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Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs. chemotherapy with 5-fluorouracil alone.We assessed the activation states of beta-catenin and nuclear factor-kappaB in the primary tumors of 202 colon cancer patients, and analyzed the data in terms of the clinicopathologic characteristics and survival of patients undergoing the two forms of adjuvant therapy.We found two distinct patterns of nuclear accumulation of activated beta-catenin in the tumor cells: diffuse nuclear accumulation in 89 cases (44 percent) and selective nuclear accumulation at the tumor invasion front in 18 cases (9 percent). Nuclear factor-kappaB activation was found in 64 cases (32 percent). In patients with diffuse nuclear accumulation-type beta-catenin activation, immunochemotherapy significantly improved recurrence-free survival, cancer death survival, and overall survival rates compared with patients receiving chemotherapy alone. No survival benefit was found in cases with nuclear accumulation at the tumor invasion front-type beta-catenin activation or no activation. Similarly, immunochemotherapy favored the survival of patients with nuclear factor-kappaB activation. Multivariate analysis established the TNM stage and administration of polysaccharide K as independent prognostic factors in the patients with diffuse nuclear accumulation-type beta-catenin activation.The presence of diffuse nuclear accumulation-type beta-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.

We report a patient with breast cancer who developed meningeal carcinomatosis that was preceded by a rapid increase in the serum level of carbohydrate antigen (CA) 19-9. A 60-year-old woman was admitted for primary breast cancer with multiple metastases to the vertebrae. She received cyclophosphamide 400 mg/m(2), epirubicin 40 mg/m(2), and 5-fluorouracil (5-FU) 400 mg/m(2) (CEF) chemotherapy every 3 weeks. Upon admission, her serum concentrations of carcinoembryonic antigen (CEA) and CA19-9 were 28.6 ng/ml and 99.2 U/ml, respectively. After three cycles of CEF therapy, her serum CEA decreased, and metastases to the vertebrae were attenuated. Her serum CA19-9 rapidly increased, however. A modified radical mastectomy was performed, but her serum CA19-9 levels still remained high (500 U/ml). After four cycles of CEF therapy, she experienced headaches and vomiting due to an increase in cerebrospinal pressure, and she was diagnosed with meningeal carcinomatosis. At the time of this diagnosis, the concentration of CA19-9 in her cerebrospinal fluid was greater than 500 U/ml, and immunohistochemical examination revealed that carcinoma cells in the cerebrospinal fluid overexpressed CA19-9. To our knowledge, this is the first report of the development of meningeal carcinomatosis from CA19-9-producing breast cancer cells, showing thatCA19-9 expression was associated with breast tumor progression.

We developed and established a new dose-finding system, the individualized maximum repeatable dose (iMRD), suitable to induce prolonged TTP rather than tumor shrinkage.We applied this system in weekly gemcitabine therapy for 18 metastatic pancreas cancer patients. We determined the iMRD at the 5th week, after weekly dose adjustments. We started at 500 mg/m2 (1/2 maximum tolerated dose) of gemcitabine and repeated the treatment with an increase or a decrease of 100 mg/m each week, if toxicity was 0 or more than grade 1, respectively.The iMRD of weekly gemcitabine was 300 mg/m2 in 2 patients, 400 mg/m2 in 3 patients, 500 mg/m2 in 5 patients, 600 mg/m2 in 6 patients, and 700 mg/m2 in 2 patients, demonstrating significant differences among individual patients. Grade 3 marrow depression occurred in only 1 patient (5.6%). Of these 18 patients, 3 (16.7%), 13 (72.2%) and 2 (11.1%) patients showed partial response, stable disease, and progressive disease, respectively. The median of times to progressive disease and survival were 4.5 and 9.5 months, respectively. There were no significant differences in 1-year survival time and more than 50% reduction rate of serum CA19-9, a tumor marker for pancreatic cancer, between patients with lower (500 mg/m2 or less) and higher (600 mg/m2 or more) iMRD.These results suggest that iMRD is a simple method to determine an individual's tailored dose for chemotherapy and could be the optimal dose for patients with noncurable cancers such as metastatic pancreas cancer.

BACKGROUND The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation. METHODS Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer. Types of beta-catenin activation (diffuse or invasion edge) and NF-kappaB activation were examined by immunohistochemistry. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay. All statistical tests were two-sided. RESULTS Compared with the beta-TrCP1 levels in normal tissues, 25 (56%) of 45 tumors had increased beta-TrCP1 mRNA and protein levels. Of the 22 (49%) tumors with beta-catenin activation, 12 had the diffuse type (i.e., nuclear accumulation throughout the tumor) and 10 had the invasion edge type (i.e., nuclear accumulation predominantly in the tumor cells that formed the invasion edge). Increased beta-TrCP1 levels were statistically significantly associated with beta-catenin activation (P =.023) and decreased apoptosis (P =.035). beta-TrCP accumulated in the nuclei of tumor cells that contained increased levels of beta-TrCP1 mRNA and the active form of NF-kappaB. Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P =.016). CONCLUSION In colorectal cancer, increased expression of beta-TrCP1 is associated with activation of both beta-catenin and NF-kappaB, suggesting that the integration of these signaling pathways by increased beta-TrCP expression may contribute to an inhibition of apoptosis and tumor metastasis.

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

The efficacy of a biological response modifier polysaccharide K in adjuvant immunochemotherapy was evaluated in primary colon cancer patients with macroscopic Dukes' C after curative resection. Employing the minimization method using three factors (lymph node metastases, preoperative serum CEA level, and institution), 446 patients were allocated into groups P and C. Group P received immunochemotherapy, oral PSK (3 g per day) followed by oral 5-FU (200 mg/body per day), while group C received only intermittent chemotherapy, oral 5-FU (200 mg per day) followed by 4-week rest. Both groups received ten courses. Survival for cancer death was significantly higher in group P than in group C, but there was no difference in 7-year disease-free survival or overall survival had. Repeated alternating administration with PSK followed by 5-FU can improve survival for cancer death.

