[An Elderly Patient with Metastatic Colon Cancer Achieved Long-Term Survival Following Single-Agent Chemotherapy with S-1].

Colorectal cancer is a common malignancy and a major health issue in geriatrics. Systemic chemotherapy should be considered for elderly patients. We report an 85-year-old man with metastatic cecal cancer who has achieved long-term survival following single-agent chemotherapy with S-1. His fecal occult blood test results were positive; he then underwent colonoscopy and was diagnosed with cecal cancer. Chest CT revealed multiple metastases in both lungs. Since radical excision was infeasible, we performed right hemicolectomy to prevent bowel obstruction. Histological examination revealed a T3, N0, M1a (PUL2), Stage IV tumor. After discharge from the hospital, the patient preferred receiving chemotherapy that would have fewer side effects. S-1 monotherapy was administered. Despite increased progression of the pulmonary metastases, he experienced no subjective symptoms, his QOL remained consistent, and he completed 42 cycles of chemotherapy in total. The patient is currently being managed on an outpatient basis. In conclusion, elderly patients with cancer should be carefully evaluated according to both disease control and individual circumstances, such as patient's tolerability, QOL, and preference.

Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer.

BACKGROUND AND OBJECTIVES: The clinical significance of CCL5 has been reported in several malignancies. In this study, we examined the prognostic impact of serum CCL5 levels and the expression of CCL5 receptors on tumor cells in patients with gastric cancer. METHODS: Serum CCL5 levels in patients with gastric cancer were measured by enzyme-linked immunoabsorbent assay. Immunohistochemical staining of three chemokine receptors, CCR1, CCR3, and CCR5, which are known as CCL5 receptors, was performed in gastric cancer tissue. RESULTS: We found that serum CCL5 levels themselves had no impact on survival; however, higher serum CCL5 concentrations were associated with more advanced disease. Eighty-six (41%), 48 (23%), and 60 patients (28%) showed positive expression of CCR1, CCR3, and CCR5, respectively, on gastric cancer cells. Among the patients who underwent curative resection for stages II-IV disease, patients with positive CCR3 expression had significantly lower survival rates compared to those with negative CCR3 expression. Unlike CCR1, positive CCR5 expression was also associated with poorer prognosis. Multivariate analysis revealed that expression of CCR3 and/or CCR5 was an independent prognostic factor. CONCLUSIONS: Tumor expression of CCR3 and/or CCR5 (receptors for CCL5) is associated with a lower survival rate in patients with gastric cancer.

Analysis of sentinel node involvement in gastric cancer.

BACKGROUND & AIMS: Sentinel node navigation surgery (SNNS) is performed for patients with early gastric cancer. Because sentinel nodes (SNs) to gastric cancer exist but they have not been well-described, we attempted to validate the SN concept at the micrometastasis level. METHODS: For 53 patients who underwent curative gastrectomy for T1/T2 (<4 cm) N0 gastric cancer, SNNS was performed with radioactive tin colloid and/or indocyanine green, and subsequent modified D1 lymphadenectomies were added. Whole formalin-fixed paraffin-embedded tissues of all resected lymph nodes from these patients were cut into 5-mum thick serial step sections at 85-mum intervals, and occult metastases were examined immunohistochemically. RESULTS: Metastases were detected in 3 (1.5%) of 204 SNs and 3 (0.33%) of 901 non-SNs in pN0 cases and in 18 (46%) of 39 SNs and 3 (1.9%) of 158 non-SNs in pN1 cases. On a patient basis, metastases were detected in 4 (9%) of 46 pN0 patients, 2 (4%) each in SNs and non-SNs, and in 7 pN1 patients, of whom 7 and 4 had SN and non-SN metastases, respectively. The sensitivity, false-negative rate, and accuracy of SN identification by SNNS were 82%, 18%, and 96%, respectively, at the occult metastasis level. However, on the basis of the concept of the sentinel lymphatic station (SLS), which represents all lymphatic stations to which SNs belong, metastases were always limited to the lymph nodes in SLS in the 11 cases with metastases. Non-SN metastases occurred in 3 (60%) of 5 patients with SN metastases >2.0 mm in diameter but not in 4 patients with SN metastases

Transcript and protein expression profiles of the NCI-60 cancer cell panel: an integromic microarray study.

