracic lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma (SCC) has been reported to be a negative risk factor for long-term survival, only a few studies have evaluated the clinicopathologic difference between the impact of metastasis to the paraesophageal lymph nodes and to the nonparaesophageal lymph nodes. The purpose of this study was to evaluate surgical outcome after the clearance of metastatic thoracic lymph nodes. Retrospectively reviewed were 164 consecutive patients with thoracic esophageal SCC who had not had preoperative treatment and underwent surgery from 1980 to 2005 and were found to have thoracic lymph node metastases. Of these patients, 83 underwent surgery from 1980 to 1994 and 81 from 1995 to 2005. Univariate and multivariate analyses were performed to evaluate the impact of nonparaesophageal lymph node metastasis on survival. Univariate analysis revealed that T3/T4 tumors and the presence of nonparaesophageal node metastases were associated with only a 20% overall five-year survival rate. The overall five-year survival for the most recent period was significantly better than for the former period (42% vs. 13%, p < 0.01). Based on a multivariate analysis of prognostic impact of each nonparaesophageal node, the presence of metastatic subcarinal and/or posterior mediastinal nodes was an independent risk factor for reduced survival. Surgical outcome for patients with thoracic esophageal cancer and metastatic thoracic lymph nodes has improved during the last 25 years. Although postoperative chemotherapy might improve survival, the presence of T3/T4 tumors and/or metastatic nonparaesophageal nodes were unfavorable factors for survival.

Background: The influence of lower body mass index on the survival in cancer patients has not been fully estimated. While, many studies suggest that body mass index were positively associated with an increased risk of cancers of the esophagus, colon, gallbladder, pancreas, breast, endometrium, kidney, and ovary, so the rapid growth in the prevalence of obesity as new threats foretells health problems in years to come.Methods: We assessed preoperative body mass index (BMI) of 2677 patients with malignant and benign diseases who enrolled in the data base for The Japanese Society of strategies of Cancer research and Therapy from May 1975 to February 2004, for evaluating how BMI effect on the outcomes of patients, with examining some parameters.Results: During the period of this study from 1975-, the median BMI increased from 21.6 kg/m2, 21.9 kg/m2, 21.9 kg/m2, and 22.2 kg/m2, to 22.4 kg/m2. Serum gastrrin levels, T-IGR, SA, IAP, and CEA were increased significantly than those in both normal and obesity patients. The 10-year-survival rates (disease specific death) of patients of underweight, normal, overweight, and obese were 38.0 (52.0) %, 58.7 (69.5) %, 68.5 (77.4) %, and 54.3 (62.6) %, respectively. (Fig. 3 left) There were significant differences among these groups. (Underweight vs. normal, overweight, and obese, p

Purpose: We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. Patients and Methods: Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area × 1 day) and fluorouracil (800 mg/m2 × 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. Results: Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P = .037). The 5-year overall survival rate was 52% and 61%, respectively (P = .13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. Conclusion: Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.

Background. We estimated the survival of patients with advanced carcinoma of the esophagus in Japan who achieved complete response (CR) with chemotherapy and/or radiation therapy. Methods. A questionnaire was designed for patients with cancer of the esophagus with pretreatment stage II–IV (excluding organ metastasis [M1]), who were treated with chemotherapy and/or radiation therapy and achieved either a clinical CR continuing for more than 1 year, or a pathological CR in surgical specimens. All patients were treated between January 1, 1990, and December 31, 1997, in Japan. Results. Of the 169 eligible patients for whom adequate data were available, 106 patients with continuing clinical CR were defined as group A and 63 with pathological CR as group B. The overall survival rates at 5 years were 62.4% in group A and 64.8% in group B. In each of groups A and B, there was no significant difference in overall survival among subgroups of patients classified by initial pretreatment clinical stage. In group A, the survival rate of patients with concurrent chemotherapy and radiation therapy was significantly better than the rates for patients with chemotherapy alone or radiotherapy alone. In group A, the frequency of first failure at the local site of esophageal carcinoma was 7.7%. Of the 12 patients in group B (19%) who died less than 1 year postoperatively, 6 died of postoperative complications. Conclusion. The effect of CR to chemotherapy and/or radiation therapy for carcinoma of the esophagus on survival was marked. In patients with esophageal carcinoma who achieve CR, the prognosis may be independent of the initial pretreatment stage. Local failure in group A patients remains a problem, however.