Many studies on postoperative carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA)19-9 monitoring after operation for gastric cancer have been reported, but most have been retrospective.A nationwide observational study was implemented in 135 leading institutions in Japan to evaluate the significance of CEA and/or CA19-9 in postoperative monitoring for recurrence in patients with advanced gastric cancer. Three hundred and twenty-one patients examined in this analysis underwent radical gastrectomy at one of Japan's leading institutions between November 1993 and March 1996 and had been followed up for at least 5 years. Serum levels of CEA and CA19-9 were examined preoperatively and every 3 months postoperatively, with diagnostic imagings, such as chest X-ray, computed tomography (CT), and ultrasonography also being performed every 3 months.Recurrence was observed in 120 patients (peritoneum, 48; liver 16; lymph node, 16; multiple sites, 25; and others, 12). Sensitivities of CEA and either CEA or CA19-9, or both, for recurrence were 65.8% and 85.0%, respectively, both of which values were significantly higher than the preoperative positivities (28.3% and 45.0%, respectively). In most patients with high preoperative levels CEA and/or CA19-9, these tumor markers increased again at recurrence. Recurrent diseases were detected between 5 months after detection by diagnostic imagings and 12 months before detection by diagnostic imagings (mean of 3.1 +/- 3.6 months before detection by diagnostic imagings) and between 10 months after detection by diagnostic imagings and 13 months before detection by diagnostic imagings (mean of 2.2 +/- 3.9 months before detection by diagnostic imagings) by CEA and CA19-9 monitorings, respectively.These results suggest that CEA and/or CA19-9 monitoring after operation was useful to predict the recurrence of gastric cancer, especially in almost all the patients with high preoperative levels of these markers.

Background: This study was performed to determine the echo layer structures of the normal gastric wall and early gastric cancer when visualized with a 30-MHz ultrasonic miniprobe. Methods: Twelve surgically resected gastric specimens were used for an ex vivo study. Eighteen normal sites and 12 early gastric cancer sites were scanned with an Olympus (XUM-S30-25R) probe with a frequency of 30-MHz. Endoscopic ultrasound images were compared with corresponding histopathologic sections stained with hematoxylin and eosin. Results: The normal mucosa was visualized as at least four alternating echo layers; the muscularis mucosa was delineated at all normal sites. Lymphoid aggregates within the mucosa could be seen. The submucosa was clearly visualized in most cases, but the muscularis propria and subserosa were seldom depicted due to attenuation of ultrasound waves. At the sites of gastric cancer, the layered architecture of the mucosa was disturbed by an irregular hypoechoic lesion. Minimal submucosal infiltration (400 and 750 μm) was clearly depicted in two cases, without ulceration at or around the tumor site. However, attenuation at the site of a deep ulcer scar prevented adequate visualization of the tumor extent in two other cases with ulceration. Conclusion: A 30-MHz ultrasonic miniprobe may provide additional imaging information of the gastric wall and could play a role in the assessment of early cancer lesions.

Background and aims We investigated expression of E-cadherin, beta-catenin, and c-erbB-2 in gastric cancer to identify molecular factor(s) relevant to development of liver metastasis, which is a frequent cause of mortality in gastric cancer patients. Patients and methods We analyzed by immunohistochemistry and compared expression patterns of E-cadherin, beta-catenin, and c-erbB-2 in the tumor between 40 cases of gastric cancer (GC) without (GC-H(-)) and 16 with concurrent liver metastasis (GC-H(+)). Results Loss of E-cadherin expression in the primary tumor was found in 18% of GC-H(-) and in 19% of GC-H(+). Oncogenic beta-catenin activation, represented by its nuclear translocation, was detected in 13% of GC-H(-) and in 31% of GC-H(+). There was no statistical difference in incidence of alteration in these molecules between the two groups of patients. c-erbB-2 overexpression was more frequently observed in GC-H(+) (10/16, 63%) than in GC-H(-) (5/40, 13%) while the distribution of histological types of the tumors was similar in the two groups of patients. This overexpression was also detected in metastatic liver tumors and biopsy specimens in the ten of the former group of patients. Conclusion Our results strongly suggest a role of activated c-erbB-2 in the process of liver metastasis, and an importance of detection of this overexpression in biopsy specimens to identify GC patients who are at high risk of developing liver metastasis.

Releasing individuals from susceptibility to and anxiety about the development of cancer is an eventual goal of cancer research. This owes much to rapid progress in molecular oncology that is supported by advances in technology. Cancers of the colon and rectum, pancreas and lung that share certain clinical and molecular oncological characteristics represent timely and important target of this field. Of the genes altered in these types of cancers, the best documented is K-ras. Currently highlighted along with this oncogene is beta-catenin, which has roles in both cell adhesion and transformation. Molecular diagnosis and susceptibility assessment targeting of such oncogenes will be promising for improvement in treatment and prevention of cancer, thereby contributing to human healthcare. Here we review recent knowledge on molecular diagnosis of sporadic cancers, with focus on K-ras and beta-catenin oncogenes.

Background: This study aimed to evaluate a three-dimensional endoscopic ultrasonographic (3-D EUS) system in the assessment of the tumor invasion depth of early gastric carcinoma. Methods: Sixty-nine macroscopically early cancer lesions in 67 patients were recruited in an in vivo study. The surgically resected gastric specimens of 30 of them were re-examined in an ex vivo study. An Olympus 3-D EUS imaging system was employed in both studies. Diagnostic accuracy for tumor invasion depth was evaluated and compared with histopathological sections stained by H&E and Masson’s trichrome stain. Reconstructed surface-rendering images were evaluated and compared with the endoscopic and macroscopic findings. Results: Three-dimensional EUS allowed rapid tomographic assessment of the lesions in both the in vivo and ex vivo studies. The accuracy of 3-D EUS for the assessment of tumor invasion depth was 87% in the in vivo study. The accuracy rate was significantly lower (P = 0.03) for the cancer lesions associated with ulcer fibrosis (74%) than for those with no fibrosis (97%). In the 30 subjects who underwent both studies, the accuracy rates were higher in the ex vivo than the in vivo study (94%vs 77% for all the lesions, and 93%vs 74% for cancers associated with fibrosis), but were not statistically significant. The rates of good surface-rendering images were 64% and 94% in the in vivo and ex vivo studies, respectively. The differences were attributed to the clearer dual-plane reconstruction images obtained in the ex vivo study in absence of motion artifacts. Conclusions: Three-dimensional EUS is a promising imaging technique for the assessment of tumor invasion depth of early gastric cancer.

