Selection of Lymph Node-Positive Cases Based on Perirectal and Lateral Pelvic Lymph Nodes Using Magnetic Resonance Imaging: Study of the Japanese Society for Cancer of the Colon and Rectum.

PURPOSE: To investigate the optimum cutoff for lymph node size to identify cases positive for perirectal lymph node (PRLN) and lateral lymph node (LPLN) metastasis of lower rectal cancer on magnetic resonance imaging (MRI). METHODS: The subjects were 449 patients who underwent preoperative MRI. Mesorectal excision was performed in all patients (combined with lateral pelvic lymph node [LN] dissection in 324) between 2004 and 2013 at 6 institutes. Cases were classified as cN positive and cN negative on the basis of the short axis of the largest LN being greater than or equal to a cutoff or less than a cutoff, respectively. PRLN and LPLN diagnoses using 5 and 10 mm cutoffs were compared with histologic diagnoses. Of the 449 patients, 55 received preoperative chemoradiotherapy. MRI was only performed after this therapy in all of these patients. RESULTS: For PRLNs, 5 and 10 mm cutoffs gave area under the curve (AUC) values of 0.6364 and 0.5794, respectively. The 5 mm cutoff gave a significantly higher AUC value (P = 0.0152), with an accuracy of 63.7 %, sensitivity of 72.6 %, and specificity of 54.7 %. For right LPLNs, the respective AUC values were 0.7418 and 0.6326 (P = 0.0034), and the variables (5 mm cutoff) were 77.6, 68.6, and 79.7 %. For left LPLNs, AUC values were 0.7593 and 0.6559, respectively (P = 0.0057), and the variables (5 mm cutoff) were 79.3, 70.8, and 81.0 %. CONCLUSIONS: Identification of LN-positive cases on the basis of PRLN and LPLN sizes was superior at a short-axis 5 mm cutoff. Size-based diagnosis of LN metastasis is simple and useful, but further investigation is needed to clarify whether it is superior to diagnosis based on morphology, such as shape, border, and signal intensity.

OSNA-Assisted Molecular Staging in Colorectal Cancer: A Prospective Multicenter Trial in Japan.

BACKGROUND: We previously reported that the one-step nucleic acid amplification (OSNA) assay provided a judgment performance for colorectal cancer equivalent to a 2-mm-interval histopathological examination of lymph nodes (concordance 97.1 %, n = 385 lymph nodes). In this prospective multicenter study, we uncovered an OSNA-assisted pathology to detect lymph node metastasis. METHODS: A total of 204 (50 stage I, 74 stage II, and 80 stage III) colorectal cancer patients. All 4324 lymph nodes were examined by the standard histology (one-slice H&E staining) and 1925 lymph nodes (44.5 %) of them were also subject to the OSNA analysis. RESULTS: The concordance rate between 1 slice hematoxylin/eosin and OSNA assay was 95.7 % (1,842/1925 lymph nodes). The sensitivity and specificity of the OSNA assay were 86.2 % (125/145) and 96.5 % (1717/1780), respectively. Among 124 node-negative patients (pN0), the respective upstaging rates of pStages I, IIA, IIB, and IIC were 2.0 % (1/50), 17.7 % (11/62), 12.5 % (1/8), and 25 % (1/4). OSNA-positive patients had deeper invasion to the colonic wall and severe lymphatic invasion (P = 0.048 and P = 0.004, respectively). The sum of the quantitative results of OSNA and total tumor load increased as the number of metastasized lymph nodes increased: 1550 copies/µL in pN0, 24,050 copies/µL in pN1, and 90,600 copies/µL in pN2. CONCLUSIONS: The present study on colorectal cancer provided fundamental data regarding OSNA-assisted pathology of lymph node metastasis in Japan.

A multicenter phase II trial of mFOLFOX6 plus bevacizumab to treat liver-only metastases of colorectal cancer that are unsuitable for upfront resection (TRICC0808).