Objective: To investigate the clinical use of p53 autoantibodies as a marker in the postoperative monitoring of colorectal cancer. Design: Retrospective study. Setting: Teaching hospital, Japan. Subjects: 40 patients with colorectal cancer who had p53 autoantibodies in their serum preoperatively. Interventions: Serial assay of p53 autoantibodies by ELISA before and after resection. Main outcome measures: Interpretation by a qualitative analysis. Results: A significant correlation was observed between curability by surgical resection and postoperative disappearance of p53 autoantibodies. Twenty-seven (96%) of 28 patients, who had p53 autoantibodies and whose cancer was completely removed, had no such antibodies after resection and no recurrence after 7 to 26 months. Conclusions: Postoperative assays of p53 autoantibodies are potentially useful for predicting recurrence of colorectal cancer in patients who have p53 autoantibodies preoperatively.

The validity of lavage cytology for accurate gastric cancer staging is demonstrated in this study. Between 1988 and 1996, 29 cases (8. 4%) were revealed as positive among 347 patients with resectable gastric cancer in whom peritoneal lavage cytology was performed. The survival rate of cytology-positive patients in each stage was found to be worse than that of all other patients in the same stage. The prognostic factors selected by the univariate analysis were enrolled for multivariate analysis using Cox's proportional hazards model with the backward stepwise procedure. As a result, although cytology finding was selected as an independent prognostic factor, macroscopic finding of dissemination was not selected. Our data indicate that positive cytology findings indicated a poor prognosis, and therefore the results of peritoneal lavage cytology should be included as a factor in gastric cancer staging.

Background: The p53 gene alteration is identified in approximately half of all human tumors, and is now thought to be a key gene for regulating the cell cycle through the induction of p21WAF1/CIP1 and inducing apoptosis through some genes such as BAX. In this study, we investigated the prognostic value of p53 mutation for postoperative esophageal squamous cell carcinoma patients. Methods: The subjects studied were 42 esophageal squamous cell carcinoma patients who underwent esophagectomy with complete curability in our department. The cases were limited to stage II and III. DNA was extracted from paraffin-embedded tissues. A p53 gene mutation was detected by polymerase chain reaction-single strand conformation polymorphism and subsequent direct sequencing method for exons 5 to 9. The 5-year survival rate was calculated and statistically compared between the p53 mutation(+) and (−) groups by the log rank test. Results: The p53 gene mutation was identified in 14 cases (33.3%). The 5-year survival rate of the p53 mutation(−) group (n = 28) was significantly higher than the (+) group (n = 14; 51.0% versus 35.7%, P

Although peritoneal lavage cytology is widely performed during surgery for gastric cancer and the results have been reported to be one of the accurate prognostic factors, the cancer stage is determined independent of the results of lavage cytology according to the First English Edition of Japanese Classification of Gastric Carcinoma. In this study we demonstrated the validity of lavage cytology for accurately staging gastric cancer. Between 1988 and 1996, peritoneal lavage cytology was performed in 347 patients with resectable gastric cancer. Among them, cytology was positive in 29 cases (8.4%). The survival rate of the cytology-positive patients in each stage was worse than that of all patients in the same stage. The prognosis of patients with positive cytology findings and serosa-exposed gastric cancer was significantly worse than that of negative cytology findings and serosa-exposed gastric cancer, and similar to that of negative cytology findings and serosa-infiltrating gastric cancer. Our data indicated that positive cytology findings thus indicated a poor prognosis, and the prognostic difference between positive and negative cytology findings was approximately a one-stage difference in the Japanese stage grouping. Based on our findings, the results of peritoneal lavage cytology should thus be included in the factors for staging gastric cancer.