Objective: To investigate the antitumor mechanisms of the streptococcal preparation OK-432. Methods: Using C57BL/6 mouse bearing B16 melanoma, we observed the antitumor activity of OK-432 and investigated the effect of OK-432 on multi-cytokine (IL-2, IL-4, IL-6, IL-10, IL-12, IFN-γ) production of mouse splenocyte both in vitro and in vivo. Results: As compared with control, OK-432 significantly inhibited B16 melanoma growth and lengthened mice survival time (P

Background & Aims: Recent in vitro studies showed that β-catenin translocated into the tumor cell nucleus functions as an oncogene by transactivating oncogenes, including MMP-7. We conducted a large-scale analysis of β-catenin and MMP-7 expression in human colon cancer to determine the potential clinical importance of these molecules. Methods: In 202 colon cancer patients with known postoperative outcomes, we determined the expression of β-catenin and MMP-7 in the tumors immunohistochemically and correlated the findings with the patients' clinicopathological characteristics and survival. Results: We found 2 distinct patterns of β-catenin nuclear accumulation (NA) in the colon cancers: diffuse NA (NAd) in 89 cases (44%) and selective NA at the invasion front (NAinv) in 18 cases (9%). The presence of the NAinv pattern was significantly correlated with advanced Dukes' stage ( P = 0.0187) and tumor recurrence ( P = 0.0005) as well as with MMP-7 expression in the tumor invasion front ( P = 0.0025), resulting in extremely unfavorable clinical outcomes. A multivariate analysis determined that the NAinv expression pattern and Dukes' C stage were independent prognostic factors. Conclusions: Oncogenic activation of β-catenin in the tumor invasion front, as represented by its NAinv pattern of expression, may be an independent and reliable indicator of membership in a subset of colon cancer patients who are highly susceptible to tumor recurrence and have a less favorable survival rate. GASTROENTEROLOGY 2002;122:60-71

Objective: We evaluated intraperitoneal cytology during surgery as a significant predictor of survival and tried to establish strategies for preventing peritoneal carcinomatosis. Methods: The study included 236 patients with gastric carcinoma macroscopically invading the serosa who underwent intraperitoneal cytological examination during surgery. In the 215 resected patients, the relationship between cytological positivity for cancer cells and various clinicopathologic features was analyzed. Additionally, postoperative survival was assessed in relation to the positivity of intraoperative cytology. Results: Cancer cells were positive [Cy(+)] in 78 (33.1%) of 236 patients who underwent cytological examinations. Among 73 patients with peritoneal metastases, 53 patients (72.6%) were Cy(+), as were 25 (15.3%) of the 163 patients without peritoneal metastases. Multivariate analysis indicated that peritoneal metastasis (p = 0.0001) and the depth of tumor invasion (p = 0.0069) were significant factors correlated with Cy(+). Among patients with curative surgery, the 5-year survival rate of the Cy(+) group was 22.2%, which was worse (p = 0.0004) compared with that of the Cy(–) group (60.9%). Among Cy(+) patients, the survival rate of the group treated with intraperitoneal administration of mitomycin C (MMC) and OK-432 was better (p = 0.0108) than that of the historical control group. Conclusion: These results suggest that intraperitoneal cytological examination can be a significant prognostic factor for gastric carcinoma with serosal invasion. In addition, dissemination of cancer cells in the peritoneum may be controlled by intraperitoneal immunochemotherapy with MMC and OK-432.

金沢大学医薬保健研究域医学系, A 43-year-old woman with a huge portal-systemic shunt accompanied by myxedema showed slow speech and behavior. Several imaging studies revealed a bold portal-systemic shunt from the splenic vein to the left renal vein. In addition, hypothyroidism caused by chronic thyroiditis was diagnosed, and synthesized thyroxine replacement was effective for the symptoms. However, the serum ammonia and indocyanin green retention remained in the abnormal range, nevertheless the portal vein pressure was normal and findings of liver cirrohsis were not recognized histologically. Surgical shunt closure was performed, resulting in normalized serum ammonia levels and serum branched chain amino acids/aromatic amino acids ratio, and improvement of the ammonia tolerance test.

PURPOSE: We studied serum ELAM-1 levels in colon cancer patients. METHODS AND RESULTS: Serum ELAM-1 levels were significantly higher in 52 patients with colon cancer (mean ± standard deviation, 69.3±28.6 U/ml) compared with 32 healthy volunteers (36.5±11.9 U/ml;P

We examined the production and tissue localization of matrix metalloproteinase-7 (MMP-7 = matrilysin) in human gastric carcinomas and analyzed the data in connection with the clinicopathological factors. Sandwich-enzyme immunoassay for the zymogen of MMP-7 (proMMP-7) showed enhanced production of MMP-7 in carcinoma tissues compared with control normal gastric mucosa. Immunohistochemical studies demonstrated that MMP-7 is localized predominantly to the carcinoma cells in 71% of the carcinoma samples (30/42 cases). The percentage of immunoreactive carcinoma cells to total carcinoma cells (positive ratio) was significantly higher in intestinal-type carcinomas (26%, median) than in diffuse-type carcinomas (3%, median) (p < 0.05). The positive ratio was markedly higher in carcinoma groups with vascular invasion (28%) or lymphatic permeation (12%) than in those without invasion (6%) or permeation (0%) (p < 0.05). It was also significantly higher in carcinoma groups with liver (49%) or lymph-node metastases (15%) than in those without metastases (6 and 2% respectively) (p < 0.05). Both proMMP-7 of 28 kDa and active MMP-7 of 19 kDa were detected in the carcinoma tissues by immunoblotting. Reverse-transcription-PCR showed specific amplification in 50% of the carcinoma cases (6/12 cases) and 8% of the normal control specimens (1/12 cases). In situ hybridization demonstrated that the carcinoma cells almost selectively express MMP-7 mRNA. These data suggest that enhanced production of proMMP-7 and its activation are implicated in invasion and metastasis of human gastric carcinomas. Int. J. Cancer (Pred. Oncol.)79:187–194, 1998.© 1998 Wiley-Liss, Inc.