BACKGROUND: A phase II clinical trial was conducted on colorectal cancer patients with only liver metastases (focal diameter exceeds 5 cm or the number of liver metastases is ≥5; H2·H3) to evaluate the liver resection rate and safety after 6 cycles of mFOLFOX6+bevacizumab (BV) therapy. METHODS: mFOLFOX6+BV therapy was applied for 6 cycles to the patients with H2·H3 liver only metastasis. Hepatectomy was considered after the sixth cycle as a rule, and was performed if possible. The primary endpoint was the curative hepatectomy rate (R0 resection rate). RESULTS: Forty-six patients were registered and 45 patients were included in the efficacy analysis. Of the 19 patients rated as unresectable before therapy, 18 completed 6 cycles of mFOLFOX6+BV therapy and subsequently underwent hepatectomy (16 were R0-resected). Of the 26 initially unresectable patients, 6 underwent hepatectomy (4 were RO-resected). The overall R0 resection rate was 44.4% (20/45). Chemotherapy-associated grade 3 or higher adverse events included neutrophil decreased (17.4%) and leukocyte decreased (8.7%), fatigue (6.5%) etc. Only hypertension (6.5%) and venous thromboembolism (2.2%) were BV-associated grade 3 or higher adverse events. Among the 25 patients who underwent hepatectomy, intraoperative/postoperative complications included grade 3 wound infections (2 cases), biloma, delayed wound healing and intraperitoneal abscess (each 1 case). CONCLUSIONS: In colorectal cancer patients with liver-only metastases, mFOLFOX6+ BV therapy yielded a high hepatectomy rate and a high percentage of initially unresectable and subsequently resectable cases. The chemotherapy associated adverse events and hepatectomy complications were both within acceptable ranges.

Proposal of a new prognostic staging system for pulmonary metastases from colorectal cancer.

PURPOSE: The aim of this retrospective study was to establish a new prognostic staging system for pulmonary metastases from colorectal carcinoma (CRC). METHODS: The baseline characteristics and outcomes on 352 CRC patients who underwent complete pulmonary resection were collected from 19 institutions by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Study Group (group A). The clinical and pathological factors were entered into a multivariate analysis to identify independent variables that were helpful for accurately predicting the long-term prognosis after pulmonary resection. Using the selected variables in group A, we developed a new prognostic staging system (PSS). The new PSS was examined in a validation study in a series of 841 patients from 110 institutions of the JSCCR by the 78th society of the JSCCR (group B). RESULTS: We evaluated four variables selected in the multivariate analysis: the number of pulmonary metastases, the distribution, the disease-free interval and the lymph node metastases of primary cancer in group A. Using these four variables, we developed a new PSS. This PSS was found to significantly predict the prognosis in group B. CONCLUSIONS: Our new PSS was useful for the selection of patients suitable for pulmonary resection.

Fatty acid synthase inhibitor C75 ameliorates experimental colitis.

Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or dimethyl sulfoxide (DMSO) (vehicle) was administered intraperitoneally from d 2 to 6. Clinical parameters were monitored daily. Mice were euthanized on d 8 for histological evaluation and measurements of colon length, chemokine, cytokine and inflammatory mediator expression. C75 significantly reduced body weight loss from 23% to 15% on d 8, compared with the vehicle group. The fecal bleeding, diarrhea and colon histological damage scores in the C75-treated group were significantly lower than scores in the vehicle animals. Colon shortening was significantly improved after C75 treatment. C75 protected colon tissues from DSS-induced apoptosis by inhibiting caspase-3 activity. Macrophage inflammatory protein 2, keratinocyte-derived chemokine, myeloperoxidase activity and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1ß and IL-6) in the colon were significantly downregulated in the C75-treated group, compared with the vehicle group. Treatment with C75 in colitis mice inhibited the elevation of FASN, cyclooxygenase-2 and inducible nitric oxide synthase expression as well as IκB degradation in colon tissues. C75 administration alleviates the severity of colon damage and inhibits the activation of inflammatory pathways in DSS-induced colitis. Thus, inhibition of FASN may represent an attractive therapeutic potential for treating IBD.

Lateral pelvic lymph node dissection can be omitted in lower rectal cancer in which the longest lateral pelvic and perirectal lymph node is less than 5 mm on MRI.