To evaluate the utility of transcript profiling for prediction of protein expression levels, we compared profiles across the NCI-60 cancer cell panel, which represents nine tissues of origin. For that analysis, we present here two new NCI-60 transcript profile data sets (A based on Affymetrix HG-U95 and HG-U133A chips; Affymetrix, Santa Clara, CA) and one new protein profile data set (based on reverse-phase protein lysate arrays). The data sets are available online at http://discover.nci.nih.gov in the CellMiner program package. Using the new transcript data in combination with our previously published cDNA array and Affymetrix HU6800 data sets, we first developed a "consensus set" of transcript profiles based on the four different microarray platforms. Using that set, we found that 65% of the genes showed statistically significant transcript-protein correlation, and the correlations were generally higher than those reported previously for panels of mammalian cells. Using the predictive analysis of microarray nearest shrunken centroid algorithm for functional prediction of tissue of origin, we then found that (a) the consensus mRNA set did better than did data from any of the individual mRNA platforms and (b) the protein data seemed to do somewhat better (P = 0.027) on a gene-for-gene basis in this particular study than did the consensus mRNA data, but both did well. Analysis based on the Gene Ontology showed protein levels of structure-related genes to be well predicted by mRNA levels (mean r = 0.71). Because the transcript-based technologies are more mature and are currently able to assess larger numbers of genes at one time, they continue to be useful, even when the ultimate aim is information about proteins.

High-level Skp2 expression in pancreatic ductal adenocarcinoma: correlation with the extent of lymph node metastasis, higher histological grade, and poorer patient outcome.

OBJECTIVES: Recent studies have shown that overexpression of S-phase kinase-associated protein 2 (Skp2) occurs in many cancers at an advanced stage. We examined the clinicopathologic significance and prognostic implication of Skp2 expression in pancreatic invasive ductal carcinoma. METHODS: Tissue samples from 46 pancreatic carcinomas were examined immunohistochemically for Skp2. The proportion of constituent tumor cells with Skp2 expression was analyzed and classified as high-level nuclear expression when more than 20% of the cancer cells were positive, or low-level nuclear expression otherwise. RESULTS: High-level Skp2 overexpression was detected in 13 (28.3%) of the 46 tumors. The incidence of high-level Skp2 was correlated with higher histological grade (P = 0.0056), the extent of lymph node metastasis (P = 0.0086), the level of lymphatic permeation (P = 0.0024), and poorer patient outcome (P = 0.0189). Multivariate analysis showed that high-level Skp2 expression was an independent predictor of overall patient survival (P = 0.0140). CONCLUSIONS: It is suggested that examination of Skp2 expression might be clinically useful for prognostication in patients with pancreatic carcinoma and that Skp2 protein might be a novel therapeutic molecular target.

Combined hepatocellular carcinoma and cholangiocarcinoma with components of mucinous carcinoma arising in a cirrhotic liver.

A rare autopsy case of combined hepatocellular and cholangiocarcinoma, occurring in a 54-year-old man with liver cirrhosis, is presented. Initial laboratory data included CEA 52.1 ng/mL, DUPAN-2 1600 U/mL, AFP 2 ng/mL, and negativity for hepatitis B surface antigen, hepatitis B early antigen and hepatitis B core antibody. Ultrasonography and CT scan showed a large tumor node in the liver with ringed enhancement, swelling of several para-aortic lymph nodes, and ascites. Clinically, it was not possible to determine whether the hepatic tumor was an intrahepatic cholangiocarcinoma or a metastatic carcinoma. Histologically, the primary lesion was composed solely of hepatocellular carcinoma (HCC) with a trabecular pattern, and the intrahepatic metastases consisted of a variable admixture of HCC and cholangiocarcinoma (CC) with excessive mucin production. Interestingly, the tumor cell cluster showing a trabecular growth pattern produced mucin and had immunohistochemical expression of hepatocyte, cytokeratins 7 and 8. It is concluded that these hepatic tumor cells had both HCC and CC characters.

AbMiner: a bioinformatic resource on available monoclonal antibodies and corresponding gene identifiers for genomic, proteomic, and immunologic studies.

BACKGROUND: Monoclonal antibodies are used extensively throughout the biomedical sciences for detection of antigens, either in vitro or in vivo. We, for example, have used them for quantitation of proteins on "reverse-phase" protein lysate arrays. For those studies, we quality-controlled > 600 available monoclonal antibodies and also needed to develop precise information on the genes that encode their antigens. Translation among the various protein and gene identifier types proved non-trivial because of one-to-many and many-to-one relationships. To organize the antibody, protein, and gene information, we initially developed a relational database in Filemaker for our own use. When it became apparent that the information would be useful to many other researchers faced with the need to choose or characterize antibodies, we developed it further as AbMiner, a fully relational web-based database under MySQL, programmed in Java. DESCRIPTION: AbMiner is a user-friendly, web-based relational database of information on > 600 commercially available antibodies that we validated by Western blot for protein microarray studies. It includes many types of information on the antibody, the immunogen, the vendor, the antigen, and the antigen's gene. Multiple gene and protein identifier types provide links to corresponding entries in a variety of other public databases, including resources for phosphorylation-specific antibodies. AbMiner also includes our quality-control data against a pool of 60 diverse cancer cell types (the NCI-60) and also protein expression levels for the NCI-60 cells measured using our high-density "reverse-phase" protein lysate microarrays for a selection of the listed antibodies. Some other available database resources give information on antibody specificity for one or a couple of cell types. In contrast, the data in AbMiner indicate specificity with respect to the antigens in a pool of 60 diverse cell types from nine different tissues of origin. CONCLUSION: AbMiner is a relational database that provides extensive information from our own laboratory and other sources on more than 600 available antibodies and the genes that encode the antibodies' antigens. The data will be made freely available at http://discover.nci.nih.gov/abminer.