We studied the role of angiogenesis in patients with medullary type poorly differentiated adenocarcinoma (MTPDA) of the stomach. Immunohistochemical analyses were conducted using antibodies against factor VIII (endothelial cells), vascular endothelial growth factor (VEGF) and its receptors (KDR andflt-1), and basic fibroblast growth factor (bFGF) and its receptors (bek andflg). Archival specimens of MTPDA (n=22) and non-MTPDA (n=47) were studied. The expression of VEGF and bFGF, the vessel count, and positivity of KDR on endothelium were all significantly higher in MTPDA than in non-MTPDA. The vessel count correlated with the VEGF expression in MTPDA. The vessel count and VEGF expression increased with the increasing stage of disease in MTPDA but not in non-MTPDA. The expression of bFGF and its receptors did not correlate with the vessel count and stage of disease in either type. These findings thus suggest that the biological behavior of medullary type poorly differentiated adenocarcinoma of the stomach is angiogenesis-dependent. The correlation of the VEGF expression and its endothelial receptors with the vessel count and the stage of disease thus suggests that VEGF is a factor responsible for the induction of angiogenesis in this type.

A 53-year-old woman had shown repeated, partial responses to chemotherapy for large, multiple liver metastases of sigmoid colon cancer. After a partial response to 5-fluorouracil plus leucovorin therapy, an 89.7% reduction of the 5-fluorouracil-resistant metastatic tumor was achieved by giving CPT-11 (irinotecan) at a dose of 100 mg/body per week. We suggest that CPT-11 should be recommended as an effective second-line treatment for unresectable liver metastases of colon cancer, after 5-fluorouracil-based chemotherapy.

A large-scale retrospective study was undertaken to evaluate the association between preoperative plasma carcinoembryonic antigen (CEA) levels and the prognosis of 2768 gastric cancer patients who underwent curative gastrectomy between 1983 and 1984 at 66 leading medical institutions in Japan. Postoperative follow-up was at least 5 years. Preoperative plasma CEA levels were also analysed against other prognostic factors. Preoperative plasma CEA levels showed strong correlations to the degree of lymph node metastasis ( P P = 0.004) and the histopathology of the gastric cancer ( P P

We examined the production and tissue localization of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in gastric carcinoma tissues. MMP-1 (tissue collagenase), MMP-9 (gelatinase B) and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 (gelatinase A) on tumor cell membranes, whereas no or little immunostaining for MMP-3 (stromelysin-1) and TIMP-1 was seen in carcinoma cells. Stromal cells in carcinoma tissue were also positively stained for these MMPs and TIMPs. MMP-2 immunostaining was observed exclusively on advanced gastric carcinoma cells and correlated with vascular invasion by tumor cells. Sandwich enzyme immunoassays revealed enhanced production of MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1 by carcinoma tissues. Gelatinolytic activities were significantly higher in carcinoma samples than in normal controls. Using gelatin zymography, active forms of MMP-2 and MMP-9 were more frequently detected in carcinoma tissue, and the activation rate of the zymogen of MMP-2 (proMMP-2), but not that of proMMP-9, correlated well with degree of local invasion and lymphatic permeation. Our data indicate an enhanced production of 4 MMPs in gastric carcinoma tissue and suggest that activation of pro-MMP-2 may be a key step for spreading of gastric carcinoma cells.

Endoscopic ultrasonography has become an important diagnostic procedure complementary to endoscopy and histopathological study in the preoperative evaluation of gastric carcinoma. Despite allowing visualization of tumoral infiltration with quite high accuracy, certain factors have limited the accuracy of this modality or even led to misinterpretation. We designed a prospective study to evaluate the accuracy of gastric carcinoma diagnosis with special reference to factors resulting in misdiagnosis. During a 22 month period, 86 patients with early and advanced gastric carcinoma underwent surgical or endoscopic resection on the basis of endosonographic findings. In all patients, endosonographic findings, location and macroscopic type of the tumor and histopathological characteristics including depth of invasion, malignant cell type and/or differentiation, and the presence/absence of ulceration in the tumor focus were recorded. The endosonographic and histopathological results were compared at the end of the study. Overall accuracy was 85% using the TNM staging system. There were no significant differences in accuracy in the location of the tumor, histological grading or macroscopic type of tumor, although the accuracy rate was lower for tumors located in the antrum. Ulceration in the tumor focus was a major factor leading to misinterpretation of the findings of early gastric cancer (p

Background. Although there are many reports regarding the growth rate of human tumors, those discussing stomach cancer are rare due to the difficulty in evaluating the growth rate of stomach cancer. Stomach cancers grow with either a large central depression or through severe invasion. Metastatic sites of stomach cancer, however, grow expandingly, as with pulmonary tumors. Methods. The reported doubling time estimate, based on the serum level of carcinoembryonic antigen (CEA), agreed with the actual tumor doubling time investigated in 112 previously untreated patients with recurrent gastric cancers. The influencing factors of the CEA doubling time were studied clinicopathologically, and a possible correlation between postoperative survival and the CEA doubling time was noted. Results. The CEA doubling time ranged from 12 to 105 days, with a mean of 37.5 ± 20.5 days (mean ± standard deviation) and a median of 32 days. The CEA doubling time did not differ significantly between sexes or between patients of varying ages. However, the CEA doubling time was significantly shorter in patients with papillary adenocarcinoma than in those with well or moderately differentiated tubular adenocarcinoma. The CEA doubling time of patients with poorly differentiated adenocarcinoma was divided into two groups-a shorter one and a longer one. The doubling time was also significantly shorter in patients with liver metastasis than in those with lymph node metastasis or peritoneal dissemination. Furthermore, among patients who did not receive any chemotherapy, a significant correlation was observed between the CEA doubling time and postoperative survival time. Most treated patients survived longer than untreated patients. Conclusion. The influencing factors on growth rates in recurrent stomach cancers were histologic type and metastatic sites. This growth rate plays an important role in determining the degree of biologic malignancy and may be influenced by some chemotherapeutic regimens. Cancer1995;75:1497-502.