症例は59歳の女性で症状はなく, 腹部超音波検査で膵体部腫瘍を指摘された. Dynamic CTにて腫瘍はほぼ均一で良好にenhanceされ膵島細胞腫が疑われたが膵ホルモンの測定ではいずれも正常範囲内であった. 手術は腫瘍摘出術が行われた. 腫瘍は大きさ1×1×1cmで被膜を有し, 病理組織では腫瘍細胞が硝子様の結合組織の中に増生しており, 索状・リボン状の配列が認められた. 悪性所見はみられず膵島細胞腫瘍と考えられたが, 免疫組織染色によってグルカゴンの産生が証明され, 無症候性のグルカゴン産生腫瘍と診断された. 現在, 術後6年で無再発生存中である.無症候性グルカゴン産生腫瘍 (以下, A群) と症状を示す症候性グルカゴン産生腫瘍 (以下, S群) とを臨床病理学的に比較検討したところ, 腫瘍径ではA群の方が小さくグルカゴン血中濃度ではA群の方が低かった. さらに, A群はS群に比べ良性の腫瘍が多く, 予後良好と考えられた.

Prediction of radiosensitivity would be valuable for heavy-ion radiotherapy. Premature chromosome condensation (PCC) technique has been a potential predictive assay in photon radiotherapy, but has not been investigated for hepatomas receiving heavy ions. Two human hepatoma cell lines, i.e., HLE and HLF, were irradiated with either 290 MeV/u carbon ions or 200 kVp X rays. Cell lethality was assayed by colony formation and compared with the unrejoined fraction of chromatin breaks as measured by PCC technique. Carbon ions at linear energy transfer (LET) of 76 keV/micron produced cell death more effectively than those of 13 keV/micron and X rays. For the cell killing, the relative biological effectiveness (RBE) of 13 and 76 keV/micron carbon ions compared with X rays was 1.10-1.24 and 2.57-2.59, respectively. Mean number of chromosomes in HLE and HLF cells was similar to each other, i.e., 60.48 and 60.28. RBEs for chromatin breaks of 13 and 76 keV/micron carbon ions were 1.30-1.31 and 2.64-2.79, respectively. A strong correlation between unrejoined chromatin breaks and cell killing for human hepatoma cells was observed irrespective of radiation quality. We conclude that PCC provides a potential predictor for the radiosensitivity of individual hepatoma that are treated with photon as well as heavy ion irradiation.

The feasibility of the new classification of stage grouping by the Japanese Research Society for Gastric Cancer was evaluated. During the 22-year period between January 1975 and December 1996, a total of 1294 patients with primary gastric cancer underwent laparotomy at the Department of Surgery, Chiba University; 1222 had their lesions removed during the gastrectomy and 72 remained nonresected. Cases of direct operative death totaled 17 (1.3%). Five hundred patients (38.6%) died of a relapse of the original cancer and 42 (3.2%) died of other diseases within the followup period. Six patients (0.5%) were lost during the followup. The 5-year cumulative patient survival rates of the seven stages of the new stage grouping were distinctly proportional, and the differences were also statistically significant except between stages IIIb and IVa. The two major revised points in the new stage grouping, new classification of the depth of cancer invasion, and new stage grouping by a mosaic combination of the degree of invasion and lymph node metastasis were thus found to be reasonable based on the actuarial 5-year survival rates of the subgroups in the same stage. The present study also showed that the classification of stage IV still requires further discussion.

A 46-year-old Japanese man was referred to our hospital for treatment of an esophageal stricture. Esophageal cancer was suspected after detailed investigations, and a right transthoracic esophagectomy was performed. The resected specimen showed only nonspecific esophagitis with severe fibrous thickening in the submucosa, but no evidence of malignancy. Between 1906 and 1993, only 19 similar cases of benign esophageal strictures with fibrous thickening, excluding congenital and iatrogenic strictures, have been reported in Japan. These lesions occurred in the middle to lower third of the esophagus in 15 of 19 cases (78.9%), and 8 of the 19 patients (42.1%) were aged between 30 and 50 years. The interval between onset and hospital admission was short, being less than 1 year in 8 of the 12 patients for whom this information was available. Our patient demonstrated a disorder resembling the diffuse severe esophagitis described by Roth in 1974.

