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After endoscopic treatment for esophageal cancer, a 65-year-old male underwent surveillance esophagogastroduodenoscopy. A 12-mm discolored flat lesion was noted on the greater curvature of the middle gastric body. Magnifying endoscopy with blue laser imaging demonstrated an irregular papillary surface. Biopsy revealed atypical cells with mucus and irregularly distributed nuclei. The lesion was diagnosed as a gastric-type neoplasm with low atypia. Thereafter, endoscopic submucosal dissection (ESD) was conducted and specimen was sent for biopsy. The ESD specimen suggested a signet-ring cell carcinoma with MUC5AC-positive phenotype and adenocarcinoma of the fundic gland type, with MUC6 positivity and pepsinogen I positivity in the shallow and deeper layers, respectively. Moreover, the cervical region of fundic glands demonstrated a transformation zone of the signet-ring cell carcinoma into an adenocarcinoma of the fundic gland type. Herein, we report this rare case along with a literature review.

Endoscopic submucosal dissection (ESD) of lesions using expanded indications for early gastric cancer (EGC) has been accepted as an alternative treatment for cases without lymph node metastasis. We herein report a rare case of metastatic lymph node tissue in mixed adenoneuroendocrine carcinoma (MANEC) after curative ESD using the expanded pathological criteria. A 70-year-old man underwent ESD for two EGC lesions. A pathological examination revealed lesions that required curative resection based on the expanded pathological criteria of the Japanese classification of gastric carcinoma. However, lymph node metastasis was detected at 26 months after ESD. Additional surgical resection was performed and MANEC was pathologically diagnosed in the metastatic lymph node. The patient subsequently underwent additional chemotherapy and remains alive at 2 years after surgery. Even though MANEC is a rare tumor, this case suggests that periodic follow-up is important when patients undergo curative resection by ESD based on the expanded indications because of the high malignant potential and the poor prognosis.

A 54-year-old man was presented at our hospital with weight loss.He diagnosed with colorectal cancer, multiple liver metastases and para-aortic lymph node metastasis.After undergoing colostomy, he was treated sequentially with mFOLFOX6 plus bevacizumab(Bmab), FOLFIRI plus Bmab or Pmab, according to the guideline.Since these chemotherapy resulted in progressive disease, regorafenib was administered as a salvage-line treatment.PET -CT showed only para-aortic lymph node swelling with high FDG uptake.Severe adverse effects were developed shortly after regorafenib treatment so he requireda reduction in dose.Three years after treatment with regorafenib, the response of the target lesion was stable disease according to the RECIST criteria.Tumor growth had been controlled for a long time.

A 38-year-old male presented to our hospital with complaint of vomiting. A CT demonstrated a mass sized 42mm in the pancreatic head invading to the duodenum and a liver mass sized 15mm in the medial segment. Biopsy revealed adenocarcinoma. Due to liver metastasis, he was deemed surgically unresectable. He was started on FOLFIRINOX therapy after gastrojejunum bypass operation. After 15 courses of the therapy, restaging showed a decrease in pancreatic tumor size and a disappearance of a liver mass along with PET-CT revealing no FDG-avid uptake. A serum value of DUPAN-2 was also normalized. He was offered resection as a potentially curative treatment. He underwent curative pancreaticoduodenectomy(PD), which was difficult to perform because of adhesion and hard fibrous tissues. Operating time and blood loss were 600 minutes and 1,933 mL, respectively. Histologic examination revealed Grade 1a histological chemotherapy effect. His cancer recurred 11 months after PD. He received nab-paclitaxel and gemcitabine regimen at out-patients clinic.

An 87-year-old man visited our hospital with a chief complaint of melena. Invagination caused by rectal cancer or sigmoid colon cancer was suspected as a result of physical and radiological examinations. Since there were no subjective symptoms, laparoscopic surgery was planned electively. As an operative finding, a tumor was found in the rectosigmoid colon and caused invagination. The invagination was released during an operation, and high anterior resection with D3 dissection was performed laparoscopically. The operation time was 108 minutes and the amount of blood loss was 22 mL. Although anastomotic leakage occurred as a postoperative complication, recovery was achieved conservatively by percutaneous drainage. In many cases, invagination of adults is caused by a solid tumor such as bowel carcinoma, which commonly occurs at the cecum or sigmoid colon. Although invagination of the rectosigmoid colon fixed to the retroperitoneum is relatively rare, the fragility of the supporting tissues in the pelvis accompanied by aging is considered to be a cause. In cases of a large tumor occupying the lumen of the intestine, appropriate preoperative diagnosis is needed and the method of operation should be chosen carefully.

Objective: The criteria for endoscopic resection for early gastric cancer include absolute and expanded indications. Consensus already exists for the absolute indications. However, the suitability of the expanded indications must be validated by long-term outcome analyses since such lesions have only recently become resectable with the development of endoscopic submucosal dissection. The aim of this study is to clarify the suitability of the expanded indications for the treatment of early gastric cancer with endoscopic submucosal dissection., Materials and Methods: The medical records of 1161 patients with early gastric cancers (1332 lesions) treated by endoscopic submucosal dissection and meeting the criteria for absolute or expanded indications without additional treatment with gastrectomy were divided into absolute indication group or expanded indication group., Results: Complete resection rates were 96.4% and 93.4% in absolute and expanded indication groups, respectively, with no significant differences between the groups. Delayed bleeding rates were significantly higher in the expanded indication group, whereas all cases were successfully managed conservatively. The 5-year overall survival and recurrence-free rates were 93.7%/99.77% and 90.49%/98.90% in the absolute and the expanded indication groups, respectively, with no significant differences between the groups for either measure. Multivariate analyses revealed that affected horizontal margin and tumor location were independent predictive factors for recurrence., Conclusion: The expanded indication group showed excellent post-endoscopic submucosal dissection short-term and long-term outcomes compared with the absolute indications group, demonstrating that expanded indications are suitable for endoscopic submucosal dissection for early gastric cancer.

