Hidetaka Mochizuki

The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma.

Objectives: Recent studies have shown that some growth factor receptors with tyrosine kinase activity, eg, the epidermal growth factor receptor (EGFr) and the c-erbB-2 (HER-2) oncoprotein, are associated with aggressive biologic behavior of various cancer cell types. We examined the clinicopathological significance of the expression and localization of EGFr and HER-2 in both invasive and intraductal components of ductal adenocarcinomas of the pancreas. Methods: Tissue samples from 76 archival cases of pancreatic ductal adenocarcinoma were immunohistochemically analyzed for both membrane and cytoplasmic overexpression of EGFr and HER-2 oncoprotein. The rate of incidence between the invasive and intraductal components was analyzed and then their correlation with tumor differentiation and patient prognosis was analyzed. Results: Cytoplasmic EGFr overexpression was more frequent in invasive components (47 of 76, 62%) than in intraductal components (19 of 76, 25%), while membrane EGFr overexpression was more frequent in intraductal components (41 of 76, 54%) than in invasive components (11 of 76, 14%). The membrane HER-2 overexpression was also more frequent in intraductal components (15 of 76, 20%) than in invasive components (2 of 76, 3%), but the incidence of cytoplasmic HER-2 overexpression did not differ between intraductal components (12 of 76, 16%) and invasive components (8 of 76, 11%). The cytoplasmic EGFr overexpression in invasive components was more frequent in grade 3 group (32 of 33, 97%) than in grade 2 (15 of 32, 47%) and grade 1 groups (0 of 10, 0%) (P < 0.001). Patients with adenocarcinoma with cytoplasmic EGFr overexpression showed shorter overall survival than those with adenocarcinoma without cytoplasmic EGFr overexpression (P = 0.02). Conclusion: It is suggested that the cytoplasmic overexpression of EGFr plays a significant role in the progression of pancreatic ductal adenocarcinoma, especially in the invasion and acquisition of aggressive clinical behavior. Both membrane and cytoplasmic expression of HER-2 showed no significant correlation between tumor differentiation and poor survival.

Decrease of CD56+T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma

CD56+T cells and CD56+natural killer (NK) cells are abundant in the human liver. The aim of this study was the further characterization of these cells in the liver with or without hepatitis C virus (HCV) infection. Liver mononuclear cells (MNC) were isolated from liver specimens obtained from the patients during abdominal surgery. In addition to a flow cytometric analysis, liver MNC and PBMC were cultured with the immobilized anti‐CD3 Ab, IL‐2, or a combination of IL‐2 and IL‐12 and their IFN‐γ production and the antitumor cytotoxicity were assessed. The liver MNC of HCV (−) patients contained 20% CD56+T cells whereas the same proportions decreased to 11% in chronic hepatitis livers and to 5% in cirrhotic livers. The proportion of NK cells also decreased in the cirrhotic livers. On the other hand, the populations of these cells in PBMC did not significantly differ among patient groups. The IFN‐γ production and the cytotoxicity against K562 cells, Raji cells, and a hepatocellular carcinoma, HuH‐7 cells, greatly decreased in the cirrhotic liver MNC. In contrast, the cytotoxicity in PBMC did not significantly differ among the patient groups and was lower than that in the liver MNC of HCV (−) patients. CD56+T cells and NK cells but not regular T cells purified from liver MNC cultured with cytokines showed potent cytotoxicities against HuH‐7 cells. These results suggest that a decreased number of CD56+T cells and NK cells in cirrhotic livers may be related to their susceptibility to hepatocellular carcinoma.

Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions.

PURPOSE Factors affecting treatment prognosis and therapeutic results for hepatic metastasis of colorectal cancer were investigated. METHODS Therapeutic results, especially of hepatectomy, were investigated for hepatic metastasis of colorectal cancer in 763 patients (585 underwent hepatectomy) treated between 1992 and 1996 at 18 institutions that participated in the “Study for establishing treatments for hepatic and pulmonary metastasis of colorectal cancer” sponsored by a Grant-in-Aid (10-11) for Cancer Research from the Ministry of Health, Welfare and Labor of Japan. RESULTS The five-year survival rate for those treated by hepatectomy was significantly higher (32.9 percent) than for those not undergoing hepatectomy (3.4 percent). After hepatectomy for hepatic metastasis, the most prevalent form of recurrence was in the remnant liver (41.4 percent), followed by recurrence of pulmonary metastasis (19.2 percent), and other (7.2 percent). Factors of the primary tumor adversely affecting prognosis after hepatectomy for hepatic metastasis included poorly differentiated adenocarcinoma or mucinous carcinoma, depth of invasion of si/ai, lymph-node metastasis of Stage n3 and n4 by the Japanese classification of colorectal carcinoma, number of metastatic lymph nodes of more than four, and Dukes Stage D. Factors at the time of hepatectomy adversely affecting prognosis after surgery for hepatic metastasis included residual tumor, extrahepatic metastasis, hepatic metastasis of degree H3 stipulated by the Japanese classification of colorectal carcinoma, number of metastases of four or more, pathology of hepatic metastasis of poorly differentiated adenocarcinoma, resection margin of <10 mm, and carcinoembryonic antigen value higher than normal preoperative and one month postoperative. CONCLUSIONS Among therapies for hepatic metastasis of colorectal cancer, the present study clearly revealed that hepatectomy is the treatment of choice whenever feasible. Postoperative recurrence often is localized in the remnant liver, or there may be a systemic recurrence of pulmonary metastasis. Thus, methods of prevention will be a future theme.