We evaluated clinicopathological characteristics and prognosis of 45 patients for primary colorectal cancer with invasion to the adjacent organs operated on at the hospital from 1990 through 1996. Only 23 (51.1%) patients of them were verified microscopically to have tumor invasion to the other organs. These cancers were predominantly located in the left side of large bowel and extracolonic invasion frequently involved the urinary bladder, abdominal wall, small intestine, and female genital organs. Microscopic tumor invasion was recognized in the stomach and small intestine most frequently, urinary bladder and uterus next, and the rate of microscopic invasion was low in the abdominal wall compared with other organs. The rate of lymph node metastasis only has a significant difference between clinicopathological studies and microscopic invasion. The rate of microscopic invasion was as high as the clinical stage in pararel. No significant difference in prognosis was found between patients with direct histological invasion and those without such invasion, combined resection of the cancer and the surrounding organs is recommended for better prognosis in colorectal cancer for surgically curative cases.

The p53 gene has been shown to be commonlymutated in various human cancers, and mutant p53 can actas a dominant oncogene. The intact p53 protein is alsoknown to induce the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and is implicated incell cycle arrest. We investigated p53 gene alterationsin gastric adenocarcinoma and esophageal squamous cellcarcinoma to elucidate the association of the nuclearaccumulation of the p53 protein and/orp21WAF1/CIP1 protein. Abnormalities of thetumor suppressor gene p53 protein and the expression ofp21WAF1/CIP1 protein were analyzed byimmunohistochemical techniques in 32 cases of gastric adenocarcinoma and 15 cases ofesophageal squamous cell carcinoma. Twenty cases ofgastric cancer and five cases of esophageal cancer werealso analyzed for p53 gene mutation by polymerase chain reaction and direct nucleotide sequencing.Overexpression of p53 protein was found in 13/32 (41%)of gastric cancers and 5/15 (33%) of esophageal cancers.We found immunodetectable p53 in 10/14 cases with mutations and in none of 11 cases withoutmutations in gastric and esophageal cancers. Hence,immunohistochemical and genetic analyses gave concordantresults in 84% of 25 cases, revealing a good correlation between immunostaining of p53 and missensemutation of the p53 gene. p53 immunostaining was notobserved in cases with frameshift or splicing mutation.The expression of p21WAF1/CIP1 protein wasfound in 9/32 (29%) of gastric cancers and 4/15 (27%) ofesophageal cancers and in 2/14 (14%) cases withalteration of the p53 gene and in 5/11 (45%) without.These results suggest that abnormalities of p53 may be closely associated with the pathogenesisof gastric adenocarcinoma and esophageal squamous cellcarcinoma and that the immunoreactivity of p53 proteinis a general indicator of the tumors with altered p53 function. The expression ofp21WAF1/CIP1 protein was suppressed in theneoplastic tissues with and without p53 genealteration.

Hepatic functional reserve after portal embolization was assessed in eight patients according to the functional volume index (FVI), a new index obtained using positron emission tomography (PET) withl-[methyl-11C] methionine. FVI in residual liver was 1744–5252 (mean, 3441) (normal range, 3106–6211) before percutaneous transhepatic portal embolization (PTPE) and 2457–6906 (mean, 4590) after PTPE. FVI exceeded 4000 in five patients and did not reach 4000 in three patients after PTPE. Two patients with FVI values of more than 4000 survived after hepatectomy and one with FVI under 4000 died of liver failure. FVI is a useful criterion for determining indications for PTPE; a value exceeding 4000 is needed before major hepatectomy can be safely performed after PTPE.