BACKGROUND AND OBJECTIVES: The goal of the study was to examine the use of magnetic resonance imaging (MRI) for identification of patients with lower rectal cancer who may benefit from lateral pelvic lymph node dissection (LPLD). METHODS: Diagnoses and oncological outcomes were examined in 160 cases. Patients in whom the long-axis diameter of the longest detected lymph node was < 5 mm or ≥ 5 mm were classified as LPLN(-) (n = 102) and LPLN(+) (n = 58), respectively. RESULTS: Diagnostic results gave a 21.6% positive predictive value (PPV) and a 95.0% negative predictive value (NPV) for the LPLN. These values were 59.6% and 91.5%, respectively, for the perirectal lymph node (PRLN). Multivariate analysis showed that a pathologic PRLN (pPRLN)(+) status was an independent prognostic factor for relapse-free survival (RFS) (P = 0.0424) in the LPLN(-) group. The 5-year RFS did not differ significantly between cases that did not and did undergo LPLD (90.0% vs. 83.8%) in the LPLN(-) and pPRLN(-) groups. CONCLUSIONS: The low PPV and high NPV indicate that it is difficult to identify patients who may benefit from LPLD. However, the results show that LPLD has no benefit in LPLN(-) and PRLN(-) cases and that these cases can be identified based on MRI findings.

Japanese D3 lymph node dissection in low rectal cancer with inferior mesenteric lymph node metastases.

BACKGROUND: There is currently no consensus on the significance of Japanese D3 lymph node dissection in low rectal cancer with inferior mesenteric lymph node (IMLN) metastasis. This is partly because, despite a number of studies on the subject, cases of IMLN metastasis are relatively rare, and there are few cases of curative resection because of metastasis to other organs. A retrospective study involving a large number of patients was conducted. METHODS: The subjects were 2,743 patients registered in the national registry of the Japanese Society for Cancer of the Colon and Rectum. The data were analyzed for (1) prognostic factors for IMLN metastasis, and (2) outcomes in R0 cases with IMLN metastasis. RESULTS: In the control group, 67 patients (2.7 %) were considered positive for IMLN metastasis. The outcomes in the 35 R0 cases with IMLN metastasis were 50.8 % for 5-year relapse-free survival (RFS) and 61.9 % for 5-year overall survival (OS), which were each better than for R1+R2 cases (5-year RFS 16.1 %, p = 0.0001; 5-year OS 26.7 %, p = 0.0002). The outcomes for R0 cases (total metastatic lymph nodes ≥7) with IMLN metastasis (5-year RFS 53.9 %, 5-year OS 68.8 %) did not differ significantly from those for IMLN(-) cases (5-year RFS 54.6 %, 5-year OS 57.1 %) (RFS: p = 0.9515, OS: p = 0.4621). CONCLUSIONS: It was confirmed that cases of IMLN metastasis in low rectal cancer tend to have a large total number of metastatic lymph nodes, but if curative resection can be performed, a good prognosis can be expected. These results demonstrate the value of radical Japanese D3 lymph node dissection in low rectal cancer with IMLN metastasis.

Intraoperative diagnosis of lymph node metastasis by transcription-reverse transcription concerted reaction assay in gastric cancer.

BACKGROUND: Increasing evidence has been accumulated to substantiate the clinical usefulness of quantitative evaluation of gene expression. This study was undertaken to assess diagnosis of metastasis in dissected lymph nodes through quantitative evaluation of the expression of carcinoembryonic antigen mRNA (CEA mRNA) by a rapid, simple transcription-reverse transcription concerted reaction (TRC) assay using dissected lymph node washings. METHODS: A total of 110 dissected lymph nodes from 40 patients undergoing surgery for gastric cancer were studied. Each dissected lymph node was cut crosswise and washed with physiological saline. The washings were assayed for CEA mRNA and the assay results were assessed in comparison with the pathological diagnosis [hematoxylin and eosin (H&E) staining]. All lymph nodes were also subjected to immunostaining for cytokeratin (CK staining) and assessed comparatively. RESULTS: By H&E staining, 29 lymph nodes were found to be positive and 81 to be negative for metastasis. By TRC assay, 38 lymph nodes were found to be positive and 72 to be negative. According to the results of CK staining, there were 37 metastasis-positive lymph nodes and 73 negative nodes. The sensitivity and specificity of H&E staining relative to those of CK staining were 78.4 and 100 %, respectively, while the sensitivity and specificity of TRC assay relative to those of CK staining were 91.9 and 94.5 %, respectively. CONCLUSIONS: The TRC assay method using lymph node washings is a rapid, simple genetic diagnosis with greater sensitivity than conventional diagnosis by H&E staining of permanent specimens, and enables conservation of lymph nodes in toto as permanent specimens. This TRC method would enable rapid diagnosis even in town hospitals where no pathologist is ordinarily stationed, and is considered to contribute to the clinical application of the sentinel node theory of gastric cancer treatment.