Potential crosstalk between insulin-like growth factor receptor type 1 and epidermal growth factor receptor in progression and metastasis of pancreatic cancer.

The insulin-like growth factor receptor type 1 (IGF1R) and epidermal growth factor receptor (EGFR) are reportedly overexpressed in pancreatic cancer. However, the correlation between activated EGFR and IGF1R and their clinicopathological implications still remain unclear. The cellular localization and overexpression of IGF1R and EGFR were investigated immunohistochemically in primary invasive ductal pancreatic carcinomas obtained from 74 patients who underwent radical surgical resection. We also compared the status of IGF1R and EGFR overexpression between primary tumors and hepatic metastatic tumors obtained from 44 autopsied patients. Among the 74 surgically resected primary tumors, cytoplasm- and membrane-dominant EGFR overexpression was detected in 22 (30%) and 7 (9%), respectively, whereas cytoplasm- and membrane-dominant IGF1R overexpression was detected in 8 (11%) and 28 (38%), respectively. Membrane-dominant EGFR and cytoplasm-dominant IGF1R were more frequent in lower-grade tumors and correlated with favorable prognosis, whereas cytoplasm-dominant EGFR and membrane-dominant IGF1R were more frequent in higher-grade tumors and correlated with poor prognosis. In 36 autopsy specimens of pancreatic tumor with concurrent overexpression of IGF1R and EGFR, there was an inverse correlation between the IGF1R and EGFR localization patterns (P = 0.001). In the hepatic metastatic tumors obtained by autopsy, the incidences of both IGF1R and EGFR overexpression were much higher than in the surgically resected primary tumors. More than half of the autopsy cases consistently showed membrane-dominant EGFR expression in both the primary tumor and hepatic metastases, whereas IGF1R expression showed considerable variation. Crosstalk between differently localized IGF1R and EGFR might play a role in determining the biological aggressiveness of pancreatic cancer, although their cellular localization may often alter during the process of metastasis.

Usefulness and limitation of multiple endoscopic biopsy sampling for epidermal growth factor receptor and c-erbB-2 testing in patients with gastric adenocarcinoma.

BACKGROUND: Our objective was to examine the utility of endoscopic biopsy specimens in judging the status of epidermal growth factor receptor (EGFR) and c-erbB-2 genes and proteins in the entire tumor. METHODS: Endoscopic biopsy specimens and specimens of whole representative cut surfaces of corresponding surgically resected tumors were obtained from 14 patients with gastric carcinoma, and immunohistochemistry and fluorescence in situ hybridization were then performed to determine the protein expression and gene amplification profiles, respectively, of EGFR and c-erbB-2 in these biopsy and surgical specimens. RESULTS: Among the eight endoscopic biopsy specimens obtained from three gastric carcinomas in which EGFR protein overexpression and gene amplification were judged to be positive in the corresponding surgically resected tissue specimens, EGFR overexpression was detected in three specimens (38%), but EGFR amplification was not detected (0%). Among the 19 endoscopic biopsy specimens obtained from five gastric carcinomas in which c-erbB-2 protein overexpression and gene amplification were judged to be positive in the corresponding surgically resected tissue specimens, c-erbB-2 overexpression and amplification (c-erbB-2/CEP17 ratio) were detected in 14 (74%) and 16 (84%) specimens, respectively. All three cases with EGFR overexpression and all five cases with c-erbB-2 overexpression showed intratumor heterogeneity with regard to their EGFR and c-erbB-2 status, respectively. CONCLUSIONS: The c-erbB-2 status could be adequately assessed not only by examining surgically resected materials, but also by examining multiple endoscopic biopsy specimens. On the other hand, to assess the EGFR status accurately, the use of surgically resected samples appeared to be more reliable than the use of multiple endoscopic biopsy samples.