The effects of manumycin, a competitive farnesyltransferase (FTase) inhibitor, on pancreatic cancer cell lines with or without K-ras mutation were studied. Manumycin inhibited the growth of human pancreatic cancer cells (SUIT-2, MIA PaCa-2, AsPC-1, BxPC-3) in a dose-dependent manner. The 50% inhibitory concentration (IC 50 ) in cell lines with a mutant K-ras gene (SUIT-2, MIA PaCa-2, AsPC-I) was lower than that in BxPC-3 with a wild-type ras. Both mitogen-activated protein kinase activity after growth stimuli and the ability for chemotactic invasion were markedly more inhibited by manumycin in SUIT-2 than in BxPC-3. These results suggest that mutated Ras is more sensitive to manumycin than the wild type. Furthermore, tumor growth and liver metastasis in nude mice inoculated with manumycin-treated SUIT-2 cells were inhibited dose dependently. Inhibition of Ras activity might be a new anticancer strategy in pancreatic cancer in which Ras plays a role.

Objective: To determine whether postoperative adjuvant chemotherapy confers a survival benefit on patients with esophageal squamous cell carcinoma undergoing radical surgery, we undertook a cooperative, prospective randomized controlled trial. Methods: A total of 205 patients underwent transthoracic esophagectomy with lymphadenectomy at eleven institutions between December 1988 and July 1991. These patients were prospectively randomized into two groups (100 patients underwent surgery alone and 105 patients had additional two courses of combination chemotherapy with cisplatin (70 mg/m 2 ) and vindesine (3 mg/m 2 ). The two groups did not differ with respect to sex, age, location of tumor, and distributions of pT, pN, pM, or p stage. Results: The 5-year survival was 44.9% in the surgery alone group and 48.1% in the surgery plus chemotherapy group. The relative risk was estimated to be 0.89 (95% confidence interval, 0.61 to 1.31) in the surgery plus chemotherapy group compared with the surgery alone group. No significant differences in survival were detected between the two groups, even with lymph node stratification. Conclusion: Postoperative adjuvant chemotherapy with cisplatin and vindesine has no additive effect on survival in patients with esophageal cancer compared with surgery alone. J Thorac Cardiovasc Surg 1997;114:205-9

To evaluate residual liver functional reserve before major hepatectomy, volumetry of the residual liver was measured by computed tomography (CT) and the uptake of l-[methyl-11C] methionine of the residual liver was expressed by differential absorption ratio (DAR) with positron emission tomography (PET). Residual liver functional volume was quantified as the functional volume index (FVI). FVI of 11 normal whole liver was 8697 ± 2009 (mean S.D.). Cases, 11, of malignant liver tumors with obstructive jaundice underwent major hepatectomy. FVI of the eight patients (5561 ± 1087) who had good course after operation was significantly higher than that of the other cases (266 +- 685) died of liver failure (P < 0.005). FVI is a useful index to quantify residual liver functional reserve to avoid liver failure after major hepatectomy.

Background/Aims: The integration of HBV DNA is thought to be involved in the initial stage of hepatocarcinogenesis, and it has been reported that transactivating factors encoded by the X and preS2/S genes stimulate transcription of multiple viral and cellular genes. We assessed the possible contributions of hepatitis B virus integration to the occurrence of hepatocellular carcinoma in hepatitis C virus-infected as well as in hepatitis B virus-infected patients by identifying the integrated HBV DNA sequence, and the X and preS2/S regions were further investigated in HBV DNA-integrated cases. Methods: Southern blot hybridization for detecting HBV DNA in tumor tissues from 28 hepatocellular carcinoma patients was carried out with full-length HBV DNA, and then with X and preS2/S regions as probes. We also carried out reverse transcription-polymerase chain reaction for detecting HCV RNA to confirm hepatitis C virus-infection in liver tissues. Results: Clonally integrated HBV DNA sequences were demonstrated in 16 of 28 patients (57.1%), including five HBsAg seropositive and 11 HBsAg sero-negative patients. Of these 11 HBsAg seronegative patients, 10 were also positive for anti-HCV in their sera, and all nine examined cases had HCV RNA in liver. Furthermore, the X region was identified in 14 of 16 HBV DNA integrated cases (87.5%), and the preS2/S region in 616 (37.5%). Conclusions: The present Southern blot analysis demonstrates that clonally integrated HBV DNA sequences were identified even in hepatitis C virus-infected hepatocellular carcinoma patients at a high rate (1018, 55.6%), and suggests that integrated hepatitis B virus, whose major component is the X gene, may play an important role in hepatocarcinogenesis in hepatitis B virus-integrated cases with and without hepatitis C virus infection.