The rupture of a metastatic mixed adenoneuroendocrine carcinoma (MANEC) has not been previously reported, although the neuroendocrine cell carcinoma is often associated with a high incidence of hepatic metastases. The patient was a 39-year-old male who presented with upper abdominal pain over 3 months. Computed tomography showed multiple tumors in both hepatic lobes, while lower gastrointestinal endoscopy revealed a tumor in the transverse colon. Histopathologic examination of the tumor revealed it to be a neuroendocrine cell carcinoma. After the resection of the primary tumor, hepatic metastases rapidly increased, and one of them in the left lateral segment was ruptured with significant hemorrhage. The rupture led us to undertake the emergency operation to stop the bleeding. Histology showed a high-grade large-cell neuroendocrine carcinoma associated with moderately differentiated tubular adenocarcinoma. The Ki-67 labeling index was 80% (G3). The diagnosis was mixed adenoneuroendocrine carcinoma according to the 2010 World Health Organization guidelines. Hepatic arterial infusion chemotherapy, systemic chemotherapy, and transcatheter arterial chemoembolization did not decrease the tumor progress, and the patient died on postoperative day 110. Reporting this highly malignant case, I hope all doctors can be interested in MANEC.

In the present study, we assessed the involvement of hepatocyte growth factor (HGF)/c-Met signalling with vascular endothelial cell growth factor (VEGF) and hypoxia inducible factor (HIF)-1α expression in the downstream pathways phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) in CT26 cells, to determine the mechanisms of the potent anti-angiogenic effect of NK4. We established genetically modified CT26 cells to produce NK4 (CT26-NK4). VEGF expression in subcutaneous CT26 tumours in vivo and in culture supernatants in vitro was determined by ELISA. HIF-1α expression in nuclear extracts was evaluated by western blot analysis. VEGF and HIF-1α mRNA levels were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR). The DNA binding activity of HIF-1α was evaluated using an HIF-1α transcription factor assay kit. Our results demonstrated that VEGF expression was reduced in homografts of CT26-NK4 cells, compared to those of the control cells. In vitro, VEGF expression, which was induced by HGF, was inhibited by anti-HGF antibody, NK4 and by kinase inhibitors (PI3K, LY294002; MAPK, PD98059; and STAT3, Stattic). HGF‑induced HIF‑1α transcriptional activity was also inhibited by the kinase inhibitors. Real-time RT-PCR demonstrated that HGF‑induced HIF‑1α mRNA expression was not inhibited by LY294002 and PD98059, but was inhibited by Stattic. These data suggest that the PI3K/Akt, MAPK and STAT3 pathways, downstream of HGF/c‑Met signalling, are involved in the regulation of VEGF expression in CT26 cells. HGF/c‑Met signalling may be a promising target for anti-angiogenic strategies.

Sarcoidosis is an idiopathic systemic disease with non-caseating granuloma that is reported to occur concomitantly with various malignant tumors. We report here a case of advanced gastric cancer with sarcoidosis, for which precise preoperative diagnosis was difficult. A 69-year-old woman was diagnosed with a far-advanced gastric cancer because multiple intra-abdominal and intra-thoracic lymph node swellings and a tumorous lesion in the spleen were detected by multidetector computed tomography and fluorodeoxyglucose positron emission tomography. However, these multiple changes might be derived from sarcoidosis, because the multiple lymph node swellings were nonspecific changes for gastric cancer. With appropriate informed consent, surgery was selected in order to accurately confirm the stage of progression. Consequently, these changes were shown to not be metastatic, and curative surgery was performed. In conclusion, careful examination and a reasonable treatment strategy are important for avoiding the risk of overdiagnosis in gastric cancer patients with sarcoidosis.

Background & Aims: Identification and purification of cancer stem cells (CSCs) could lead to new therapeutic targets, but their heterogeneous expansion is an obstacle to their study. We investigated whether it is possible to monitor pancreatic CSCs in real time, based on their intrinsic low level of proteasome activity., Methods: We engineered human pancreatic adenocarcinoma cells (PANC1, MIAPaCa2, BxPC3, and KLM1) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg accumulates in CSCs as a result of low activity of the 26S proteasome. Cells with high and low levels of fluorescence (Gdeg(high) and Gdeg(low)) were isolated by flow cytometry; tumor growth was analyzed in immunocompromised mice. We performed a screen for agents that were specifically toxic to pancreatic CSCs, in a synthetic lethal manner., Results: Gdeg(high) cells, but not Gdeg(low) cells, formed spheres and underwent asymmetric division-features of CSCs. Injection of as few as 10 Gdeg(high) cells led to tumor formation in mice. Gemcitabine was toxic to cultured Gdeg(low) cells, whereas Gdeg(high) cells were resistant. We observed that quercetin was toxic to Gdeg(high) cells in culture and in pre-established tumors grown from these cells in mice. Nuclear accumulation of β-catenin was detected in Gdeg(high), but not Gdeg(low), and lost after exposure to quercetin., Conclusions: We used a fluorescence marker system for level of proteasome activity to identify pancreatic cancer cells with features of cancer stem cells. We identified quercetin as a compound that is specifically toxic to pancreatic CSCs., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: This study was designed to evaluate the clinical significance of undifferentiated component in differentiated T1/T2 gastric adenocarcinoma., Methods: Two hundred thirty-one patients who underwent curative gastrectomy were diagnosed pathologically as differentiated type T1/T2 gastric cancer according to Japanese Classification of Gastric Carcinoma (JCGC). The patients were divided into subgroups, pure differentiated type (pure D group, 181 patients) and differentiated-predominant mixed type (D > U group, 51 patients). The clinicopathological features of D > U group were compared with those of pure D group, and also those of undifferentiated-predominant type (U > D group)., Results: Patients in D > U group were more likely to have larger and deeper tumors with lymphatic invasion and metastases than pure D group. However, there was no significant difference in clinicopathological factors between D > U and U > D groups, except for depth of tumor invasion. The postoperative 5-year survival rate of D > U group was significantly poorer than that of pure D group (88% and 98%, P = 0.011). Multivariate analysis revealed the presence of undifferentiated component was an independent prognostic factor., Conclusions: The presence of undifferentiated component in differentiated T1/T2 gastric cancer is associated with tumor progression. Therefore, the decision criterion of histological mixed type in TNM classification is better suited than JCGC in T1/T2 gastric cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