Correlation of KIT and EGFR overexpression with invasive ductal breast carcinoma of the solid-tubular subtype, nuclear grade 3, and mesenchymal or myoepithelial differentiation.

Although KIT and EGFR overexpressions are reported to occur in breast cancer, their pathological significance is still unclear. We examined KIT, EGFR, and c-erbB-2 overexpressions immunohistochemically in 150 cases of surgically resected breast cancer and their correlation with the histological type and grade and mesenchymal and/or myoepithelial immunophenotype of primary tumors. To facilitate the analysis, we constructed a tissue microarray comprising 2-mm diameter tissues cored from the representative tissue block of each tumor. KIT, EGFR, and c-erbB-2 overexpressions were detected in 15 (10%), 12 (8%), and 23 (15%), respectively. The KIT was more frequent in the group comprising comedo-type ductal carcinoma in situ and invasive ductal carcinomas (IDCs) of the solid-tubular subtype than in the group of other histological types (P=0.027), and the EGFR was more frequent in IDCs of solid-tubular type than in other histological types (P <0.05). KIT and EGFR overexpressions were correlated with nuclear grade 3 (P=0.0095 and 0.0005) and tended to be concurrent (P=0.005). KIT overexpression was correlated with vimentin and S-100 expression (P=0.003 and P=0.005), and EGFR overexpression was correlated with S100 expression (P=0.0001). These correlations with grade and mesenchymal/myoepithelial markers were not observed for c-erbB-2 overexpression. KIT and EGFR appeared to be indicators of high-grade breast carcinoma groups that often contain the carcinomas with mesenchymal and/or myoepithelial differentiation, which are distinct from the group with c-erbB-2 overexpression.

A proposal for diagnostically meaningful criteria to classify increased epidermal growth factor receptor and c-erbB-2 gene copy numbers in gastric carcinoma, based on correlation of fluorescence in situ hybridization and immunohistochemical measurements.

Amplification of the epidermal growth factor receptor (EGFR) and/or c-erbB-2 oncogenes and overexpression of their proteins are detected in 30% of gastric carcinomas, but there are few reports regarding the correlation between gene amplification and protein overexpression. We examined the correlation between amplification of the EGFR and c-erbB-2 genes, detected using fluorescence in situ hybridization, and overexpression of their proteins, detected using immunohistochemistry, in formalin-fixed tissue sections of 54 surgically resected gastric carcinomas. A mean EGFR copy number per nucleus of four or more and an EGFR/chromosome 7 centromere (CEP7) ratio of 1.7 or more were each detected in 4 specimens (7%). The sensitivity and specificity of both criteria for EGFR protein overexpression were 75% and 92%, respectively. A mean c-erbB-2 copy number per nucleus of 7.0 or more and a c-erbB-2/chromosome 17 centromere (CEP17) ratio of 2.0 or more were detected in six (11%) and eight (15%) specimens, respectively. The sensitivity and specificity of the former criterion to c-erbB-2 overexpression were 83% and 98%, respectively, while those of the latter were 63% and 98%. A mean EGFR gene copy number of 4.0 or more and/or an EGFR/CEP7 ratio of 1.7 and a mean c-erbB-2 gene copy number of 7.0 or more and/or a c-erbB-2/CEP17 ratio of 2.0 or more would be useful in defining increased EGFR and c-erbB-2 gene copy numbers, respectively, in gastric carcinomas.

Sentinel node concept in gastric carcinoma.

To assess the applicability of the sentinel node concept to gastric carcinoma. The location of metastatic lymph nodes was analyzed retrospectively in 119 patients with gastric carcinoma in whom metastasis was limited to one or two nodes. Intraoperative lymphatic mapping was attempted in 62 patients using indocyanine green injected endoscopically into the gastric submucosa adjacent to the tumor. Metastatic lymph nodes were distributed beyond the perigastric area in 4% of patients with a single node involved. The positive node was located along the greater curvature in 21% of the patients with a tumor on the lesser curvature. Two patients had a metastatic node totally occupied by cancer tissue. In 16% of patients with two nodes involved, a positive node was located on both the lesser and greater curvatures. Lymphatic mapping was successful in all subjects. A larger number and wider distribution of green-stained nodes were observed in patients injected with 8 ml of indocyanine green solution than in those injected with 4 ml. No metastasis was observed in any nodes in 47 (96%) of the 49 patients who had no metastasis in green nodes. In one patient showing metastasis in non-green nodes without metastasis in green nodes, the positive nodes were totally occupied by cancer tissue. Our results showed the complexity of lymphatic streams within and from the stomach. Lymphatic mapping using indocyanine green can be a tool for identifying sentinel nodes in gastric carcinoma although lymph nodes occupied by cancer tissue may not be detected by this technique.