Usefulness of the TRC method in the peritoneal washing cytology for gastric cancer.

BACKGROUND: Peritoneal dissemination from gastric cancer is the most frequent metastasis of advanced gastric cancer. Detection of cancer micrometastasis is required for improvement of cancer therapy. A method that can detect micrometastases more sensitively is desired. Against this background, for the purposes of making the genetic diagnosis of micrometastasis simple and rapid, TRC (transcription reverse transcription concerted reaction) was developed. METHODOLOGY: 69 patients with gastric cancer in those diagnosed with deeper than mp. At the time of surgery, peritoneal washing with saline was extracted. Having extracted the RNA therein, It was blended with a reagent responsive to CEAmRNA and was put into TRC. The cytology and TRC were compared and studied. RESULTS: The concordance rate between TRC and cytology was K=0.6552. The patients whom there was a discrepancy between the cytology and TRC are clinically validate the TRC results. In the study of prognosis, TRC obtained a sensitivity of 90.9% and a specificity of 98.3%. CONCLUSION: The measurement of CEAmRNA in peritoneal washing specimens by the TRC method is superior to Cytology. That is also equal to or superior to the RT-PCR method with respect to sensitivity and specificity, and superior with respect to simplicity and rapidity.

Importance of the Postoperative Carcinoembryonic Antigen Level during Follow-Up after Curative Resection in Patients with Liver Metastatic Colorectal Carcinoma.

BACKGROUND/AIMS: To validate the conventional Japanese grading of liver metastasis for no residual tumor resection in Stage IV colorectal cancer (CRC) with liver metastasis and to identify risk factors for postoperative recurrence. METHODOLOGY: The subjects of this study were 1792 Stage IV CRC patients with liver metastasis. RESULTS: In 1792 cases, including unresectable cases, there was a significantly different prognosis by grade (P < 0.0001). In 421 R0 cases, there was no significant difference between Grade A and Grade B (P = 0.8527). In 381 cases without extra-hepatic metastasis, the prognosis was not significantly different among three grades. On multivariate analysis, carcinoembryonic antigen within 3 months from R0 operation (3M-CEA) was an independent risk factor regardless of extrahepatic metastasis. There was a significantly different prognosis (P < 0.0001) among Grade A', defined as a normal 3M-CEA level, Grade B', defined as Grade A or B and an abnormal 3M-CEA level, and Grade C', defined as Grade C and an abnormal 3M-CEA level. CONCLUSIONS: The postoperative CEA level is an important risk factor during follow-up after curative resection in patients with liver metastatic colorectal carcinoma. The combination of the 3M-CEA level and conventional grading of liver metastasis is useful for follow-up of R0 resection cases.

Positive peritoneal washing cytology is a potential risk factor for the recurrence of curatively resected colorectal cancer.

PURPOSES: Whether free peritoneal cancer cells should be considered peritoneal dissemination in colorectal cancer patients remains controversial. The aim of this study was to investigate the clinical significance of positive peritoneal washing cytology (PWC) in patients with colorectal cancer. METHODS: We retrospectively analyzed the records of 771 sequential patients diagnosed with stage 0-III colorectal cancer who underwent R0 resection and had no distant metastases or peritoneal dissemination. RESULTS: PWC was performed on all 771 patients. Sixty-eight patients experienced metastasis recurrence, 10 of whom experienced peritoneal recurrence. Of the 10 patients with peritoneal recurrence, 6 had positive PWC. Out of the 771 patients, 21 had positive PWC. Of these 21 patients, 6 had peritoneal recurrence, while 4 had distant metastasis and no peritoneal recurrence during the observation period. The 5-year disease-free survival was 89.0 % in the patients with negative PWC vs. 46.8 % in the patients with positive PWC (p < 0.0001, log-rank test). A Cox proportional hazards model revealed that positive PWC was the strongest independent risk factor for cancer-specific recurrence. CONCLUSIONS: Our study highlights PWC as a useful prognostic tool in patients undergoing curative surgery for colorectal cancer, since positive PWC was shown to be a potential risk factor for recurrence.

Sub-classification of Stage II colorectal cancer based on clinicopathological risk factors for recurrence.