At the time of diagnosis, 20% to 25% of patients with colorectal cancer already have liver metastases, the presence of which is a most important prognostic factor. A 64-year-old man was admitted to our hospital for investigation of anemia and multiple liver tumors. Examinations revealed ascending colon carcinoma with more than 40 liver metastases and 2 lung metastases. We performed right hemicolectomy with lymph node dissection, which was followed by 5-fluorouracil/leucovorin, oxaliplatin, plus bevacizumab (FOLFOX-BV). After 4 courses of chemotherapy, the lung metastases were in complete remission and the liver metastases had shrunk. We suggested the option of radical liver resection, but the patient declined initially as he had not suffered any severe side effects of FOLFOX-BV. After 23 courses of the chemotherapy, he agreed to undergo hepatectomy. We performed extended right lobectomy with partial left and caudal lobe resection. All of the macroscopic metastatic lesions were resected. Histopathologically, viable cancer cells were recognized in 7 of the 43 liver metastatic lesions. Postoperatively, FOLFOX-BV was restarted and continued for 10 months. At the time of writing, 15 months after the hepatectomy, the patient was well without evidence of recurrence of the cancer.

Advances in diagnostic and surgical techniques have improved the prognosis of esophageal cancer, but there is growing concern about gastric tube cancer after esophagectomy. Gastric carcinoma arising in tubes that were reconstructed retrosternally is usually resected through a median sternotomy; however, this is invasive and carries a risk of osteomyelitis after suture-line failure. We performed video-assisted gastric tube resection, eliminating the need for sternotomy by using a sternal lifting method, on a 71-year-old man who had previously undergone esophagectomy and reconstruction retrosternally. The tumor was a Borrmann type 1 advanced cancer located near the esophagogastric anastomosis. Neck collar and upper abdominal incisions were made, and the sternum was lifted using a Kent retractor to extend the retrosternal space. Under videoscope assistance, we stripped the adhesions around the gastric tube carefully and performed total gastric tube resection. For the reconstruction, the ileocolon was lifted through the retrosternal space, and an ileoesophagostomy and Roux-en-Y reconstruction were performed. Despite leakage from an esophago-ileoanastomosis on postoperative day 6, the patient recovered well without mediastinitis or osteomyelitis of the sternum. Thus, our surgical procedure provides a good surgical view, decreases surgical stress, and reduces the risk of fatal postoperative complications.

A 62-year-old male patient with common bile duct (CBD) cancer underwent pancreaticoduodenectomy with lymphadenectomy in 2002. Histological examinations revealed moderately differentiated tubular adenocarcinoma with lymph node metastasis around the pancreas head and hepatoduodenal ligament. No adjuvant chemotherapy was performed, due to the risk of side effects. Two years after the first operation, new lesions developed at the left supraclavicular area. These lesions were considered to be Virchow's node metastasis of the original CBD cancer. However, we could not detect any other metastatic lesions in the intraabdominal lymph nodes around the aorta. We resected the lesion. Histological examinations showed a similar histological appearance of this lesion to that of the CBD cancer resected in 2002. At present, the patient has survived for more than 80 months after receiving the second surgery. In selected cases, surgery might be considered even for a Virchow's node metastasis of CBD cancers if there are no other recurrent lesions.

The case was a 36-year-old male whose chief complaints were anorexia and weight loss. Upper gastrointestinal endoscopy revealed circumferential stenosis in the fourth portion of the duodenum, while CT revealed a tumor with a diameter of 60 mm continuing as a single mass from the pancreatic body and tail to the fourth portion of the duodenum, and this was accompanied by findings that raised suspicions of circumferential invasion of the superior mesentric artery (SMA). Based on these results and biopsy, the patient was diagnosed with pancreatic and SMA invasion of duodenal cancer that was considered to be unresectable. After performing gastrojejunostomy, we administered DOC (40 mg/m2, day 1), CDDP (60 mg/m2, day 1), and S-1( 80 mg/m2, day 1-14) for 3 courses. The tumor response was PR and the images indicated the SMA invasion was disappeared. We judged that the tumor could be gone by a resection while preserving the SMA. In the surgical findings, the tumor continued as a single mass from the pancreatic body and tail to the third portion of the duodenum, and the surrounding area exhibited marked fibrosis. We performed a pancreatic tail resection along with combined resection of third and fourth portions of the duodenum, transverse colon and splenic flexure, and left adrenal gland. The case was diagnosed to be well-differentiated invasive ductal pancreatic cancer with duodenal invasion. Cancer invasion was not observed in any of the stripped surfaces surrounding the pancreas. The T3, N1, M0, fStage III antitumor effects were mildly effective. In this case, the treatment was initially started by considering the case as one of duodenal cancer, but the final results of a pathological diagnosis revealed that it was pancreatic cancer. However, either way, even though the case was unresectable before the chemotherapy performed for duodenal cancer was significantly effective for the pancreatic cancer. Therefore, a resection became possible, and an R0 resection was also effective.

Backgrounds/aims: Ampullary adenocarcinoma (AmpCA) has a greater overall survival (OS) rate than other periampullary cancers such as pancreatic cancer or bile duct cancer. Nevertheless, the OS of AmpCA is still poor. In the present study we evaluated the clinicopathologic features of AmpCA with respect to its impact on OS., Methodology: Records of 28 patients with AmpCA undergoing pancreaticoduodenectomy from 1995 to 2009 in Kyoto Prefectural University of Medicine were reviewed retrospectively. The mean age was 65.6 and mean +/- S.D. tumor size was 2.08 +/- 1.13 cm. Of the 28 patients, nine (32%) were > or = T3 tumors and nine (32%) were pN1 stage. There were seven (25%) cases of pancreatic invasion (Panc-invasion) and 15 (54%) cases of duodenal invasion (Du-invasion). Further, 14 (50%) cases involved lymphatic vessel invasion (ly+) and five (18%) cases involved histological blood vessel invasion (v+). Eleven (39%) patients experienced recurrences, of which eight were liver metastases. The median OS was 37 months (range 0.6-139.6 months) and the five-year survival rate was 56.4%. The clinicopathologic features and prognoses of these patients were analyzed and the prognostic factors determined., Results: On log-rank testing, Du-invasion (p = 0.029), ly+ (p = 0.022), and v+ (p < 0.001) were significantly associated with worse survival. According to multivariate Cox's hazard analysis using these three factors by Backward Elimination of Stepwise method, blood vessel invasion was the only significant prognostic indicator for survival (p = 0.046; Hazard ratio, 4.40)., Conclusions: Blood vessel invasion was an independent prognostic indicator, while prevention of liver metastases was important for longer survival.

