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Neopterin, a pteridine intermediate metabolite in the biopterine synthetic pathway, is synthesized and secreted by monocyte/macrophages upon stimulation, mainly by gamma-interferon by activated T cells. C-reactive protein (CRP) is one of the major acute phase reactants and its release is thought to be mediated by interleukin-6. Soluble IL-2 receptor (sIL-2R) is released by activated T cells. Plasma concentrations of neopterin, CRP and sIL-2R were synchronously analyzed in 25 determinations of 5 patients with severe infectious complications. A marked increase in neopterin, CRP and sIL-2R levels was observed. The increase in neopterin was significantly correlated to that of neopterin which is a marker of macrophage activity. These results suggest that macrophages are involved in the stimulation of sIL-2R release. In contrast, the increase in neopterin was not correlated to that of CRP and the lack of correlation between neopterin and CRP indicated that independent mechanisms control the synthesis of these two markers.

Summary Plasma 5-hydroxytryptamine (serotonin), tryptophan and neopterin levels were measured in patients with depressive cancer cachexia and in healthy controls during the same time period. Patients with advanced cancers had significantly raised neopterin, a marker of endogenous gamma-interferon (IFN-γ) production, but decreased serotonin and tryptophan levels. IFN-γ induces a high level of indoleamine dioxvgenase (IDO), a tryptophan degrading enzyme, which in turn increases metabolism along the tryptophan- nicotinic acid pathway, resulting in decreased synthesis of serotonin. These results suggest that persistent immune activation occur in patients with cancer cachexia, resulting in disorders involving tryptophan metabolism.

Although the interleukin-1 receptor antagonist (IL-1ra) has been suggested as a potentially valuable therapeutic agent and has been shown to improve outcome in various animal models of arthritis, septic shock, and inflammatory bowel disease, there is little information available about its level in the circulation in patients with cancer.Serum levels of IL-1ra, soluble interleukin-2 receptor (sIL-2r), soluble intercellular adhesion molecule-1 (sICAM-1), and cortisol were measured in normal controls and patients with colorectal cancer.The data showed that serum IL-1ra levels in patients were significantly lower than those of healthy controls (P0.05). In contrast, serum sIL-2r and cortisol levels in patients were significantly higher than those of normal controls (P0.01). Serum sICAM-1 levels in patients were the same as in normal controls.These results suggested that a reduced level of IL-1ra exists in colorectal cancer patients relative to normal controls, indicating that cancer patients have an immunologic disorder and that exogenous IL-1ra administration might be a future alternative for cancer treatment.

We previously reported that introduction of the wild-type p53 gene into human cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer for p53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, significantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.

We analysed TCR-gamma delta expression in tumour-infiltrating lymphocytes (TIL) obtained from 13 patients with colorectal cancer and simultaneously isolated the T lymphocytes from normal intestinal tissue (IL) to compare the frequencies of TCR-gamma delta expression in TIL, IL, and peripheral blood lymphocytes (PBL) in the same patient. Flow cytometric analysis showed that the frequency of TCR-gamma delta expression in TIL (2.75 +/- 1.84%) was significantly lower than that in IL (15.28 +/- 9.45%, P < 0.01). However, a larger quantity of TIL was separated than IL per unit weight of specimen, so the total number of gamma delta T cells obtained per unit weight was not different between tumour tissue and normal intestine. In addition, phenotypic analysis revealed that about half of the TCR-gamma delta + TIL were CD8+ (CD4+, 3.0 +/- 3.1%; CD8+, 54.7 +/- 19.9%, mean +/- s.d. of five patients), and a very similar result was obtained in TCR-gamma delta + IL (CD4+, 2.7 +/- 2.4%; CD8+, 53.1 +/- 17.4%). In contrast, most TCR-gamma delta + PBL were double-negative (CD4+, 3.2 +/- 3.0%; CD8+, 20.6 +/- 7.4%). These results indicated that TCR-gamma delta + CD8+ T cells selectively and consistently localized in colorectal tumour tissue, similarly to normal intestinal epithelium.