PURPOSE: To make a Stage II colorectal cancer (CRC) sub-classification based on clinicopathological factors. METHODS: The subjects of this study were 422 patients with Stage II CRC, who underwent curative surgery with dissection of more than 12 lymph nodes. We used the logistic regression analysis or model and Cox's proportional hazard regression model for analysis. RESULTS: Preoperative carcinoembryonic antigen (CEA) level (p = 0.0057), macroscopic type (p = 0.0316), and depth of invasion (p = 0.0401) were extracted as independent risk factors for recurrence, whereas the preoperative CEA level (p = 0.0045) and depth of invasion (p = 0.0395) were extracted as independent predictors of 5-year disease-free survival. We defined depth of invasion (pT4) and the preoperative CEA level (abnormal) as risk factors for recurrence, and classified Grade A as a normal CEA level regardless of depth invasion, Grade B as depth of invasion to pT3 and an elevated CEA level, and Grade C as depth of invasion to pT4 and an elevated CEA level. There were significant differences in cumulative 5-year disease-free survival rates among each grade (Grade A vs. Grade B, p = 0.0474; Grade A vs. Grade C, p < 0.0001; Grade B vs. Grade C, p = 0.0134). CONCLUSION: The sub-classification of Stage II CRC, according not only to depth of invasion but also to preoperative CEA level, is important for predicting the prognosis.

Treatment strategy for preventing pouchitis as a postoperative complication of ulcerative colitis: the significance of the management of cuffitis.

PURPOSE: The aim of this study was to examine the risk factors for and to evaluate strategies for preventing pouchitis as a postoperative complication of ulcerative colitis (UC). METHODS: A total of 119 cases of UC in which restorative proctocolectomy with an ileal pouch-anal anastomosis (IPAA) was performed at our institution between 2000 and 2012 was investigated; nine patients in whom it was impossible to close the ileostomy due to an intractable anal fistula or pelvic abscess were excluded. RESULTS: The cumulative risk of developing pouchitis 5 years after IPAA with stoma closure was 31.0%. Significant relationships with pouchitis were found for the surgical indication (p = 0.0126) and surgical method (p = 0.0214). A significant correlation was found between pouchitis and cuffitis. Pouchitis was significantly more common in the cases with cuffitis than in those without (p = 0.0002). There was also a significantly different cumulative incidence observed between the cases with and without cuffitis (p < 0.0001). In addition, pouchitis had a greater tendency to recur in the cases with cuffitis than in those without (p = 0.2730). CONCLUSION: The cumulative incidence rate of pouchitis was 10.6% at 1 year, 15.1% at 2 years and 31.0% at 5 years. Controlling cuffitis is important to prevent pouchitis.

The relevance of the intrinsic subtype to the clinicopathological features and biomarkers in Japanese breast cancer patients.

BACKGROUND: Breast cancer is a disease rich in diversity, and it can be categorized into the immunohistochemical intrinsic subtypes : ER/PR + and HER2-, ER/PR + and HER2+, HER2 type, basal-like and unclassified. METHODS: In this study, in addition to the clinicopathological features potentially associated with the intrinsic subtypes, protein expression and genetic mutations of key molecules associated with breast cancer prognosis and treatment sensitivity were analyzed. The distribution of subtypes in the patient population and the differences in marker distribution across the subtypes were investigated. RESULTS: The immunohistochemical features of 471 consecutive surgical cases of women with primary breast cancer, treated in a single institution, were examined. There were 306 patients who were ER/PR + HER2- (65%); 41 who were ER/PR + HER2+ (8.7%); 59 with HER2 type (12.5%); 37 with basal-like (7.9%); and 28 patients whose breast cancer was unclassified (5.9%). There were no significant differences between the subtypes regarding age, menopausal status, disease stage, lymphatic invasion, blood vessel invasion and lymph node metastasis. Statistically significant differences were found for histological type and grade. Regarding protein expression and genetic mutation, significant differences were found in the distribution within each subtype for six out of 12 molecules investigated. CONCLUSIONS: This study revealed that subtypes differ not only in their clinical pathological profiles, such as histological types and histological grades, but also in molecular expression. The molecular expression patterns observed for each intrinsic subtype may help the selection of an optimal treatment strategy.

Analysis of the mRNA expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) in liver metastases from colorectal cancer.