Stagel II, IVの進行胃癌においてはたとえ治癒切除がなされたとしてもその半数は腹膜や肝臓に再発がみられる. そこで胃癌の病理学的特性や腫瘍マーカーより胃癌の転移様式を予知し, 何らかの対策を講じる必要がある. そこで著者らの経験した治癒切除後の再発症例を対象に個々の再発様式を検討したところ,(1) 限局性かつ膨張性発育を示し, かつ組織学的に髄様増殖を示すタイプ,(2) 浸潤性発育かつscirrhousな増殖態度を示すタイプに分類され, 前者は血行性, 特に肝転移, 後者は腹膜再発を来たすことが判明した. そこで著老らは腹膜再発危険群と肝再発危険群を設定し, 術中予防的化学療法を試みた. まず腹膜播種危険群(n: 12) に対しMMC+OK432大量腹腔内投与を施行したところ無処置の対照群に比べ有意に生存期間の延長をみた. さらに肝転移危険群(n: 41) 例に対しては術中MMC+5-FU肝動脈内oneshot注入を行った.その結果肝動注群において肝再発の低下および再発までの期間の延長が確認された. 以上, 進行胃癌の治癒切除症例に対するtype orientedな予防的化学療法の有用性を強調した.

About 50% of colorectal adenocarcinoma in humans have been reported to contain mutated Ki-ras gene. To provide a better understanding for the possible role of this mutation and to examine whether its presence can reliably predict a risk of colorectal cancer, we have analyzed the normal appearing mucosa of patients with colorectal adenocarcinoma. With an Enriched PCR procedure, we can detect mutated Ki-ras allele in the presence of 10(3) to 10(4) normal alleles. Only by this procedure was Ki-ras mutation detected in the non-neoplastic colonic mucosa of 9 out of 50 (18%) Japanese patients with colorectal cancer. This analysis indicated that epithelial cells which carry mutated Ki-ras gene were 100- to 1000-fold less frequent in the non-neoplastic mucosa than at the tumor site. The presence of ras gene mutation in normal appearing mucosa points to a previous exposure which had initiated the multistage process of colorectal carcinogenesis.

While 50% of colorectal tumors were found to harbor K-ms codon 12 mutation, only 18% of the respective patients contain this mutation in the normal appearing tissue when enriched PCR, a sensitive method that enables detection of one mutant allele in 10(4) normal alleles, is used. To determine whether the lower percentage could be attributed to the low incidence of this mutation or to the method of sampling, we have analyzed multiple normal appearing samples obtained from the same patient. Of 90 non-neoplastic mucosal samples collected from 20 patients with colorectal cancer, K-ras codon 12 mutation was identified in 6 samples taken from 5 patients. These results indicate that only one or two of the multiple samples contain mutant ras alleles. The presence of mutant ras alleles in the normal appearing tissues did not always correlate with that in the tumor site with respect to its presence and/or the type of base pair alterations, indicating independent or late events. While pointing to the importance of proper sampling method, the ability to detect ms mutation in normal mucosal tissues suggests it may serve as a useful biomarker of internal/external exposure which precede colorectal cancer development.

It is well known that hepatic metastasis is a very important prognostic factor of colorectal cancer. The survival of patients with colorectal cancer is increasing, partly because of the aggressive treatment of hepatic metastasis or prevention against recurrence in the remnant liver following recent development of new techniques for liver surgery and postoperative management. We reviewed patients undergoing resection of hepatic metastasis of colorectal cancer and investigated the indication for this type of surgery. Among 325 patients with colorectal cancer experienced in a past 16-year period, 54 (16.6%) developed hepatic metastasis. Seventeen of the 54 patients with hepatic metastasis (synchronous in 11 cases and metachronous in 6 cases) underwent surgery of their liver tumors. The 50% survival time of the liver resection group was 3.75 years versus 0.75 years in the nonresection group. There was no significant difference in survival rate between the liver resection and nonresection groups in patients with synchronous hepatic metastasis, but a marked difference of survival was found in patients with metachronous metastasis. We experienced 5 patients (29.4%) who have a long recurrence-free period after hepatic resection, in that the clinical significance of liver resection should be emphasized for better prognosis of colorectal cancer with liver metastasis.

A 65-year-old man was hospitalized due to an abdominal tumor. Several imaging studies showed multilocular tumors in the right hepatic lobe and in the pancreatic head, 4 and 7 cm in size, respectively. The hepatic tumor rapidly grew to 9 cm in 4 weeks, associated with a rapid increase in the serum carcinoembryonic antigen level from 125 ng/ml to 1,000 ng/ml. The pathologic diagnosis of the resected liver tumor was mucinous cholangiocarcinoma. This hepatic tumor produced a large amount of mucin, but did not secrete mucin into the bile ducts. Therefore, there was no obstructive jaundice. The incidentally accompanied pancreatic tumor was a typical serous cystadenoma. The present case suggested that mucinous cholangiocarcinoma could present rapid growth of the tumor. The clinicopathological features of mucinous cholangiocarcinoma are demonstrated for the first time, and the differences between mucinous cholangiocarcinoma and mucin-producing papillary adenocarcinoma of duct-spreading type are discussed.

Interleukin 8 (IL-8) is a novel cytokine which possesses neutrophil chemotactic and activating activities in addition to chemotactic activity for basophils and T lymphocytes. It has been shown that IL-8 is produced by a variety of human somatic cells including monocytes/macrophages, dermal fibroblasts, vascular endothelial cells, keratinocytes, mesangeal cells, and several types of tumor cell lines. We have examined here whether or not human gastric cancer cell lines produce IL-8 in vitro. The production of IL-8 protein was detected by enzyme-linked immunosorbent assay in the culture supernatants derived from eight of nine human gastric cancer cell lines stimulated with either interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha), or TNF alpha plus interferon gamma (IFN gamma). In some of the gastric cancer cell lines such as MKN 45 and KATO, TNF alpha plus IFN gamma synergistically induced the production of IL-8. In MKN 45 cells, synergistic increase of the steady state level of IL-8 mRNA by TNF alpha plus IFN gamma was not inhibited by cycloheximide treatment. Scatchard analysis revealed that IFN gamma changed neither the number nor the affinity constant of TNF alpha binding sites on a gastric cancer cell line, suggesting that the synergism was a post-receptor event. Furthermore, synergistic induction of chloramphenicol acetyltransferase activity by TNF alpha plus IFN gamma was observed in MKN 45 that were transiently transfected with chimeric chloramphenicol acetyltransferase reporter genes driven by the transcriptional regulatory region of human IL-8 gene. Through the mutation of the regulatory region of the IL-8 gene, both AP-1- and NF-kB-like factor binding elements were presumed to be involved in conferring the responsiveness to TNF alpha plus IFN gamma. Moreover, gel retardation analyses revealed that TNF alpha and IFN gamma synergistically induced the binding of NF-kB like as well as AP-1 like proteins bound to these sites. These results indicated that IFN gamma synergistically enhanced TNF alpha-induced IL-8 production in a human gastric cancer cell line through synergistic activation of transcription factors without up-regulating TNF alpha receptor.