Clinicopathological and Prognostic Relevance of Uptake Level using 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Fusion Imaging (18F-FDG PET/CT) in Primary Breast Cancer

OBJECTIVE Using integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT), the clinical significance of 18F-FDG uptake was evaluated in patients with primary breast cancer. METHODS Clinicopathological correlation with the level of maximum standardized uptake values (SUV) 60 min obtained from preoperative 18F-FDG PET/CT were examined in 152 patients with primary breast cancer. The prognostic impact of the level of SUV was explored using simulated prognosis derived from computed program Adjuvant! in 136 (89%) patients with invasive ductal carcinoma (IDC). RESULTS High SUV level was significantly correlated with tumor invasive size (< or = 2 cm) (P < 0.0001), higher score of nuclear grade (P < 0.0001), nuclear atypia (P < 0.0001) and mitosis counts (P < 0.0001), negative hormone receptor status (P = 0.001), high score of c-erbB-2 expression (P = 0.006), lymph node metastasis (P = 0.002), and IDC in comparison with invasive lobular carcinoma (P = 0.004). Multivariate analyses showed tumor invasive size, nuclear grade and estrogen receptor negativity were significantly correlated with SUV in primary breast cancer (P < 0.0001,< 0.0001, and < 0.012, respectively), and nuclear grade was significantly correlated with SUV in tumors of invasive size 2 cm or less (P < 0.0001). Tumors with high SUV (cutoff value 4.0) showed higher relapse and mortality rate compared to those with low SUV (P < 0.0001). CONCLUSIONS High uptake of 18F-FDG would be predictive of poor prognosis in patients with primary breast cancer, and aggressive features of cancer cells in patients with early breast cancer. 18F-FDG PET/CT could be a useful tool to pre-therapeutically predict biological characteristics and baseline risk of breast cancer.

Expression of cyclooxygenase-2 protein in gastric adenocarcinoma

Epidemiological studies have suggested that the regular use of nonsteroidal antiinflammatory drugs, which inhibit cyclooxygenase (COX), reduces the risk of colon cancer. The inducible COX‐2 isoform has been reported to be upregulated in colorectal carcinomas and may play a role in colorectal carcinogenesis. The purpose of this study was to investigate the expression of COX‐2 protein in human gastric adenocarcinomas.

Sentinel node concept in gastric carcinoma.

To assess the applicability of thesentinel node concept to gastric carcinoma. The location of metastaticlymph nodes was analyzed retrospectively in 119 patients with gastriccarcinoma in whom metastasis was limited to one or two nodes.Intraoperative lymphatic mapping was attempted in 62 patients usingindocyanine green injected endoscopically into the gastric submucosaadjacent to the tumor. Metastatic lymph nodes were distributed beyondthe perigastric area in 4% of patients with a single node involved.The positive node was located along the greater curvature in 21% ofthe patients with a tumor on the lesser curvature. Two patients had ametastatic node totally occupied by cancer tissue. In 16% of patientswith two nodes involved, a positive node was located on both the lesserand greater curvatures. Lymphatic mapping was successful in allsubjects. A larger number and wider distribution of green-stained nodeswere observed in patients injected with 8 ml of indocyanine greensolution than in those injected with 4 ml. No metastasis was observedin any nodes in 47 (96%) of the 49 patients who had no metastasis ingreen nodes. In one patient showing metastasis in non-green nodeswithout metastasis in green nodes, the positive nodes were totallyoccupied by cancer tissue. Our results showed the complexity oflymphatic streams within and from the stomach. Lymphatic mapping usingindocyanine green can be a tool for identifying sentinel nodes ingastric carcinoma although lymph nodes occupied by cancer tissue maynot be detected by this technique.

A New Prognostic Staging System for Rectal Cancer

Objective:To clarify the appropriateness of tumor “budding,” a quantifiable histologic variable, as 1 parameter in the construction of a new prognostic grading system for rectal cancer. Summary Background Data:Patient division according to an accurate prognostic prediction could enhance the effectiveness of postoperative adjuvant therapy and follow-up. Patients and Methods:Tumor budding was defined as an isolated cancer cell or a cluster composed of fewer than 5 cells in the invasive frontal region, and was divided into 2 grades based on its number within a microscopic field of ×250. We analyzed 2 discrete cohorts comprising 638 and 476 patients undergoing potentially curative surgery. Results:In the first cohort, high-grade budding (10 or more foci in a field) was observed in 30% of patients and was significantly associated with a lower 5-year survival rate (41%) than low-grade budding (84%). Similarly, in the second cohort, the 5-year survival rate was 43% in high-grade budding patients and 83% in low-grade budding patients. In both cohorts, multivariate analyses verified budding to be an independent prognosticator, together with nodal involvement and extramural spread. These 3 variables were given weighted scores, and the score range was divided to provide 5 prognostic groups (97%; 86%; 61%; 39%; 17% 5-year survival). The model was tested on the second cohort, and similar prognostic results were obtained. Conclusions:We propose that because of its relevance to prognosis and its reproducibility, budding is an excellent parameter for use in a grading system to provide a confident prediction of clinical outcome.