The high frequency of loss of heterozygosity that has been observed on the distal region of the long arm of chromosome 9 in squamous cell carcinomas of esophagus, lung, uterus, and head and neck indicates the presence of a tumor suppressor gene(s) in this region. To investigate the possible role of the PTC gene on chromosome 9q22.3, that was identified as the cause of nevoid basal cell carcinoma syndrome, during carcinogenesis in esophagus and lung, we examined 20 esophageal squamous cell carcinomas and 10 squamous cell carcinomas of the lung for mutations in any coding exon of PTC. Using single-strand conformation polymorphism and direct sequencing, we detected no mutations other than two non-deleterious polymorphisms. Our results suggest that inactivation of some tumor suppressor gene(s) on 9q other than PTC contributes to the development of squamous cell carcinomas in these tissues.

We have investigated the antitumor effect of murine colon carcinoma cells developed to produce cytokines. Retrovirally transduced cells were inoculated into syngeneic mice, and their survivals were examined. Inoculation of interleukin-4 (IL-4)- or granulocyte macrophage-colony stimulating factor (GM-CSF)-producing cells alone did not affect the survival of the mice. In the tumors derived from an admixture of IL-4 and GM-CSF producers, however, regression developed spontaneously, and prolonged survival of the challenged mice was consequently observed. Histological examination revealed predominant infiltration of neutrophils around the tumor of a mixed population of IL-4 and GM-CSF producers.

胸部食道癌の至適切除範囲を, 食道の切除範囲, リンパ節の郭清範囲および隣接臓器の合併切除の3要因に分け検討した. 胸部食道全摘例は部分切除例に比べ残遺食道再発率が低く, 術前あるいは術中診断が困難な微小壁内転移や脈管内侵襲の遺残を防ぐために全摘することが望ましい. n (+) 例において, 3領域郭清では有意にリンパ節再発率の減少がみられ, 予後向上が得られた. リンパ節転移およびリンパ節再発の状況から, 深達度mm以上のIu・Im例およびmp以上のEi例では3領域郭清を原則とすべきである. また, 癌の浸潤が粘膜筋板に達しない症例では, 内視鏡的粘膜切除術やriskに応じたリンパ節郭清の縮小化, あるいは非開胸食道抜去術を適応することができるものと思われた. 隣接臓器浸潤例に対する重要臓器合併切除は, 手術成績・遠隔成績とも極めて不良であり, 現時点における根治手術の対象は, 術前補助療法の奏効例に限定すべきであると考えられた.

The extensive sequence homology that exists among the catalytic domains of phosphatidylinositol 3- and 4-kinases allowed us to clone a novel human gene encoding a putative phosphatidylinositol kinase, NPIK. Among other known phosphatidylinositol 3- and 4-kinases, NPIK was most closely related to yeast PIK1 phosphatidylinositol 4-kinase. Several forms of NPIK cDNAs were isolated, and expression of NPIK message was detected in a wide variety of tissues. Fluorescence in situ hybridization and radiation hybrid analyses assigned the NPIK gene to human chromosome 1. Recombinant NPIK protein catalyzed a conversion from phosphatidylinositol to phosphatidylinositol 4-phosphate. The catalytic activity of NPIK was augmented by Triton X-100, and was reduced in the presence of adenosine. Using green fluorescent protein system we determined that NPIK is localized in the cytoplasm. Taken together, the data suggest that NPIK may play a pivotal role in regulating the synthesis of phosphatidylinositol 4-phosphate at the site(s) accessible from cytoplasm.