Peripheral blood lymphocytes (PBL) of gastric cancer patients in advanced stages showed lymphokine activated killer (LAK) activities comparable to those of healthy donors, suggesting potential applicability of LAK cells induced from PBL stimulated with recombinant interleukin-2 (rIL-2) in adoptive immunotherapy (AIT) for gastric cancer. In order to generate a large number of LAK cells from PBL, lymphocytes were cultured with both rIL-2 and phytohemagglutinin (PHA). In this culture, the numbers of cells increased to a greater extent than those in culture with rIL-2 alone but cytotoxic activity did not augment, thus suggesting that this procedure would not afford sufficient clinical effects. On the other hand, a large number of LAK cells with high anti-tumor activities were efficiently induced from spleen cells of the patients by culture of rIL-2; hence clinical usefulness of these LAK cells is anticipated. In regional lymph node lymphocytes (RLNL) cultured with rIL-2, the cytotoxic activities were lower than in those induced in PBL, and a characteristic increase of CD8 + CD11 + suppressor T cells was observed after incubation with rIL-2. Nevertheless, an increase of CD4 + 4B4 + helper inducer T cells was also observed in RLNL after the culture with rIL-2. Furthermore, high cytotoxic activities were induced in RLNL in some cases in which metastasis to the regional lymph nodes was not detected. When gastric cancer patients were pretreated with biological response modifiers (BRM), especially with Lentinan, LAK cells from PBL showed higher NK and LAK activities as compared with those of patients without BRM pretreatment.

By means of a highly sensitive and quantitative assay for specific detection of metastasized tumor cells in chick embryonic organs using the polymerase chain reaction (PCR), we have examined the experimental metastatic ability of individual clones of NIH 3T3 cells, transformed with oncogenes: v-Ki-ras, v-Ha-ras, v-src, v-fos, and v-abl. Such a transformed clone had different metastatic abilities in different embryonic organs. Among them, two clones of NIH 3T3 cells transformed with ras-oncogenes (v-Ki-ras or v-Ha-ras) metastasized to liver and lungs of chick embryo, and grew there more rapidly than the other clones. The parental NIH 3T3 cells were detected as slight bands of PCR products after iv injection, indicating some cells were trapped in chick embryonic organs, but did not grow. These findings indicate that the transformed cells are able to invade the organ tissues and grow in embryonic chick organs, but non-metastatic cells such as the untransformed-NIH 3T3 cells are not able to grow in the secondary sites. These experiments clearly demonstrate the usefulness of this assay system to study genes involved in malignant transformation.

A distinct morphological variant of a diffuse type adenocarcinoma of the stomach with Paneth cell differentiation is reported. The tumor was a Borrmann's Type III carcinoma measuring 6.0 x 5.5 cm at the body along the greater curvature. It was composed of Paneth cell- and endocrine cell differentiated cancer cells in addition to tubular and poorly differentiated adenocarcinoma cells. The Paneth cell differentiation was characterized histologically by cytoplasmic distinct coarse eosinophilic granules stained red with periodic acid-Schiff and Masson trichrome reagents and reddish brown with phosphotungstic acid hematoxylin, and electron microscopically by lysozyme in cytoplasmic electron dense granules. In addition, electron microscopy revealed acid mucin globules and various intermediate forms between Paneth granules and the mucin globules which might be regarded as abortive forms of Paneth granules presumably resulting from defective incorporation of lysozyme-positive mucosubstances into acid mucin. Endocrine differentiated cancer cells consisted of serotonin-, peptide YY-, and glucagon/glicentin-positive cells. The various cell phenotypes found in the present tumor could be explained on the basis of intestinal differentiation of gastric cancer.

卵巣癌の脾臓転移例を経験したので, その穿刺細胞所見を中心に報告した.患者は74歳の女性で, 65歳時左卵巣癌のために, 両側付属器および子宮切除術をうけている.主訴は左側腹部痛.CTスキャン, MRIスキャン, 超音波では脾に10×9cm大の多房性嚢胞を認めた以外に著変はなく, 検査データではCEA, CA125の軽度上昇を認めた.脾のリンパ管腫の疑いで開腹を行った. 術中に行われた脾の穿刺細胞診では, 少数ながら乳頭状集塊もしくは散在性に異型細胞を認めた.核は偏在性で円形ないし楕円形, クロマチンは微細顆粒状で, 核小体は中心に1個もしくは非中心性に2～3個, 細胞質は淡緑色で空胞を有する腺癌の特徴をそなえていた.切除された脾臓は大きさ13×12×5cm, 重量220gであった. 割面をみると8.5×6.0×5.0cm大の嚢胞を認め, 脾門部を中心として6×4×4cm大の灰白色充実性の部分を認めた. 組織学的には乳頭状腺癌であり, 原発の卵巣癌 (乳頭状漿液性嚢胞腺癌) の組織像と類似の組織像であった.

This study presents the case of a patient with minute type Ha rectal cancer with a diameter at its largest of only 5 mm, with infiltration as far as the submucosal layer (sm) and positive parietal lymph node metastasis. The patient was a 54 year-old male who visited Yasuda Medical Hospital because of diarrhea which appeared in early May 1988. During sigmoidscopy, a small protruding lesion was seen in the rectum (Rs) about 12 cm from the margin of the anus, and the patient was referred to the authors' surgical service for an endoscopic polypectomy because of a biopsy diagnosis of adenocarcinoma. The polyp had a smooth, shiny surface, and had a well demarcated hemispherical shape. A histopathological examination of the polypectomized specimen, showed that it was an invasive carcinoma extending into the submucosal layer without any adenoma component. Since the cut end of the specimen strongly suggested positive cancer cells and lymphatic permeation was also confirmed from the polypectomized specimen, a low anterior resection was performed on August 4, 1988. The postoperative histological examination revealed a small amount of residual cancer cells in the submucosal layer which appeared to be at the cut end of the resected polyp. One metastatic focal point was seen in the pararectal lymphnode, and this patient's case provided valuable suggestions for deciding upon therapeutic policies for early cancer of the large intestine.