BACKGROUND/AIMS: We measured the mRNA expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) in liver metastases from colorectal cancer and retrospectively analyzed their association with other clinicopathological factors and the prognosis of these patients. METHODOLOGY: The study involved 55 patients of colorectal cancer with liver metastasis who underwent surgery at our department between February 1988 and April 2003. RESULTS: Analysis of the mRNA expression levels of each of the aforementioned enzymes in the liver metastases revealed no significant differences in the mRNA expression levels of the enzymes depending on the timing of development of the liver metastasis, histological type of the cancer, or the patient gender. In the analysis of the survival period, no association was observed between the survival prognosis and the mRNA expression level of DPD or OPRT in the liver metastases; on the other hand, the prognosis was better in the group showing low TS mRNA expression (median survival period: 3.77 years) than in the group showing high TS mRNA expression (median survival period: 2.39 years) (p=0.0134). CONCLUSIONS: These results suggest that the mRNA expression level of TS in the liver metastases in colorectal cancer patients is a useful prognostic indicator.

Clinical outcome of esophagogastrostomy after proximal gastrectomy for gastric cancer.

BACKGROUND/AIMS: In order to prevent reflux esophagitis after proximal gastrectomy, reconstruction by jejunal interposition (EJ) is often performed; however, this procedure is considered to be extremely complex. The purpose of this research is to consider the indication and usefulness of esophagogastrostomy (EG), as a less-invasive method of reconstruction. METHODOLOGY: From 1999, 64 proximal gastrectomy cases have been reviewed. In 46 cases, EG combined with a reflux prevention procedure was performed while in the remaining 18 cases, EJ was performed. An endoscopic examination was conducted 1 year after surgery in all cases. RESULTS: Compared to EJ, EG required less surgical time, thus resulting in less blood loss. Reflux esophagitis was frequently present in the EG cases (22 vs. 11%). In the EG group, 36 cases involving abdominal esophagus (AE) conservation due to the site of the cancer in comparison to the resection group (10), experienced a lower probability of reflux esophagitis (5.6 vs. 60%) and endoscopic examinations showed a lower severity (Grade B,C,D; 0 vs. 50%). CONCLUSIONS: EG combined with a reflux prevention procedure is simple and less invasive. In cases in which the conservation of AE is possible, less reflux esophagitis is observed and EG is therefore recommended as an appropriate reconstruction method.

Status of tissue expression and serum levels of HER2 in gastric cancer patients in Japan.

BACKGROUND: The incidence of HER2 expression in gastric cancer varies among previous studies. Furthermore, serum HER2 levels have not been well studied in patients with gastric cancer. METHODOLOGY: Cancerous gastric tissue was analyzed by immunohistochemistry (IHC) to give an IHC score (IHC0, 1+, 2+ or 3) for HER2 expression. Fluorescence in situ hybridization (FISH) was performed to examine HER2 gene expression in IHC2+ cases. Levels of HER2 in serum collected before surgery were determined by chemiluminescent enzyme immunoassay. RESULTS: Subjects were 105 gastric cancer patients who underwent surgical resection. Tissue expression of HER2 was positive (IHC3+, or IHC2+ plus FISH+) in 6.7% of patients (7/105). All HER2-positive tumors were highly differentiated. Mean serum HER2 level was 8.7±2.1 ng/dl in patients with primary gastric cancer. The mean serum HER2 level in the highly differentiated cancer group was 9.2±2.1 ng/dl, which was significantly higher than that (8.1±1.9 ng/dl) in the poorly differentiated group. CONCLUSION: Tissue expression of HER2 was found in 6.7% of examined Japanese gastric cancer patients, and all HER2-positive tumors were highly differentiated. Serum HER2 levels were significantly higher in patients with highly differentiated cancer, in good agreement with the higher tissue expression of HER2 in highly differentiated cancer.

Prognostic factors in patients undergoing complete resection of pulmonary metastases of colorectal cancer: a multi-institutional cumulative follow-up study.