We have examined the antitumor effect of murine colon carcinoma cells engineered to produce human interleukin-2 (IL-2) in syngeneic mice. Subcutaneous inoculation of retrovirally-transduced cells with IL-2 gene formed small tumors, but they became regressed spontaneously. Consequently, the inoculated mice showed prolonged survival. Histological examination of the tumors derived from IL-2-producers revealed predominant infiltration of macrophages around tumor necrotic masses. Thus, inoculation of IL-2-producing cells could protect the mice from subsequent subcutaneous or intraperitoneal challenges with wild-type cells, suggesting the induction of acquired immunity due to the effect of tumor vaccination.

p21 Cip1 was first isolated as one of the cyclin-dependent kinase (Cdk) interacting proteins induced by wild-type p53 gene product, and it appears to play an essential regulatory role in the control of cell proliferation as a potent, tight-binding inhibitor of cyclin-Cdk complex that blocks the G1/S transition of the cell cycle. We have now examined the p21 Cip1 mRNA expression levels in 16 surgically excised human colorectal tumor and non-tumor tissues by Northern-blot analysis with reference to the identification of p53 gene mutations. p53 gene mutations were detected in 6 tumor tissues but not in the other 10 tissues by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method and following direct sequencing. The mean p21 Cip1 mRNA expression level in tumor tissues was significantly suppressed compared to that of non-tumor tissues, irrespective of p53 gene mutations. In p53 gene mutation-detected cases, the mean expression level of p21 Cip1 mRNAs of tumor tissues was about 60% of that of cases without p53 gene mutation. Moreover, the relative mRNA expression levels of p21 Cip1 significantly decreased as the pathohistological stages progressed by Dukes' staging system, while in patients with liver metastasis these levels were significantly suppressed compared to those of patients without organ metastasis. These results indicate that reduced expression of p21 Cip1 mRNA is critical for growth activity and malignant potential of human colorectal carcinoma, and that the decrease in p21 Cip1 mRNA level is due to p53 gene mutation as well as other mechanisms during human colorectal carcinogenesis.

BACKGROUND. The mortality of patients with colorectal carcinoma depends mainly upon subsequent liver metastasis even after curative operation. However, it is very difficult to predict the incidence of liver metastasis by analyzing conventional tumor markers or pathologic findings. In the current study, the authors examined the genetic alterations of p53/DCC loci and Ki-ras in colorectal carcinoma in relation to liver metastasis, and investigated whether these gene alterations could be prognostic markers for liver metastasis. METHODS. Primary tumor tissue samples were collected at surgery from 30 patients with no liver metastasis and 24 patients with liver metastasis. Among the 30 patients with no liver metastasis at surgery, 9 developed liver metastasis after surgery. After the extraction of DNA, we investigated the loss of heterozygosity at p53/DCC loci and mutations of Ki-ras codon 12 in the colorectal carcinoma tissue from these patients. RESULTS. The incidence of allelic loss of the DCC locus was significantly greater for patients with liver metastasis than for patients who had no liver metastasis for more than 2 years (19/20 :95% vs. 2/5 :40%, P < 0.05). However, mutations of Ki-ras codon 12 were significantly less in patients with liver metastasis than in patients with no liver metastasis for more than 2 years (6/33 :18% vs. 6/11 :55%, P < 0.05). CONCLUSION. The current study indicated that detection of allelic loss of DCC and absence of Ki-ras codon 12 mutations are associated with the metastatic potential of colorectal carcinoma in the liver. These results suggested that these gene alterations might be reliable biologic markers for assessing the potential of liver metastasis after colorectal resection.

Murine colon carcinoma cells (colon 26) transduced by a retrovirus vector with the human interleukin-2 (IL-2) cDNA were studied for their tumorigenicity. Although cell growth in vitro was not affected by integration of the IL-2 gene, s.c. tumors of IL-2-producing colon 26 cells (H2) in syngeneic mice regressed spontaneously after producing small masses. Histological examination of the sites of tumor rejection revealed predominant infiltration of macrophages around the tumor necrotic mass. Subsequent challenge with parent colon 26 cells, but not with Meth A cells (fibrosarcoma of the same genetic background), did not result in tumor formation in mice which had been protected against H2 cells. Inoculation of H2 cells into syngeneic nude mice resulted in tumors with a retarded growth rate. Taken together, T cell-dependent, tumor-specific immunity is obtained by local IL-2 secretion around colon tumors, and this experimental animal model gives us a clue(s) for investigating host anti-tumor responses by cytokine production.