In terms of clinicopathological features of cases of gastric cancers as examined by age, the auther's investigations have confirmed that patients in their twenties and thirties hold biological properties in common. In this study, the authers examined the above patients as cases of juvenile gastric cancer and obtained the following results: Cases of juvenile gastric cancer represented 76 (9.2%) of a total of 827 resected cases, with sex ratio of 1:1. Of these 76 cases, 33 were all depressed type early cancers and 43 were advanced cancers with predominant IV type (15 cases). Juvenile 5-year-survival rate was 60.2%, which was practically equal to 59.3% for patients aged over 40 years. Curative resection was performed in 88.2% of the cases, 5-year-survival rate for which was 71.6%. Recurrence was noted in 13 curatively resected cases. Death occurred in 22 cases, 21 of which showed ps (+) as depth of penetration, and the cause was peritoneal dissemination in 19 cases.

49歳, 女性. 胸部中部食道癌 (Im, Stage IV) に対して1986年8月右開胸開腹胸部食道全摘兼胸骨後経路胃管挙上再建術を行った. 術後後照射を行い, その後経過良好であったが, 術後1年8か月後に吐血・下血を主訴としショック状態で再受診した. 緊急内視鏡にて挙上胃管後壁に深い潰瘍性病変があり, 同部には多量の凝血塊が付着し拍動性に動いていた.保存的に治療を行い, 一時的に止血しえたが, 翌日再検査中に突然噴水様の大量吐血が出現し心停止・呼吸停止状態となった. 蘇生術を施行しながら直ちに緊急手術を行った. 術中所見ではこの潰瘍は大動脈弓部前面に穿破しており, 穿破部大動脈壁の直接縫合により止血し救命することができた. 挙上胃管に発生する潰瘍性病変の報告は, 本邦では5例ときわめて少なく, このように大動脈へ穿通・穿破し, かつ救命しえた例の報告はいまだ見られない. 挙上胃管潰瘍発生の成因について検討をくわえ報告する.

Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.

We studied the role of chemotherapy in cancer cachexia, which is well known to lower QOL and responsiveness to chemotherapy. In BALB/c mice we used two clones derived from the murine colon 26 adenocarcinoma cell line; clone 5, a non-cachexigenic tumor and clone 20, a cachexigenic tumor, in which IL-6 mRNA was selectively detected. While maximum tolerated dose (MTD) of CPM and CPT-11 showed significantly smaller tumor weight and higher survival than 1/2 MTD in both drug groups with clone 5, the results were reversed with clone 20. The tumor weights with MTD of CPM or CPT-11 in combination with anti-IL-6 antibody treatment, which decreases serum IL-6 level and improves cachexia status, were significantly smaller than those in the MTD treatment-alone group with clone 20, but not with clone 5. From these results, we suggest that lower dose chemotherapy or cachexia-controlled chemotherapy, such as some chemotherapeutic agents with neutralizing cachexia-related cytokine effects, elicit anti-tumor effects in cachectic individuals that are superior to conventional MTD chemotherapy.

Immunochemotherapy using PSK used as postoperative adjuvant chemotherapy for colorectal cancer in Japan, is a treatment that depends on the immunocompetence of the host. Therefore, we analyzed the data of Hokuriku district conducted by the CIP study group to compare the long-term survival for preoperative CEA level and PPD reaction.Between February 1991 and March 1993, 87 patients with primary colon cancer and macroscopic lymph node metastasis (macroscopic Dukes' C) underwent macroscopic curative resection. The patients were randomly allocated to receive 5-FU/PSK therapy or 5-FU alone. The 7-year disease-free survival (DFS), 7-year overall survival (OS) and 7-year cancer death survival (CDS) were compared using the preoperative CEA levels and PPD values.In cases with preoperative CEA levelor =3.0 ng/mL, the 7-year DFS, 7-year OS and 7-year CDS were significantly better in the PSK group (85.7, 90.5, 90.5%) than in the control group (52.4, 52.4, 57 1%; p=0.019, 0.007, 0.014,). In cases with preoperative PPD level19.0 mm, the 7-year DFS, 7-year OS and 7-year CDS were significantly better in the PSK group (85.7, 85.7, 89.3%) than in the control group (56.7, 60.0, 63.3%; p=0.018, 0.036, 0.028). Recurrence was significantly less in the PSK group. The DFS tended to be superior in the PSK group (87.4%) compared to the control group (69.9%) for hematogenous metastasis.The present study demonstrated that preoperative CEA and PPD, that can be measured easily in the clinical setting, may be effective indicators of postoperative adjuvant immunochemotherapy using PSK.

The Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) has designed and initiated a randomized Phase II clinical trial planned as a first-line of chemotherapy for advanced or recurrent gastric cancer. The trial focuses on two groups and selecting the better of two regimens. The first group was given tailored CPT-11, adjusting individual optimal dosage using toxicity-based grading as an index in combination with TS-1, and the second group was given standard TS-1 treatment. The aim of this tailored dosage regimen for each individual patient is to continue chemotherapy as long as possible, and eventually, to prolong survival. In this trial, subsidiary pharmacokinetics analysis for the tailored arm is also proposed. We would like to introduce the significance and theory of tailored dosage chemotherapy in this paper.

To evaluate the effect of UFT (an oral antineoplastic drug combining uracil and tegafur) as an adjuvant chemotherapy.We examined whether UFT inhibits micrometastasis of the liver from colon cancer implanted into the cecum of nude mice in an orthotopic model. Moreover, we studied whether our early detection system using a polymerase chain reaction (PCR) of the human beta-globin gene would be useful in this model.The administration of 20 mg/kg UFT p.o., which is a relatively small dose compared with 65 mg/kg of the maximum tolerated dose of this drug in mice, inhibited liver metastasis completely when started immediately after a cecectomy (micrometastasis present at this time), but did not inhibit liver metastasis significantly when started at 4 weeks after a cecectomy (gross tumor present at this time). There were no severe toxicities at this dose. In our PCR study, all livers in 10 mice to which therapy was given immediately after a cecectomy and without liver metastasis showed no PCR-amplified fragment, while 7 of 10 livers in the nontreatment group in which gross liver metastases were not observed demonstrated this fragment.These findings indicate that UFT is useful for either adjuvant chemotherapy or the inhibition of micrometastasis, and our system to detect micrometastasis by examining the human beta-globin gene is useful for the early evaluation of the efficacy of these drugs.