患者は68歳, 男性.他院で肺癌に対し肺切除および縦隔への術中照射20Gyを施行されたが, 術後約3ヵ月で放射線食道潰瘍を発症.潰瘍は7ヵ月後には食道気管支瘻に発展し, 肺炎を併発したため, 手術から9ヵ月後に当科に紹介された.保存的治療を行うも諸症状は増悪したため手術を施行した.病変部近傍の食道は剥離が困難なため, 粘膜のみ切除した.潰瘍より下方の食道筋層を有茎筋弁として利用し, 瘻孔部に縫合してこれを閉鎖した.食道再建は二期的に行った.食道を温存できない状況での食道気管支瘻の処理には, 食道筋層を有茎筋弁として用いるのが有効である.縦隔に対する術中照射を行う場合, 20Gyの線量でも個体によっては高度の食道障害を生じる危険性があることを考慮して, 照射方法を設定する必要がある.

We investigated serum tryptophan (Trp), neopterin (NPT) and immunosuppressive acidic protein (IAP), one of tumor-associated tumor marker, concentrations in 28 patients with gastrointestinal tumors representing cancer cachexia and 10 healthy controls. NPT comes from activated macrophages presumably activated by tumor-sensitized T cells via gamma-interferon (IFN-gamma) excitation of the macrophages. We found that the NPT level was significantly higher than the control value. The negative correlation of NPT and Trp concentrations indicates activity of indoleamine 2,3-dioxygenase (IDO), a Trp degradating enzyme, in cancer-burden patients. The activity of IDO can be induced by cytokines such as IFN-gamma, and therefore low Trp levels may result from endogenous IFN-gamma production due to immune activation against tumors. We also found a positive correlation between NPT and IAP levels, suggesting that host immune activation against tumors played a role in the immunosuppression of cancer-burden states, followed by cancer-cachexia.

Pokeweed mitogen (PWM) was found to induce rapidly killer cells in human peripheral blood mononuclear cells (PBMC). To avoid PWM contamination in infused lymphocytes, PBMC were stimulated with PWM-coated beads, CMC-1. One hour of stimulation with CMC-1 led to distinct cytotoxic activity in PBMC at 7 h, this reaching a peak at 23 h in the following in vitro culture. The cytotoxic activity and target cell spectrum of CMC-1-activated killer (PWM-AK) cells were similar to those of lymphokine-activated killer (LAK) cells, the precursor cells of PWM-AK cells, as are those of LAK cells which are also low-density lymphocytes. The in vivo antitumor effects of PWM-AK cells were examined in nude mice with peritoneal carcinomatosis generated by the human colon cancer cell line, RPMI 4788. The intraperitoneal (i.p.) injection of PWM-AK cells immediately after stimulation with CMC-1 significantly prolonged the survival of tumor-bearing mice, suggesting that these cells could be of value for clinical cancer therapy.

Lateral lymph node dissection has been advocated for advanced low rectal tumours. However, its benefit is debatable because of the possibility of postoperative bladder and sexual impairment. To assess the role of lateral lymph node dissection 95 patients who underwent the procedure between 1981 and 1991 were reviewed and compared with 83 who had resection of rectal cancer without lateral node dissection. Only ten (11 per cent) of the 95 patients had lateral lymph node involvement; all had Dukes'C tumours. Lymphovascular invasion was present in 50·6 per cent of all patients and neural invasion in 27 per cent of 65 examined specimens. Local recurrence, distant metastasis and overall 5-year survival rates were 7, 9 and 76 per cent respectively in patients undergoing extended lymphadenectomy and 16, 7 and 72 per cent respectively in those who had resection alone. There were no statistically significant differences in survival between the two groups for any Dukes' stage. Recurrence, metastasis and survival were related more to venous or neural invasion and tumour spread than to node dissection. These results demonstrate that patients with Dukes' A tumours do not benefit from latera lymph node dissection, and that local recurrence rates in those with Dukes' B and C lesions are not significantly decreased. It is concluded that extended lymphadenectomy is unlikely to provide significant benefit to patients with low rectal cancer.