Tumor Budding at the Invasive Margin Can Predict Patients at High Risk of Recurrence After Curative Surgery for Stage II, T3 Colon Cancer

AbstractPURPOSE: The aim of this study was to identify indicators that can predict patients at high risk of tumor recurrence in Stage II, T3 colon cancer. METHODS: A total of 138 patients classified as Stage II, T3 underwent curative resection of colon cancer between 1981 and 1993. Clinical variables included age, gender, bowel obstruction, tumor location, and emergency presentation. For each colon tumor specimen, the following histopathological variables were assessed: maximum tumor diameter (<5 vs. ≥5 cm), depth, tumor grade (well and moderate vs. other), lymphatic and venous invasion (absent vs. present), perineural invasion, tumor necrosis, and tumor margin (expanding vs. infiltrating). We also categorized tumor budding, defined as a single cancer cell or small clusters of undifferentiated cancer cells in the invasive frontal lesion, into two categories: none or minimal (BD-1), and moderate or severe (BD-2). Univariate analysis for factors regarding recurrence and disease-specific survival were performed with the logistic regression model and the log-rank test. RESULTS: Among the factors analyzed, tumor budding was the only factor that was significantly associated with recurrence and survival. The numbers of patients with BD-1 and BD-2 tumors were 111 and 27, respectively. Forty-eight percent of BD-2 tumor patients developed recurrence, compared with 4.5 percent of BD-1 tumor patients (P < 0.0001). The cumulative disease-specific survival rates at five years for patients with BD-1 and BD-2 tumors were 98 and 74 percent, respectively (P < 0.0001). CONCLUSION: The presence of moderate or severe budding at the invasive margin in Stage II, T3 colon cancer indicated a high risk of tumor recurrence after curative surgery, providing useful information for the decision regarding postoperative adjuvant chemotherapy.

Utility of 18F-fluoro-deoxyglucose emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in combination with ultrasonography for axillary staging in primary breast cancer

BackgroundAccurate evaluation of axillary lymph node (ALN) involvement is mandatory before treatment of primary breast cancer. The aim of this study is to compare preoperative diagnostic accuracy between positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) and axillary ultrasonography (AUS) for detecting ALN metastasis in patients having operable breast cancer, and to assess the clinical management of axillary 18F-FDG PET/CT for therapeutic indication of sentinel node biopsy (SNB) and preoperative systemic chemotherapy (PSC).MethodsOne hundred eighty-three patients with primary operable breast cancer were recruited. All patients underwent 18F-FDG PET/CT and AUS followed by SNB and/or ALN dissection (ALND). Using 18F-FDG PET/CT, we studied both a visual assessment of 18F-FDG uptake and standardized uptake value (SUV) for axillary staging.ResultsIn a visual assessment of 18F-FDG PET/CT, the diagnostic accuracy of ALN metastasis was 83% with 58% in sensitivity and 95% in specificity, and when cut-off point of SUV was set at 1.8, sensitivity, specificity, and accuracy were 36, 100, and 79%, respectively. On the other hand, the diagnostic accuracy of AUS was 85% with 54% in sensitivity and 99% in specificity. By the combination of 18F-FDG PET/CT and AUS to the axilla, the sensitivity, specificity, and accuracy were 64, 94, and 85%, respectively. If either 18F-FDG PET uptake or AUS was positive in allixa, the probability of axillary metastasis was high; 50% (6 of 12) in 18F-FDG PET uptake only, 80% (4 of 5) in AUS positive only, and 100% (28 of 28) in dual positive. By the combination of AUS and 18F-FDG PET/CT, candidates of SNB were more appropriately selected. The axillary 18F-FDG uptake was correlated with the maximum size and nuclear grade of metastatic foci (p = 0.006 and p = 0.03).ConclusionThe diagnostic accuracy of 18F-FDG PET/CT was shown to be nearly equal to ultrasound, and considering their limited sensitivities, the high radiation exposure by 18F-FDG PET/CT and also costs of the examination, it is likely that AUS will be more cost-effective in detecting massive axillary tumor burden. However, when we cannot judge the axillary staging using AUS alone, metabolic approach of 18F-FDG PET/CT for axillary staging would enable us a much more confident diagnosis.

Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis

Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). TLR-4 expression on monocytes/macrophages was examined in patients with sepsis and in murine peritonitis and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before their exposure to LPS resulted in a significant dose-dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil-derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.