The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation.Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer. Types of beta-catenin activation (diffuse or invasion edge) and NF-kappaB activation were examined by immunohistochemistry. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay. All statistical tests were two-sided.Compared with the beta-TrCP1 levels in normal tissues, 25 (56%) of 45 tumors had increased beta-TrCP1 mRNA and protein levels. Of the 22 (49%) tumors with beta-catenin activation, 12 had the diffuse type (i.e., nuclear accumulation throughout the tumor) and 10 had the invasion edge type (i.e., nuclear accumulation predominantly in the tumor cells that formed the invasion edge). Increased beta-TrCP1 levels were statistically significantly associated with beta-catenin activation (P =.023) and decreased apoptosis (P =.035). beta-TrCP accumulated in the nuclei of tumor cells that contained increased levels of beta-TrCP1 mRNA and the active form of NF-kappaB. Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P =.016).In colorectal cancer, increased expression of beta-TrCP1 is associated with activation of both beta-catenin and NF-kappaB, suggesting that the integration of these signaling pathways by increased beta-TrCP expression may contribute to an inhibition of apoptosis and tumor metastasis.

We studied roles of angiogenesis in patients with alpha-fetoprotein (AFP)-producing gastric carcinoma (APGC), which is well known to have a poor prognosis and frequent liver metastases. Immunohistochemical analyses were conducted using antibodies against alpha-fetoprotein, factor VIII (endothelial cells) and vascular endothelial growth factor (VEGF). Archival specimens of APGC (n=25) and non-APGC (n=68) were studied. Expressions of vessel density and VEGF were significantly higher in APGC than those in non-APGC (p

The expression levels of thymidylate synthase (TS) affect the sensitivity of tumor cells to fluorinated pyrimidine cytotoxic agents and determine the response of patients with colorectal cancer to fluorinated-pyrimidine-based chemotherapy. The correlation between the expression of TS and the prognosis of patients with colorectal cancer was examined in a prospective study. Evaluation of biomarkers including TS expression was performed using tumor specimens from 229 colorectal cancer patients. Immunohistochemical analysis of TS expression was performed using an antibody raised against a C-terminal epitope (D 186 -V 313 ) of the human TS. The intensity of TS staining and the expression of other biomarkers were blindly scored. The five-year survival rates were 63.4% and 85.6% among patients with high and low intratumoral TS expressions, respectively (p=0.0007). Similarly, the disease-free survival (DFS) rate was 51.2% and 80.3% in the high and low TS expression groups, respectively (p=0.0004). In a subset analysis of Dukes' stage C patients, the survival and DFS rates were 44.0% and 40.0% in the high TS expression group, and 73.5% and 67.4% in the low TS expression group, respectively. Significant differences were observed in both survival (p=0.0048) and DFS (p=0.0054) rates. No significant correlation was observed between the expression of other biomarkers and prognosis. Significantly poorer prognosis of curatively resected colon cancer in patients with high TS expression levels in tumor tissue was confirmed by a double-blind prospective study conducted on samples obtained from patients enrolled in an adjuvant immunochemotherapy randomized clinical trial.

PURPOSE AND STUDY DESIGN: Recent studies have shown that beta-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the beta-catenin oncogenic signaling cascade along with its twin, the K-ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we analyzed oncogenic beta-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those of mutational activation of K-ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact.We found two distinct patterns of beta-catenin activation, i.e., diffuse NA in 20 cases (27%) and selective NA at the tumor invasion front (NAinv) in 19 cases (26%). The presence of the NAinv pattern was significantly correlated with advanced Dukes' stage tumor (P = 0.0005) and the presence of distant metastases (P = 0.0064). K-ras proto-oncogene was mutated in the tumors of 31 cases (42%). Activated beta-catenin or K-ras was detected in most (78%) colorectal cancers analyzed, although a weak inverse correlation was found between the activities of the two oncogenes in the tumors. Importantly, most (7 of 8) patients with tumor showing both K-ras activation and the NAinv pattern of beta-catenin activation were in Dukes' stage C at surgery, and half of them developed distant metastases to the liver and lungs.The results suggest that although oncogenic activation of beta-catenin and K-ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes. Consequently, activation of either or both of these oncogenes may serve as a genetic marker for molecular diagnosis.

Our previous study showed that the combination of irinotecan (CPT-11) and OK-432 had an additive antitumor effect. The purpose of this study was to analyze the mechanism by which this combined treatment had an effect on immunity.To investigate the immune effects of murine splenocytes stimulated by SN-38 (the active form of CPT-11) and OK-432, endogenous interleukin (IL)-12 p70 production was assayed by ELISA and flow cytometry.Endogenous IL-12 production was increased by SN-38 stimulation of cultures of OK-432-activated splenocytes from C57BL/6, C3H and Balb/c mice, which was not observed with LPS-activated splenocytes. IL-12 production by splenocytes was higher at an early stage after tumor inoculation. SN-38 and OK-432 stimulated IL-12 production in cultures of peritoneal exudate macrophages (PEM), and T cell cooperation was essential in cultured splenocytes.These results suggest that the interaction of SN-38 and OK-432 may support a type 1 T helper (Th1)-dominant state through increasing endogenous IL-12 production, mainly by macrophages.

The efficacy of a biological response modifier polysaccharide K in adjuvant immunochemotherapy was evaluated in primary colon cancer patients with macroscopic Dukes' C after curative resection.Employing the minimization method using three factors (lymph node metastases, preoperative serum CEA level, and institution), 446 patients were allocated into groups P and C. Group P received immunochemotherapy, oral PSK (3 g per day) followed by oral 5-FU (200 mg/body per day), while group C received only intermittent chemotherapy, oral 5-FU (200 mg per day) followed by 4-week rest. Both groups received ten courses.Survival for cancer death was significantly higher in group P than in group C, but there was no difference in 7-year disease-free survival or overall survival had.Repeated alternating administration with PSK followed by 5-FU can improve survival for cancer death.