Lactosucrose is a non-digestible carbohydrate available for fermentation as a substrate for the intestinal microflora. It has been reported that lactosucrose is selectively used by the Biffidobacterium, and that its number significantly increase after the oral administration. In this study, we have examined the changes of the postoperative serum endotoxin level in ten patients with colorectal cancer. Five patients were served as controls, and the remaining five patients were given 30g of lactosucrose daily, during 1 week up to 3 days before operation. Serum endotoxin levels were measured prior and after lactosucrose ingestion, and also on day 1, 3, 5, and 7 postoperatively. Fecal pH, organic acid contents and intestinal microflora were also analyzed before and after lactosucrose administration. The control group had blood and fecal samples taken in a similar manner to the lactosucrose group. Fecal pH had the tendency to decrease, and the concentration of fecal organic acids had the tendency to increase in the lactosucrose group when compared with the control group. The count of Gram-negative rods, which were reported to produce endotoxin, decreased in a ratio statistically significant (p

家族性大腸ポリポーシスにて,全結腸切除・直腸粘膜釖除・回腸肛門吻合術を施行後,下痢,便通異常を訴える28歳女性に対し,難消化性糖質ラクトスクロース(Lactosucrose: LS)を経口投与した.その結果,LS投与により糞便水分は92%から86%とやや低下し,糞便pHも低下した.LS投与前では大量のコノハク酸が検出されたが,LS投与によりコハク酸は検出限界以下に消失し,著量の乳酸が検出された.腸内細菌叢は,LS投与前はBacteroidaceae優勢であったが,LS投与後bifidobacterium, streptococcus, peptococcaceaeの顕著な増加が観察された.大腸切除後,下痢など便通異常を来たしている症例に対し,bifidobacteriumに選択的に利用される難消化性糖質LSの経口投与は,異常な腸内環境を改善することが明かとなり,臨床応用が期待される.

30 out of 358 patients operated for a colorectal cancer had multiple cancer of the large intestine and other organs (multiple group). There was no difference in sex, age, location and macroscopic classification of colorectal cancers between the multiple and non-multiple groups. The most common site as the other organ was the stomach, followed by the uterus, lung, bladder, prostate and mamma. The most common histological classification was well differentiated adenocarcinoma in both groups, but, mucinous carcinoma was significantly more frequent in the multiple group. There was a tendency to having advanced cancers in the multiple group, and especially colorectal cancers preceded by the other organ cancer were significantly in a more advanced stage than those in non-multiple group. Therefore, it might be difficult to diagnose a colorectal cancer in an early stage during follow-up period for a cancer of other organ. Higher frequencies of family history of cancers, multiple colorectal cancers and complication of benign neoplastic polyp were demonstrated in the multiple group, and the existence of hereditary oncogenous factors was suggested. It is important to perform careful preoperative examination and postoperative follow-up, entertaining a probable multiple cancer, because it is very difficult to predict.

A new surgical approach using esophageal mucosal stripping technique in the treatment of major leakages of the esophagojejunostomy after total gastrectomy is presented. This procedure is indicated for patients with such major leakage in whom local infection can not be controlled even by sufficient drainage and nutrition management and fatal septic process is progressing. This procedure was successfully performed in 2 such patients. First, the intrathoracic esophageal mucosa is stripped off by the help of a vein stripper after separating the anastomosis. Edematous part of the jejunal end is resected and the stump is closed. After a Witzel jejunostomy is performed, the closed limb is brought out to the level of the abdominal wall and fixed subcutaneously. The cervical esophagus is exteriorized and both proximal and distal ends of the intrathoracic esophagus are tied. The merits of this approach are: 1) The ultimate objective which is mandatory for the treatment of infection is achieved, because the source of contamination is eradicated. 2) It is a rapid and technically easy procedure resulting in less operative trauma to the already compromised patient. 3) Enteral feeding can be started immediately after operation. 4) Differing from whole esophageal stripping, there is no risk of iatrogenic dissemination of infection intramediastinally. Hemostasis is easily achieved by the tamponadary effect of the accumulated blood in the esophageal muscle tube.