We previously isolated the mel-18 gene, a mammalian Polycomb group (PcG)-related gene with homology to bmi-1 oncogene. We show in this paper the existence of a new gene, mel-13, which overlapped with the mel-18 anti-oncogene. We discuss the relationships between mel-13 and the mel-18, bup, and Su(z)2 genes.

The mechanism by which the E6 protein of human papillomavirus type 16 (HPV-16) transactivates heterologous virus promoters has not been established. In this study, the involvement of p53-mediated transcriptional repression in transactivation by the HPV-16 E6 protein was examined using several virus promoters. HPV-16 E6 transactivated the TATA box-containing simian virus 40 early promoter and the Rous sarcoma virus long terminal repeat in p53-containing cells but not in p53-deficient cells. In contrast, the adenovirus E2 promoter was transactivated both in p53-containing and p53-deficient cells. These results indicate that the transactivation activity of the HPV-16 E6 protein is mediated by p53-dependent and promoter-specific p53-independent pathways.

Murine colon carcinoma cells which secrete several kinds of cytokine after retroviral transduction with corresponding genes, were examined for their antitumor effects in syngeneic mice. The mice inoculated with granulocyte macrophage-colony stimulating factor (GM-CSF) producer cells showed not only prolonged survival but also reduced tumorigenicity. The antitumor effect caused by the expression of interleukin-4 was less than that of GM-CSF, and interleukin-6 producer cells did not show any effects on the survival of the host animals. Histological examination of the GM-CSF-producing tumor revealed predominant infiltration of neutrophils and necrotic change of the tumor. The present study indicates the feasibility of cancer gene therapy with the expression of GM-CSF gene in tumor cells.

BACKGROUND & AIMS: Recent studies have shown that some variant forms of CD44, a transmembrane glycoprotein expressed on various cell surfaces, might be involved in tumor progression or tumor metastasis. The aim of this study was to analyze the expression of CD44-messenger RNA (mRNA) in colorectal cancer and colorectal adenoma to further elucidate the role of CD44 in colorectal tumorigenesis. METHODS: The expression of CD44-mRNA was examined in 90 specimens from 44 patients with colorectal cancer or colorectal adenomatous polyps and in the peripheral blood leukocytes from 7 healthy volunteers by reverse transcription- polymerase chain reaction and Southern blot hybridization. RESULTS: Strong expression of the epithelial form and variant forms containing exons 11 or 12 of the CD44 gene, which conferred metastatic behavior to rat cells, was detected in primary and metastatic tumor tissues, whereas it was very weak or not detectable in normal colonic mucosae, normal liver tissue, or peripheral blood leukocytes. However, adenomatous colorectal polyps also showed as strong an expression of epithelial and variant forms of CD44 as primary and metastatic tumor tissues. CONCLUSIONS: These results suggest that variant forms of CD44- mRNA might be expressed in an early stage of colorectal carcinogenesis. (Gastroenterology 1996 Feb;110(2):362-8)

極めてまれな魚骨穿通による肝膿瘍の1例を経験したので文献的考察を加えて報告した.患者は56歳の男性.右上腹部痛を主訴に来院.US, CT, MRIにて肝後下区域 (S6) に腫瘤を認めたため, 肝細胞癌と診断した.開腹の結果, 魚骨が十二指腸より肝臓に穿通したための肉芽性肝膿瘍であった.魚骨除去, 十二指腸縫合閉鎖術を施行し, 良好な経過を得た.魚骨による消化管穿孔・穿通の本邦報告例は384例であり, そのうち肝臓への穿通例は自験例を含めて7例と極めてまれであった.一般的に本症の診断は困難であるが, 肝臓穿通例においては, 腹部CT, 超音波検査における針状石灰化像に着目すれば正診が可能であると思われた.