In gastric cancer, several tumor suppressor and tumor-related genes are silenced by aberrant methylation. Previously, we demonstrated that BCL2L10, which belongs to the pro-apoptotic Bcl-2 family, was transcriptionally repressed by promoter hypermethylation and that its overexpression caused apoptosis and growth inhibition of gastric cancer cells. In this study, we investigated the methylation status of BCL2L10 and its expression in 21 gastric cancer tissues and corresponding non-neoplastic mucosae along with the methylation status of p16, RUNX3, and hMLH1 genes by using methylation specific PCR. In addition, we examined the association between the methylation status of each gene and the expression of EZH2, which was associated with DNA methylation of its target genes. As a result, aberrant methylation of BCL2L10 was detected in 38% of gastric cancer and in 24% of corresponding non-neoplastic mucosae and correlated with low expression of BCL2L10. Methylation of p16, RUNX3, and hMLH1 was found in gastric cancer and in corresponding non-neoplastic mucosae at almost similar frequencies as previous reports. Expression of EZH2 was detected more frequently in tumors (48%) as compared to corresponding non-neoplastic mucosae (10%) (p=0.006), however, no significant difference was found between expression of EZH2 and the methylation frequency of each gene. In conclusion, our data suggest that silencing of BCL2L10 by aberrant methylation is a common feature in gastric cancer and its inactivation may be involved in the early steps of gastric carcinogenesis.

Hepatocyte growth factor (HGF) has been shown to be involved in malignant behaviors, such as invasion and metastasis, in different tumors. Hence, HGF could be a target molecule for control of the malignant potential of cancer. NK4 is a competitive antagonist for HGF and exerts an antitumor activity, not only by HGF antagonism but also by antiangiogenesis. Here, we studied the participation of cellular immunity in CT26 tumor regression by NK4 gene transfer. In vivo experiments showed that NK4-induced inhibition of subcutaneous tumor growth (as demonstrated in immunocompetent BALB/c mice) was weakened in T lymphocyte-deficient nude mice. In addition, the immunocompetent BALB/c mice that had shown complete regression of CT26-NK4 tumors generated an immune memory against repeated challenge with the same tumor antigen. Immunohistochemistry of tumor-infiltrating lymphocytes showed that the ratio of CD8/CD4 in CT26-NK4 tumors was significantly higher than that in control tumors. Also, the presence of tumor-specific cytotoxic T lymphocytes (CTL) was demonstrated by cytotoxicity assays. Depletion of CD8+ T lymphocytes markedly abrogated the antitumor activity of NK4. However, NK4 had no direct effect on the in vitro cellular immune system. Taken together, these data indicate that NK4 expression by gene transfer, at the tumor site, triggers tumor-specific CTL activation, resulting in complete CT26 tumor regression in vivo. This action was considered to be due to apoptosis induced by NK4's potent antiangiogenic and HGF antagonistic effects., (Copyright (c) 2009 UICC.)

Objective: The purpose of this study was to investigate the diagnostic impact of preoperative serum p53 antibody (S-p53 Ab) in patients with endometrial cancer., Study Design: A hospital-based series of 67 patients, comprising 58 endometrioid adenocarcinomas (EA) and 9 serous adenocarcinomas (SA) between 1998-2002 were included. First, preoperative pathology was compared with final pathology in terms of histologic classification and tumor grade. Second, S-p53 Ab and CA125 were measured using preoperative serum samples, and immunohistochemical staining for p53 protein was assessed using hysterectomy specimens., Results: There were discrepancies between preoperative and final pathology in terms of histologic classification (7%) and tumor grade in EAs (30%); other objective tests, therefore, were needed to minimize the diagnostic problems. S-p53 Ab titers varied from 0.27-786 (mean, 124) in SAs and from 0.1-7.47 (mean, 0.46) U/mL in EAs, respectively, and were positive in 6 (67%) SAs and in 3 (6%) EAs using 1.3 U/mL as cut-off. S-p53 Ab-positive rate was significantly correlated with SA histology and grade 3 EA tumor (odds ratio, 40; P = .005; 95% confidence interval, 3.04-525.43) with higher sensitivity and higher specificity than p53 staining and CA125, respectively., Conclusion: S-p53 Ab could conveniently and specifically identify high-risk endometrial cancer.

Unlabelled: We examined the effect of the combination of herpes simplex virus type1-thymidine kinase (HSV-TK)-suicide gene therapy and interleukin-21 (IL-21) immune gene therapy., Materials and Methods: To improve tumor specificity and the safety of gene therapy, we designed the suicide gene (HSV-TK) to be driven by midkine (MK) minimal promoter (MKp-TK). Plasmid DNA containing HSV-TK-suicide gene or IL-21 gene was injected into TE2 and Colon26 tumors developed in nude mice and electric pulses were then delivered., Results: Tumors transduced with the MKp-TK gene demonstrated increased sensitivity to ganciclovir (GCV) in vitro and in vivo. MK minimal promoter conferred efficient transcriptional activity to the HSV-TK-suicide gene and in vivo electroporation was an effective method for transducing the MKp-TK gene. IL-21-transduced tumors disappeared completely in syngeneic BALB/c mice. However, the tumors were not suppressed completely in T-cell-depleted nude mice, and antitumor effects were absent in NK-cell-depleted mice. These data suggest that IL-21 induces T- and NK-cell-dependent antitumor effects. Furthermore, the growth of IL-21-producing tumors subsequently transduced with MKp-TK by electroporation was significantly retarded compared with control groups., Conclusion: Using the minimal promoter region of MK to drive the HSV-TK gene and in vivo electroporation to transduce IL-21 DNA into the tumors produced an efficient gene therapy with improved safety. To our knowledge, this is the first report of a combination gene therapy using HSV-TK/GCVand IL-21.