Although many agents that interfere with clotting mechanisms have been investigated for their potential to inhibit metastasis, their toxicity has prevented administration of sufficiently high doses to achieve inhibition of metastasis in clinical trials. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, inhibited liver metastasis in a CDF1 mice model with colon 26 adenocarcinoma cells. The apparently dose-dependent inhibitory effect was seen 21 days after all of the doses tested (0.3, 1.0, 3.0 and 10.0 nig/kg for 7 days) but the effect was only statistically significant ( P < 0.01) at the highest dose. The blood concentrations 3 min after dosing were less than 10−6M for all of the doses tested. At a concentration of 10−5M or less nafamostat mesilate was not cytotoxic towards colon 26 cells in vitro. The results indicate that it may not be difficult to achieve blood nafamostat mesilate concentrations that inhibit metastasis in mouse liver. Possible mechanisms of nafamostat mesilate are inhibition of extravasation and invasion of cancer cells, inactivation of collagenase due to inhibition of plasmin activity and inhibition of the formation of the cancer cell thrombus, and arrest in the capillaries through inhibition of thrombin activity. These preliminary results suggest that peri-operative administration of nafamostat mesilate may prevent metastasis into the liver after surgery for gastrointestinal malignancies.

Perforin is a protein present in the cytoplasmic granules of killer cells and is considered to be an important effector molecule. We assessed the perforin appearance via flow cytometry in human peripheral blood mononuclear cells stimulated in vitro for 3 days by recombinant interleukin-2 (rIL-2) or OK-432, a biological response modifier. The relationship between the lymphocyte subsets and perforin was investigated via two-color assay. CD4-positive cells had almost no perforin, and most of the CD16-positive cells did. Regarding the relationship with CD8, some of the bright positive cells (which were likely T cells) and most of the dull positive cells (likely NK cells) had perforin. Mean fluorescence was greatest in perforin-positive cells incubated with rIL-2, less in cells incubated with OK-432, and minimal in cells incubated in a medium without additives. Immunohistochemical staining with antiperforin antibody revealed that blast-transformed and enlarge cells were stained positively and that the intensity of staining of each cell alone was enhanced in cells incubated with OK-432 or rIL-2. If the fluorescence intensity of perforin-positive cells correlates with the amount of perforin in those cells, then the appearance of perforin was enhanced with OK-432, more enhanced with rIL-2, and consistent for cytotoxicity against K562 and Daudi cells. IL-2 was induced by OK-432, suggesting that the indirect effect of this IL-2 may play a role in OK-432-perforin induction. The results suggest that perforin may be an effector molecule in killer cells induced by rIL-2 or OK-432.

1978年から1990年までの13年間に教室で経験した大腸癌手術症例は372例で,そのうち非治癒切除88症例(23.7%)を対象に臨床病理学的検討を行った.非治癒因子についてみると,結腸癌ではH因子は76.5%で最も多く,ついでP因子19.6%,N因子17.6%の順であった.直腸～肛門管癌ではH因子56.8%,P因子27.0%,N因子21.6%の順であった.肉眼型では2型および3型が多く,組織型では直腸癌で中分化腺癌の占める割合が高かった.壁深達度ではss(a1)以上が大部分を占め,n(+),ly(+)/v(+)例が多かった.術後生存率は,結腸癌では1生率55%,2生率29%,3生率19%で,直腸癌では,1生率47%,2生率25%,3生率15%であった.非治癒因子別では,結腸癌,直腸癌ともH因子,N因子で比較的長い生存期間であった.

The changes in the intestinal microflora were examined in patients with advanced carcinoma of the large intestine, and healthy subjects were surved as control. Comparing to control, patients group revealed high fecal moisture and fecal pH, but showed low levels in various organic acids except succinic acid. Only succinic acid was detected in high level and frequency. No significant difference in the number and occupation rate of Gram-positive bacteria participating in the endogenous endotoxin production was noted between both groups. The pattern of fecal microflora in patients group was similar to that in control. However, the aerobic microorganisms including Staphylococcus were highly found in patients group. These results suggested that the colonic enviornment of the patients with large bowel carcinoma was in aerobic state in comparison with healthy subjects.