PURPOSE: The aim of this retrospective study was to establish the prognostic factors for overall survival after pulmonary resection for lung metastases of colorectal carcinoma (CRC). METHODS: The baseline characteristics and outcomes of 266 CRC patients undergoing complete pulmonary resection were collected from 19 institutions by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Study Group. We used the Cox proportional hazard regression to identify independent prognostic factors for OS. RESULTS: The 5-year overall survival rate of patients undergoing complete resection of isolated pulmonary metastases was 56.5 %. The independent unfavorable prognostic factors after pulmonary resection included stage T4 (p = 0.0004) and N2 (p = 0.0082) as primary cancer-related factors, and more than three metastases (p = 0.0342), bilateral distribution (p = 0.0450), metastatic disease-free interval (DFI) of less than 2 years (p = 0.0257), and a preoperative carcinoembryonic antigen (CEA) level greater than 5.0 ng/mL (p = 0.0209) as pulmonary metastases-related factors. CONCLUSIONS: This retrospective analysis suggested that the indications for pulmonary resection of CRC metastases should be decided not only by the status of lung metastases, but also by pulmonary-related factors such as the T and N stage of the primary lesion, preoperative CEA level, and the DFI.

Immunohistochemical analysis of the DNA methyltransferase 3b expression is associated with significant improvements in the discrimination of ulcerative colitis-associated neoplastic lesions.

PURPOSE: Making a clinicopathological diagnosis of dysplasia is crucial. We herein assess the significance of the DNA methyltransferase 3b (DNMT3b) expression as a diagnostic marker of ulcerative colitis (UC)-associated neoplasia. METHODS: Thirty-one patients with long-standing and extensive UC were included in this study. The expression of DNMT3b in non-neoplastic rectal epithelium (non-dysplasia in 31 patients) and colorectal neoplasia (dysplasia in 43 patients and invasive cancer in 34 patients) was determined using immunohistochemistry. The presence of immunoreactive DNMT3b was assessed in the areas with the highest density of cells with positively staining nuclei. DNMT3b was expressed as the percentage of positive cells relative to the total number of cells counted under high power magnification. RESULTS: The DNMT3b expression in neoplastic rectal epithelium (0.76, range 0.59-0.84) was increased compared to that observed in non-neoplastic epithelium (0.32, range 0.18-0.67, P < 0.001). A ROC curve analysis confirmed 0.68 to be the best diagnostic cut-off value for the DNMT3b expression in neoplastic epithelium (area under the curve = 0.810). The sensitivity of the diagnostic test was 66.2 %, the specificity was 86.7 %, the positive predictive value was 95.7 % and the negative predictive value was 36.1 %. The positive likelihood ratio was 4.98 and the negative likelihood ratio was 0.20. The accuracy was 69.9 %. CONCLUSIONS: An immunohistochemical analysis of the DNMT3b expression was associated with significant improvements in the discrimination of UC-associated neoplastic lesions.

Multicenter study for optimal categorization of extramural tumor deposits for colorectal cancer staging.

OBJECTIVE: This study aimed to determine the optimal categorization of extramural tumor deposits lacking residual lymph node (LN) structure (EX) in colorectal cancer staging. BACKGROUND: The TNM classification system categorizes EX on the basis of their contour characteristics (the contour rule). METHODS: We conducted a multicenter, retrospective, pathological review of 1716 patients with stage I to III curatively resected colorectal cancer who were treated at 11 institutions (1994-1998). In addition, 2242 patients from 9 institutions (1999-2003) were enrolled as a second cohort for validating results. EX were classified as isolated foci confined to vascular or perineural spaces (ie, lymphatic, venous, or perineural invasion) or as tumor nodules (ND). N- and T-staging systems employing different categories for staging were compared in terms of their prognostic power. In addition, the diagnoses of extramural, discontinuously spreading lesions made by 11 observers from different institutions were assessed for interobserver agreement. RESULTS: EX were observed in 18.2% of patients in the first cohort. The method of categorization of EX in tumor staging has a stronger impact on N than T staging. The N-staging system in which all ND types were classified as N factor (the ND rule) could more effectively stratify the survival outcome than the contour rule (Akaike information criterion, 3040.8 vs 3059.5; the Harrell C-index, 0.7255 vs 0.7103). EX were observed in 16.9% of patients in the second cohort. Statistically, the ND rule was more informative than the contour rule for N staging. The Fleiss kappa coefficient for distinguishing LN metastases from EX (0.74) was lower than expected for complete agreement, and it decreased further to 0.51 when calculated for the judgment of ND with smooth contours. CONCLUSIONS: Classifying all ND types as N factors irrespective of contours can simplify the tumor staging system by enhancing diagnostic objectivity, resulting in improved prognostic accuracy.