We have evaluated the 5-fluorouracil sensitivity of cancer cells from colorectal cancer patients using the collagen gel droplet embedded drug sensitivity test under multiple drug concentrations and contact durations. After converting drug concentration and contact time to the area under the curve (AUC) and plotting against the growth inhibition rate, the correlation between AUC and the growth inhibition rates was approximated to the logarithmic regression curve. In this study, to further validate the reliability of the regression curve, the growth inhibition rate was calculated from the regression curve and the actual growth inhibition rate was compared at AUC of 48 mug h/ml. No significant difference was observed in the growth inhibition rates between the two groups by paired t-test (P=0.590). A strong positive correlation was found between the two groups by regression analysis (y=0.7555x+10.514, R=0.8236). This result strongly suggests that in-vitro antitumor effect of 5-fluorouracil depends on the AUC in colorectal cancer and the AUC-inhibition rate curve is reliable. We can obtain the inhibition rate from AUC and vice versa using the AUC-inhibition rate curve. We can also calculate the individualized AUCIR50, AUC value that gives 50% growth inhibition, using the AUC-inhibition rate curve. This could be useful to establish individualized chemotherapy using the collagen gel droplet embedded drug sensitivity test.

Mono-(adenosine 5'-diphosphate) (ADP)-ribosylation, which transfers an ADP-ribose from nicotinamide adenine dinucleotide (NAD) to an acceptor protein, is an important post-translational modification of cellular proteins. Several bacterial toxins are known to possess the mono-ADP-ribosyltransferase activity to catalyze this reaction as a possible pathogenic factor. Therefore, the aim of this study was to examine whether H. pylori may also induce mono-ADP-ribosylation in a human gastric mucosal protein in association with gastric cancer development. Tumorous and adjacent non-tumorous mucosal tissue specimens were obtained from the surgically removed stomachs of 5 patients with gastric adenocarcinoma, and then were homogenized into cytosolic and membranous fractions. Each homogenate or an H. pylori extract was assayed for mono-ADP-ribosylation with [adenylate-(32)P]-NAD and 3-aminobenzamide, a potent inhibitor of poly-ADP-ribosylation. The radiolabeled proteins were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis followed by radio-image analysis. In the extracts from H. pylori, a strain-dependent, endogenous radiolabeling of 70-kDa protein was detected. An assay of the membranous fractions from 5 gastric adenocarcinomas with the extract of OMH4, a clinical H. pylori isolate, revealed notable radiolabelings of 55- and 45-kDa proteins, which were not found without the OMH4 extract. In contrast, the radiolabelings were minimal in the membranous fractions from respective non-tumorous mucosae, and they were not detected in any of the examined cytosolic fractions. All three radiolabelings of 70-, 55-, and 45-kDa proteins were dependent on NAD, but not on ADP-ribose. Snake venom phosphodiesterase digestion of the 3 radiolabeled proteins released only AMP. We thus found that H. pylori had an enzymatic mono-ADP-ribosyltransferase activity which enabled it to modify the 55- and 45-kDa membranous proteins of human gastric adenocarcinoma, as well as the 70-kDa protein of H. pylori itself. The possible roles underlying our observations on carcinogenesis or development of human gastric carcinoma are yet to be elucidated.

We investigated the feasibility, safety, biological activity and therapeutic efficacy of adenovirus-mediated p53 gene transfer in patients with chemoradiation resistant advanced esophageal carcinoma. Eligible patients were not surgical candidates and had measurable, advanced squamous cell carcinoma of the esophagus that was resistant to chemoradiation therapy. On a 28-day cycle, intratumoral injections of Ad5CMV-p53 (INGN 201; ADVEXIN) were administered on days 1 and 3 at four dose levels (10 x 10(11) particles to 25 x 10(11) particles) and treated for up to five cycles. Ten patients received a total of 26 cycles with no dose-limiting toxicity. Administration of multiple courses was feasible and well-tolerated. Local tumor responses revealed stable disease in nine cases and progressive disease in one case. The overall responses were stable in six and progressive in four cases. Using polymerase chain reaction (PCR) analyses, gene transfer and p53 specific transgene expression were detected in tumor biopsy tissue from all patients. mRNA levels of p53, p21 and MDM2 increased in all but one case. Three patients showed absence of disease upon repeat biopsies. Substantial improvement in swallowing was observed in one patient with stenotic lesions. Intratumoral injection of Ad5CMV-p53 is safe, feasible and biologically active when administered in multiple doses to patients with esophageal cancer. Observations from this study indicate that this treatment results in local antitumor effects in chemoradiation resistant esophageal squamous cell carcinoma.

Purpose: Clinical trials of carbon ion therapy have been performed due to the advantages of high-dose energy delivery with precise localization control to targeted organs and strong cell-killing activities to cancers. Perforated intestines as a late morbidity after carbon ion radiotherapy for uterine cancers were examined to reveal the biological characteristics of carbon ion for future applications for the treatment of gastrointestinal cancers., Methods: Between June 1995 and December 2004, 94 patients with carcinoma of the uterine cervix or corpus were treated with carbon ion therapy. Among them, 9 patients (9.6%) developed major late gastrointestinal (GI) complications. Four out of 9 patients had intestinal perforations excised operatively at our institute. The postoperative clinical courses and histopathological findings of the excised intestine were investigated., Results: Carbon ion irradiation severely damaged smooth muscle layers by coagulation necrosis as well as atrophy of the intestinal epithelium and middle-sized arterial thromboses of the intestines. After evaluating late complications, the dose constraints on the GI tracts were set under 60 GyE to prevent major complications. Thereafter, the incidence of major GI complications markedly decreased., Conclusion: Our findings demonstrated the characteristic histopathological effects of carbon ion radiotherapy and thus are expected to facilitate future additional applications of carbon ion radiotherapy for the treatment of gastrointestinal cancers.