家族性大腸ポリポーシスにて全結腸切除・直腸粘膜切除・回腸肛門吻合術, 回腸瘻造設術が施行された20歳, 男性を対象とし, 術後1, 3, 4, 10, 12か月の計5回糞便を採取し, 糞便試料について, 固形分, pH, 有機酸, 腸内細菌叢の測定を行った. 回腸瘻は初回術後8か月めに閉鎖した.糞便水分, pHは術後経過とともに低下, 回腸瘻閉鎖後は健常人近似の値となった. 術後1, 3, 4か月における糞便有機酸濃度は低く, bifidobacteriumは検出されなかったが, 回腸瘻閉鎖後, 糞便有機酸濃度は上昇し, 健常人特有のパターンに移行し, 術後10, 12か月におけるbifidobacteriumの占有率はそれぞれ, 23.9%, 49.3%と検出された. また, 術後1, 12か月の糞便の嫌気性菌/好気性菌検出比は, 3.0, 37.0であり, 術後経過とともに腸内細菌数の増加と, bi藪dobacteriumを始めとする嫌気性菌占有率の増加がみられ, 小腸の大腸機能代償を裏づけた.

The clinical features of 6 operated cases of Crohn's disease experienced at the department were studied. The anatomical sites of these lesions were the small bowel, small and large bowels, and large bowel (including one case of rectal Crohn's disease) in each two cases. Indications for surgery included intestinal stricture in four cases, abscess, and fistula in each one case. Intestinal stricture was seen in two cases of enteritis, one case of enterocolitis, and one case of colitis (rectal lesion). Abscess and fistula were seen in one case of enterocolitis and colitis, respectively. Bowel resection was performed as short in length as possible, about 10 cm length from the margin of the main lesion. The postoperative recurrence occurred in one case. In this case, the recurrence lesion was improved by medical treatment. There were no cases of reoperation and death. Although postoperative follow-up is limited in durations from one and a half to ten years, all 6 patients are working without recurrence now.We discussed surgical treatment for Crohn's disease including indication for operation, surgical procedures and prognosis, together with a review of the literature.

A case of pseudomembranous colitis presenting with tachycardia, fever, and shock, but not accompanying by abdominal pain and diarrhea in an early stage after gastrectomy is described. Pseudomembranous colitis, if it occurs in an early stage after gastrointestinal operation, often lacks in abdominal symptoms. This case, being sucessfully diagnosed to start the treatment in a relatively early postoperative period, is rare.A 52-year-old man underwent total gastrectomy for primary malignant lymphoma. Cefotaxim (CTX) administration was started on the day of operation. From the 3rd postoperative day severe tachycardia, fever, and shock occurred, and nosotropic therapy failed to improve the general condition. Cause searching try also failed to disclose any complications such as anastomotic leakage and abdominal bleeding. On the 4th day a large amount of water diarrhea appeared. Endoscopic examination of the large intestine was performed. Based on macroscopic findings and biopsy cytodiagnosis, a diagnosis of pseudomembranous colitis was made. Administration of vancomycin hydrochloride and a large quantity of transfusion led to rapid symptomatic remission.

The expression of Fas, a cell surface receptor directly responsible for triggering cell death by apoptosis, and its ligand (FasL) was investigated on both human colonic intraepithelial T lymphocytes (IELs) and peripheral blood mononuclear lymphocytes (PBMLs). FACS analysis indicated that IELs have increased expression of Fas compared with PBMLs, together with the progress activation marker, CD45RO. A discrete fraction of freshly isolated IELs also constitutively expressed FasL, perhaps as a result of recent in vivo activation. Using monoclonal antibody APO2.7, which detects mitochondrial 7A6 antigen specifically expressed by cells undergoing apoptosis, we further investigated the apoptosis-inducing effect of anti-Fas monoclonal antibody (CH11) on both IELs and PBMLs. FACS analysis revealed that CH11 increased the percentage of apoptotic cells, in IELs but not in PBMLs. Culture with anti-FasL monoclonal antibody (4H9) significantly recovered cell viability in IELs, but not in PBMLs. These results indicate that IELs constitutively express both Fas and FasL and that Fas crosslinking generates signals resulting in apoptosis, outlining a potential mechanism involved in intestinal tolerance.

SUMMARYIntestinal intraepithelial lymphocytes (IEL) constitute the first lymphoid compartment to encounter dietary antigens and intestinal pathogens. IEL are proposed to be involved in the defence against bacterial and viral invasion and to play an important role in mucosal immunity. Fas (CD95/APO-1) is a surface receptor that induces apoptotic cell death upon ligation with Fas ligand (FasL). The aim of this study was to examine the expression and function of Fas and FasL on freshly isolated normal human colonic IEL. The expression and function of Fas and FasL on IEL isolated from 40 normal colonic specimens were examined by flow cytometry, reverse transcriptase-polymerase chain reaction, immunohistochemistry, and DNA-release cytotoxicity assay. Virtually all CD3+ IEL (95.2 ± 4.3%) expressed Fas and were sensitive to agonistic anti-Fas antibody, whereas only 56.6 ± 8.4% of peripheral T lymphocytes expressed Fas and were resistant to the antibody. We also detected FasL mRNA and protein (40.1 ± 4.2%) on IEL, and found that IEL exerted FasL-mediated cytotoxicity against Fas-expressing target cells. These findings suggest that human IEL are activated in situ but are tightly regulated by the constitutive expression of functional Fas and FasL to maintain homeostasis of the mucosal immune system.

The p21WAF1/CIP1 gene, which encodes a cyclin-dependent kinase inhibitor, may be critical for tumor suppressor gene p53-induced cell cycle arrest. The p53 gene is known to regulate G1 checkpoint, which can either induce G1 arrest or initiate apoptosis. To directly examine the role of p21WAF1/CIP1 in the control of p53 function, we have introduced human p21WAF1/CIP1 gene into a p53-deficient human non-small cell lung cancer cell line H1299 using a p21WAF1/CIP1-expressing adenoviral vector (AdCMVp21). Infection with AdCMVp21 resulted in high levels of p21WAF1/CIP1 expression and significantly suppressed the growth of H1299 cells through the G1 arrest of the cell cycle. In contrast, transient expression of the wild-type p53 gene by a recombinant adenoviral vector (AdCMVp53) in H1299 cells induced apoptotic cell death and resulted in a rapid loss of cell viability. We then examined the effects of combined infection with AdCMVp21 and AdCMVp53 on H1299 cells to explore the dominant function of these molecules. Interestingly, introduction of exogenous p53 overcame p21WAF1/CIP1-mediated cell cycle arrest at G1 and induced apoptosis, although viral-transduced p21WAF1/CIP1 expression level was unaffected. These observations suggest that p53 expression converts a p21WAF1/CIP1-mediated growth arrest into apoptosis. The result was repeated with two additional human colon adenocarcinoma cell lines with the different p53 status, mutant p53-expressing DLD-1 and wild-type p53-expressing LoVo, suggesting that this phemonenon is a general event among human cancer cells. Thus, p53-mediated apoptotic pathway is dominant over the growth arrest pathway, indicating that p53 may be an essential upstream mediator of p21WAF1/CIP1 in the regulation of a cell process leading either to growth arrest or to apoptotic suicide.

Alteration of the wild-type (wt) p53 gene by mutation, deletion or re-arrangement is a major factor in the development of human colon cancer. Recent studies have demonstrated that p53 might be an essential component of the apoptotic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We examined the anti-tumor effects of adenovirus-mediated wt-p53 gene transfer in combination with a chemotherapeutic drug on the human colon cancer cell line WiDr, which is homozygous for a mutation in the p53 gene. Treatment with the chemotherapeutic drug cisplatin following infection with a replication-deficient, recombinant adenoviral vector expressing wt-p53 (termed AdCMVp53) significantly suppressed the growth of WiDr cells compared to single treatments alone. To evaluate the in vivo efficacy of AdCMVp53 and cisplatin given sequentially, WiDr cells were inoculated s.c. in nu/nu mice. After 3 days, AdCMVp53 was injected s.c. into the area where tumor cells were implanted, followed by i.p. administration of cisplatin. Analysis of initial growth inhibition at 21 days demonstrated a profound therapeutic cooperativity, though administration of either AdCMVp53 or cisplatin alone was followed only by a slowing of growth. Our results suggest that gene therapy using wt-p53-expressing adenovirus in combination with a chemotherapeutic DNA-damaging drug could be a useful strategy for treating human colon cancer.