We report herein a case with stage IV gastric cancer previously treated with TS-1 completely responding to second-line chemotherapy with weekly paclitaxel therapy. A 65-year-old female was diagnosed as having type 3 gastric cancer with para-aortic lymph node metastases. She underwent total gastrectomy with extended lymph node dissection on March 2003. Histopathological examination revealed that the tumor was poorly-differentiated adenocarcinoma with para-aortic lymph nodes metastases and completely resected. After the operation,she was treated by adjuvant chemotherapy with TS-1. In March of 2004, she suffered from hematuria, and a CT scan revealed para-aortic lymph nodes metastases and left kidney metastasis. Then, she was treated by a weekly infusion of paclitaxel as second-line chemotherapy. After 3 courses, the tumor disappeared and efficacy was judged as CR. Moreover, CR was maintained after 7 courses. At this writing in January of 2005, she is well and has been treated with paclitaxel without any severe adverse events. Therefore, weekly paclitaxel therapy was considered to be one of the promising second-line chemotherapies for advanced or recurrent gastric cancer previously treated by TS-1.

Comparative analysis of the diagnostic accuracy of FDG PET, single-voxel, and multi-voxel proton MRS for differentiation between radiation-induced necrosis and tumor recurrence was done in 9 patients with brain metastases treated by gamma knife radiosurgery. In all cases enlargement of the lesion and increase of the perilesional edema were demonstrated by MRI on average 10.6+/-2.6 months after initial treatment. Radiation-induced necrosis was identified in 5 patients (histologically in 2, clinically in 3). In one of these a false positive result of FDG PET was observed, whereas data of proton MRS were always correct. The diagnosis of tumor recurrence was established in 4 patients (histologically in 3, clinically in 1). Among these both FDG PET and single-voxel proton MRS showed false negative results (each method twice), whereas multi-voxel proton MRS always permitted us to establish the correct diagnosis. The present study demonstrates the higher diagnostic accuracy of multi-voxel proton MRS, in comparison with single-voxel proton MRS and FDG PET, for the differentiation of the radiation-induced necrosis and tumor recurrence. Its use is especially important in mixed lesions with co-existence of both post-irradiation changes and viable neoplasm. Monitoring of the treatment response by serial multi-voxel proton MRS seems to be reasonable during follow-up of patients with brain metastases after radiosurgery.

The monoclonal antibody A7 (Mab A7) against human colonic cancer also reacts with human gastric cancer at a high rate. We produced a conjugate of neocarzinostatin (NCS) with Mab A7 (A7-NCS). The in vitro anticancer effect of A7-NCS on the antigen-positive human gastric cancer cell line MKN45 was stronger than that of free NCS. Nude mice models of peritoneal dissemination were established by the intra-peritoneal inoculation of MKN45. These models were divided into three groups. The anticancer effect observed in the group that received the intra peritoneal injection of A7-NCS was superior to that observed in the group that received the intra-venous injection and the group that received no treatment. In conclusion, the intra-peritoneal injection of A7-NCS was a useful treatment method for the peritoneal dissemination of gastric cancer.

The patient was a 76-year-old man, diagnosed with sigmoid colon cancer with unresectable multible liver metastases. After sigmoidectomy with D2 regional lymphnode dissection on June 21, 2002 (moderately differentiated adenocarcinoma, ss, n(-), H3, P0, M(-), Stage IV), intermittent hepatic arterial infusion chemotherapy using 5-FU (1,250 mg/body/3 hr) and CDDP (10 mg/body/30 min) was performed weekly for 23 times, and then biweekly for 15 times. The total dosages of 5-FU were 47.5 g. During the regional chemotherapy, IFNANK therapy was performed biweekly as systemic immunotherapy. As a result, serum levels of tumor markers were remarkably decreased, and the metastatic liver tumors had disappeared in the CT finding in July 2003. Thereafter, IFNANK therapy was continued without the chemotherapy. However, CT and PET detected the recurrent liver tumors in December 2003, and the tumors were curatively resected on January 28, 2004.

Gastric cancer is one of the most common malignancies in the world, and in Asian countries its incidence and mortality rates are very high. Worldwide, Japan ranks first in the incidence of this type of cancer for both sexes. To shed light on the mechanisms underlying the development and/or progression of gastric cancer, we compared the expression profiles in gastric cancer cells obtained from surgical dissection of 20 gastric adenocarcinoma specimens with those in the corresponding non-cancerous mucosa, by cDNA microarray analysis. In total, 8,000 cDNA clones were randomly picked up and their 5'-end nucleotide sequences were determined. On the basis of sequence information, 4,608 independent clones were selected and used to produce the cDNA microarray. We identified 26 genes that were commonly up-regulated and 44 genes that were commonly down-regulated in cancerous tissues. To validate the cDNA microarray analysis, real-time PCR was performed. We found that gene S100A11 expression was associated with the development of lymph node metastases. S100A11 gene expression was clearly up-regulated in specimens from patients with lymph node metastases relative to those from patients without lymph node metastases. S100A11 gene expression status was useful to distinguish gastric cancers with lymph node metastases from those without lymph node metastasis. This genome-wide information contributes to an improved understanding of molecular changes during the development of gastric cancers. It may also help clinicians predict the development of lymph node metastases and assist researchers in identifying novel therapeutic targets for patients with gastric cancer.

Intrabiliary growth of liver metastases from colorectal cancer has rarely been studied. A surgically resected case of a metastatic liver tumor with prominent intrabiliary growth derived from rectal cancer is reported. The patient was a 62-year-old man who had received a low anterior resection for rectal cancer in March 2000. He was re-admitted due to obstructive jaundice in January 2003, and was diagnosed with hepatic malignancy in segment II of the liver with an intrabiliary tumor extending from the intrahepatic bile duct of segment II to the common hepatic duct. He underwent a left hepatectomy, a partial resection of segment VI, and an extrahepatic bile duct resection with reconstruction of the biliary tract. In the resected specimen, there were whitish tumors of 3 cm and 1.5 cm in diameter in segments II and VI, respectively, and an intrabiliary tumor originating from the main tumor in segment II extended to the common hepatic duct. Both the liver tumors and the intrabiliary tumor consisted of a well- to moderately differentiated adenocarcinoma, which showed the same histological features as the rectal cancer. The immunohistochemical findings strongly supported that these tumors, including the intrabiliary growth, were liver metastasis from the rectal cancer. The intrabiliary invasion and growth of metastatic liver tumors has generally been overlooked, notwithstanding their frequently observed biological behavior. The present case is informative, and further investigation into this type of metastatic liver tumor may be warranted.