PURPOSE: Mucocele of the appendix is an uncommon disorder, usually found incidentally during ultrasonography or radiographic studies. We report two cases of combined appendiceal mucocele and colonic cancer. METHODS: The two cases were analyzed for the clinicopathologic characteristics such as history, presentation, laboratory data, radiologic and endoscopic studies, pathology, and p53 immunoreactivity. RESULTS: Two patients were diagnosed with an appendiceal mucocele by ultrasound of the abdomen, together with computed tomography. Colonoscopic examination subsequently revealed synchronous colonic adenocarcinoma in both patients. Ileocecal resection following endoscopic polypectomy and a right hemicolectomy was performed for each patient. An appendiceal mucocele was histologically diagnosed as a mucinous cystadenoma. Immunohistochemical detection of abnormally high level of p53 protein was observed in colonic adenocarcinomas of both patients, whereas both appendiceal cystadenomas were negative for p53. CONCLUSIONS: To be remembered is the high frequency of concomitant gastrointestinal tumors in patients with appendiceal mucocele, especially caused by mucinous neoplasms. A total colonoscopic surveillance will afford earlier diagnosis of synchronous colonic cancers in these patients.

We have studied the effects of oral administration of a biological response modifier (BRM), PSK, on hepatic lymphocytes. Many PSK positive cells were observed in the liver by anti-PSK antibody staining. Flow cytometric analysis revealed an increase in the number of OX8 (CD8) positive cells in the non-parenchymal nonadherent liver cells (NPNALCs) which were isolated from the liver enzymatically digested by perfusion with collagenase. NPNALCs were fractionated by discontinuous density gradient centrifugation, and the number and cytotoxic activity of these cells were examined n each fraction. Although the yield of lymphocytes in each fraction was not significantly increased by the oral administration of PSK, the natural killer (NK) activity was markedly enhanced in low density fractions. The present findings suggest that oral administration of PSK is effective for prevention of liver metastasis through the augmentation of organ-associated NK activity.

Eighteen patients with advanced adenocarcinoma of the pancreas were treated with a combination of natural human tumor-necrosis factor-α, natural human interferon-α, and tegafur. Complete and partial response was observed in one and two patients respectively(17% response rate). Seven patients (39%) showed stable disease. The median survival period for the overall population of patients treated is 209 days. Patients with evidence of tumor response or with apparent disease stabilization had a median survival of 313 days, while patients with progressive disease lived 154 days.

Twenty-four patients seen between 1978 and 1990 with early colorectal carcinoma were reviewed to determine the outcome of surgical treatment. The mean age was 62 (range 35–79) years; there were 16 men and eight women. The site of the tumour was the ascending colon in two patients, sigmoid colon in ten and rectum in 12. The polypoid and flat-elevated ulcerated (IIa + IIc) subtypes were detected in 14 and nine lesions respectively. Restorative colectomy was carried out in 19 patients, andjive required Miles' operation. There were no postoperative complications or deaths at a mean follow-up of 71 (range 12–151) months. Neither recurrence nor distant metastasis was found during follow-up. There was a close relationship between the depth of submucosal invasion and presence of flat-elevated ulcerated subtype lesions with lymphatic infiltration. This association may play an important role in the mechanism of metastasis. Major surgical resection is probably required if longer disease-free intervals and better cure rates are desired.

Genomic instability and genetic instability are 2 major pathways contribute to colorectal carcinogenesis. We have identified E2F-4, an important transcription factor in cell cycle control, having frequent tumor-specific mutations at the coding microsatellite in human colorectal cancer of the latter pathway. It was also shown that somatic mutations in the E2F-4 gene are closely associated with defects in the hMSH3 gene.We are thinking to apply gene therapy by transfection of wt-p53 recombinant adenovirus vector (AdCMVp53) for colorectal cancer on the basis of following results. Transfection of AdCMVp53 induced apoptosis on DLD-1, LoVo, SW620 colon cancer cell lines. Suboptimal dose of Ad-p53 and aspirin or CDDP cooperatively induced apoptosis on DLD-1 cells. Experiments using diffusion-membrane cham-bers in athymic mice demonstrated that AdCMVp53 inhibited neovalscularization of SW620 tumors. These results suggest that the p53 gene replacement may be applicable for the treatment of colorectal cancer in combination with anticancer drugs or aspirin as a potent apoptosis inducing or antiangiogenic therapy.