We conducted a clinical study of cancer vaccine therapy with dendritic cells (DCs) and HLA-A24-restricted carcinoembryonic antigen (CEA)-derived peptide to assess the feasibility and efficacy of such therapy. Eighteen patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinomas who were positive for human leukocyte antigen (HLA)-A24 were enrolled. DCs were generated from the patients' autologous monocyte-enriched fractions of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. The generated DCs were pulsed with CEA-derived, HLA-A24-restricted 9-mer peptide (CEA652) and injected into the patients intradermally and subcutaneously every 2 weeks. Toxicity and clinical and immunological responses were closely monitored in each patient. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. Although no definite tumor shrinkage occurred in any patient, long-term stable disease or marked decreases in the serum CEA level were observed in some patients after therapy. Most of the patients in whom treatment was clinically effective showed a positive skin response to CEA652-pulsed DCs (delayed-type hypersensitivity skin test) and a positive in vitro CTL response to CEA652 peptide after therapy. We conclude that active specific immunotherapy using DCs pulsed with CEA652 is a safe and feasible treatment that is clinically effective in some patients with metastatic gastrointestinal or lung adenocarcinomas. Our results will hopefully encourage further refinement and development of DC-based immunotherapy with HLA-A24-restricted CEA-derived peptide for refractory solid cancers that express CEA.

The patient was a 58-year-old female who had a cancer of the rectum with multiple lymph node metastases including paraaortic lymph nodes and Virchow lymph nodes. Abdominoperineal resection was performed palliatively. After the operation, weekly bolus of 5-fluorouracil combined with levofolinate was carried out. After 2 courses of chemotherapy, metastases of paraaortic lymph nodes and Virchow lymph nodes completely disappeared upon CT examination. Chemotherapy has continued for 14 months, and she is well and has maintained a complete response for more than 1 year. This case suggests that this combination chemotherapy of LV/5-FU, admitted in Japan, is effective against advanced colorectal cancer.

Background: Increasing evidence supports the sentinel lymph node (SN) concept for melanoma and breast cancers. SN biopsy may replace routine lymph node dissection in the treatment of these cancers. But there are little data evaluating this concept in patients with gastric cancer. The objective of this study was to test the feasibility of SN mapping in gastric cancers by using the dual-mapping procedure with dye and radioactive colloid., Study Design: Thirty-one consecutive patients preoperatively diagnosed as T1-2 and N0 underwent SN biopsy using the dual-mapping procedure. Distributions of SNs identified by the dye-guided technique (blue nodes; BNs) were compared with those identified by the gamma probe guided technique (hot nodes; HNs)., Results: Among the 31 patients, 7 were found to have lymph node metastases. All positive nodes were detected by SN biopsy using the dual method. So, an accuracy rate of 100% was achieved in predicting the status of regional lymph nodes. Both BNs and HNs were identified in 28 of 31 patients (90%), but significant discrepancy of distribution was noted between BNs and HNs. Among the 28 patients with identified BNs, there was one metastasis in a non-BN. So the accuracy rate was 96% for the dye-guided technique. In contrast, among the 28 patients with identified HNs, 2 patients had metastasis in non-HNs, making the accuracy rate 93% for the gamma probe-guided technique., Conclusions: SN mapping is feasible in gastric cancer, but the dye-guided and gamma probe-guided techniques are complementary. So we recommend the dual-mapping procedure., (Copyright 2003 by the American College of Surgeons)

Background: The prognostic value of the number of metastatic lymph nodes in early gastric cancer has not been evaluated much, although the significance of metastatic lymph nodes is defined by the location of positive nodes, according to the JRSGC for gastric cancer., Methods: The postoperative courses of 305 early gastric cancer patients who had undergone D2-extended lymphadenectomy were followed up for a median of 108 months to evaluate the significance of the number of metastatic lymph nodes on recurrence of the disease., Results: Recurrence of gastric cancer was more frequently observed in submucosal cancer than in mucosal cancer. All patients but one who revealed recurrence had nodal metastasis at the time of surgery. In cases with 1-3 metastatic lymph nodes, no patient had revealed any sign of recurrence; however, in cases with 4 or more metastatic lymph nodes, 6 of 7 patients died of recurrent disease. There were 3 cases of bone metastases, 2 of peritoneal dissemination, and 1 each of both recurrent diseases., Conclusions: These data suggest that in n-positive cases, in which there are 4 or more metastatic lymph nodes, there is a high probability of recurrence of early gastric cancer, and especially of hematogenic metastasis., (Copyright 2003 S. Karger AG, Basel)

A 46-year-old man underwent polypectomy of sigmoid colon in January 1996. The adenocarcinoma invaded the submucosal layer, and sigmoidectomy and D2 lymph node dissection were performed one month later. Follow-up CT revealed liver metastases, and partial hepatectomy was performed in January 1998. Afterward, weekly high dose intra-hepatic arterial chemotherapy (5-FU: 1,000 mg/body) was performed 41 times, but CT revealed multiple liver metastases in October 1998. Therefore, intra-hepatic arterial infusion of mitomycin C (MMC) with degradable starch microspheres (DSM) was given in November 1998. As follow-up CT revealed that the liver metastases were growing, partial hepatectomy was performed again in March 1999. No carcinoma was seen in the resected liver. After the second hepatectomy, intra-hepatic arterial infusion of MMC with DSM was performed five times. No evidence of recurrence has been seen. Intra-hepatic arterial infusion of MMC with DSM is recommended for liver metastases of colorectal cancer as a second line treatment.

Background: Mutation of the p53 gene is a genetic alteration found in human cancers. Overexpression of p53 has been found to induce antibody production in serum, and, recently, the simple detection of serum antibody has been made possible. The aim of this study was to evaluate the potential role of serum p53 antibody in the early diagnosis of superficial colorectal cancer and in the monitoring of its treatment after endoscopic resection., Methods: In a prospective study, our subjects were 27 patients with superficial colorectal adenocarcinomas, whose results were compared with those in 38 patients with benign adenomas; all patients were treated by endoscopic resection. The correlation between serum p53 antibody levels before and within 3 weeks after resection was determined, using an immunoassay. Immunohistological staining for p53 was also performed, and its sensitivity was compared with that of two other tumor markers., Results: Preoperatively, serum p53 antibody was detected in 63.0% (17/27) patients with adenocarcinoma and in 2.6% (1/38) patients with adenoma, showing a significant difference (P < 0.001). However, the two other markers carcinoembryonic antigen (CEA) and carbohydrate antigen CA19-9, showed no significant difference between superficial colorectal adenocarcinoma and adenoma. The serum p53 antibody status was strongly correlated with p53 immunostaining in adenocarcinoma (P = 0.0065), but there was no significant correlation in adenoma (P = 0.973). Sixteen (94.1%) of 17 seropositive adenocarcinoma patients, showed negative conversion after complete tumor resection, and all these 16 patients remained seronegative., Conclusion: The detection of serum p53 antibody is expected to serve as a new genetic marker, determined by serological analyses, for aiding in the early diagnosis of superficial colorectal cancer and indicating its local curability after endoscopic treatment.

Background and Objectives: Alteration of the p53 gene product occurs frequently during progression of colorectal cancer. Recently, mutated p53 protein was found to induce the production of anti-p53 antibodies in the serum of patients. The purpose of this study was to evaluate the relationship between p53 status in serum and chemosensitivity in resectable colorectal cancer patients., Methods: A total of 22 patients with primary colorectal cancer who underwent surgical treatment were examined for chemosensitivity with iable tumor samples using the Histoculture Drug Response Assay (HDRA). Serum samples of these patients for p53 antibodies were obtained before tumor resection and assayed in duplicate using an enzyme-linked immunosorbent assay kit., Results: The inhibition index of 5-fluorouracil and cis-diamminedichloroplatinum (CDDP), determined by the HDRA method, in the seropositive group was significantly lower than that in the seronegative group (P < 0.01). Furthermore, significant statistical differences in chemosensitivity to 5-fluorouracil and CDDP were revealed depending on the presence of serum p53 antibodies., Conclusions: Detection of serum p53 antibodies, which reflects p53 mutations in tumor tissue, is a simpler method which correlates with chemosensitivity and may contribute to the selection of favorable chemotherapeutic strategies for colorectal cancer.

The presence of circulating anti-p53 antibodies (p53Ab) was investigated in 81 gastric cancer patients by ELISA. Preoperatively, anti-p53Ab were revealed in 13 cases (16%), including 3 early gastric cancers. No significant correlation of p53Ab with patient age, sex, pathological parameters and tumor markers, such as CEA and CA19-9 was observed, although p53Ab positivity tended to be associated with a higher rate of lymph node metastases (p = 0.073). We have found no significant correlation between p53Ab and poor survival rate (p = 0.325). In conclusion, we have observed that p53Ab are detectable in gastric cancer patients, even at early stages of disease, however, p53Ab have not served as a predictor of poor prognosis in gastric cancer in this series.

The most important factor influencing the use of monoclonal antibody immunoconjugates for cancer treatment is effectiveness of enhancement for tumor targeting. We call attention to the vasoactive agents angiotensin II (ATII) for selective increase in tumor blood flow and cytokine tumor necrosis factor (TNF) to improve the vascular permeability of the tumor. Tumor localization and biodistribution were investigated by nude mice transplanted human colon adenocarcinoma (LS-180) with radiolabeled carboplatin immunoconjugates. Tumor activity 48 h after administration of ATII and TNF was significantly higher than in the control group. However, nonspecific accumulation in normal organs was not observed. In vivo anti-tumor effects in animals with ATII and TNF was significantly stronger than in those given the same dose drug alone or immunoconjugates alone. These results indicate that ATII and TNF could be useful tools for induction of stronger inhibition of tumor growth without systemic toxicity.

Purpose: To establish the indications for proximal resection with dissection of perigastric lymph nodes in order to treat adenocarcinoma of the gastric cardia., Methods: We analyzed the clinicopathological features of 110 resected adenocarcinomas of the gastric cardia with respect to the appropriate operative method and extent of lymphadenectomy for treatment., Results: Of the 110 patients, 93 underwent curative resection. The D2 group (total gastrectomy with dissection of extended regional lymph nodes) revealed higher morbidity and mortality rates compared to the D1 group (proximal resection with dissection of perigastric lymph nodes). The risk of lymph node metastasis was determined by depth of invasion, size of tumors, and gross findings of tumors., Conclusion: The appropriate operative method for adenocarcinoma of the gastric cardia requires: (i) tumor size less than 4 cm; and (ii) gross findings indicating a superficial type of lesion, which are recommended for proximal resection with dissection of perigastric lymph nodes.

We have examined the antitumor effect of the retrovirally expressed interleukin-2 (IL-2) gene in murine colon carcinoma cells (Colon 26) on a disseminated model within the peritoneal cavity. Intraperitoneal injection of IL-2-producing Colon 26, but not wild-type cells, into syngeneic mice did not cause animal death and conferred T-cell-dependent, tumor-specific protective immunity on the inoculated mice. Direct administration of the retrovirus harboring IL-2 gene into the peritoneal cavity of the mice that had intraperitoneal tumor of wild-type cells significantly prolonged the survival of the mice compared with that of the mice that received control retrovirus. In the surviving mice treated with the retrovirus we also observed the induction of protective immunity with tumor specificity. Integrated retrovirus DNA was not detected in any organs examined. Thus, in vivo IL-2 gene transfer by retrovirus enabled tumor-bearing mice to generate antitumor immunity without unnecessary retroviral insertion into host genome.