Localized biphasic malignant peritoneal mesothelioma presenting as a rectal tumor.

An 84-year-old male presented with bloody stool. On digital rectal examination, a large and firm tumor was palpated in the anterior wall of the rectum at 2 cm from the anal verge. The colonoscopy revealed an ulcerated mass with smooth margins in the anterior wall of the rectum. Enhanced computed tomography showed a huge tumor in the pelvis, invading rectum, urinary bladder and the prostate, with signs of splenic and peritoneal metastases. Findings from an endoscopic biopsy and endoscopic ultrasound-guided fine needle aspiration suggested spindle cell carcinoma. We tentatively diagnosed as spindle cell carcinoma of the rectum and administered panitumumab as palliative chemotherapy. He eventually died at 4 months after the first visit to our institution. The autopsy findings resulted in the confirmed diagnosis as biphasic malignant peritoneal mesothelioma. There are only four previous reports on malignant peritoneal mesothelioma presenting as a colorectal tumor. Although rare, malignant peritoneal mesothelioma should be considered in differential diagnosis of colorectal tumors.

Utility of Endoscopic Ultrasonography Screening for Small Pancreatic Cancer and Proposal for a New Scoring System for Screening.

OBJECTIVES: This study aimed to evaluate the utility of endoscopic ultrasonography screening for small pancreatic cancer (PC) and propose a new simple scoring system for selecting individuals who should be screened. METHODS: Risk factors or symptoms related to PC were tentatively divided into high- and low-grade risk groups based mainly on reported relative risk values. Numbers of risk factors were designated as risk scores. Endoscopic ultrasonography screening was performed for 632 individuals. We analyzed scores for PC detection prospectively, and risk factors and scores of PC patients retrospectively. RESULTS: We detected 10 small malignant pancreatic neoplasms (size ≤20 mm; 8 PCs; 9 Tis or T1) and 14 advanced PCs. All small PCs and 95.5% of PCs were found in individuals with low-grade risk scores of at least 3 points (P) or high-grade risk scores of at least 1P. Both average risk scores were significantly higher in patients with small PCs (P ≤ 0.04). Cutoffs for low- and high-grade risk scores implying the presence of small PC and all PC were 3P and 1P, respectively. When subjects having one or both cutoff scores were screened, sensitivity and specificity were 100% and 64.4% for small PCs and 95.5% and 64.4% for all PCs. CONCLUSION: Endoscopic ultrasonography screening combining new scoring is effective for detecting small PC.

Δ133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells.

p53 functions to induce cellular senescence, which is incompatible with self-renewal of pluripotent stem cells such as induced pluripotent stem cells (iPSC) and embryonic stem cells (ESC). However, p53 also has essential roles in these cells through DNA damage repair for maintaining genomic integrity and high sensitivity to apoptosis for eliminating severely damaged cells. We hypothesized that Δ133p53, a physiological inhibitory p53 isoform, is involved in the balanced regulation of self-renewing capacity, DNA damage repair and apoptosis. We examined 12 lines of human iPSC and their original fibroblasts, as well as three ESC lines, for endogenous protein levels of Δ133p53 and full-length p53 (FL-p53), and mRNA levels of various p53 target genes. While FL-p53 levels in iPSC and ESC widely ranged from below to above those in the fibroblasts, all iPSC and ESC lines expressed elevated levels of Δ133p53. The p53-inducible genes that mediate cellular senescence (p21WAF1, miR-34a, PAI-1 and IGFBP7), but not those for apoptosis (BAX and PUMA) and DNA damage repair (p53R2), were downregulated in iPSC and ESC. Consistent with these endogenous expression profiles, overexpression of Δ133p53 in human fibroblasts preferentially repressed the p53-inducible senescence mediators and significantly enhanced their reprogramming to iPSC. The iPSC lines derived from Δ133p53-overexpressing fibroblasts formed well-differentiated, benign teratomas in immunodeficient mice and had fewer numbers of somatic mutations than an iPSC derived from p53-knocked-down fibroblasts, suggesting that Δ133p53 overexpression is non- or less oncogenic and mutagenic than total inhibition of p53 activities. Overexpressed Δ133p53 prevented FL-p53 from binding to the regulatory regions of p21WAF1 and miR-34a promoters, providing a mechanistic basis for its dominant-negative inhibition of a subset of p53 target genes. This study supports the hypothesis that upregulation of Δ133p53 is an endogenous mechanism that facilitates human somatic cells to become self-renewing pluripotent stem cells with maintained apoptotic and DNA repair activities.

Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer.

BACKGROUND: Gastric cancer (GC) is the fifth commonest malignancy worldwide and still one of the leading causes of cancer-related death. The aim of this study was to identify a novel prognostic marker or therapeutic target for GC. METHODS: We analyzed candidate genes from our previous Escherichia coli ampicillin secretion trap (CAST) libraries in detail, and focused on the FKTN gene because it was overexpressed in both GC cell line CAST libraries, MKN-1 and MKN-45. RESULTS: Quantitative reverse transcriptase PCR analysis of FKTN revealed that FKTN messenger RNA was overexpressed in nine of 28 (32.1 %) GC tissue samples compared with nonneoplastic gastric mucosa. Immunostaining of fukutin showed that 297 of 695 cases (42.7 %) were positive for fukutin. Fukutin-positive GC cases were significantly associated with differentiated histological features, and advanced T grade and N grade. In addition, fukutin expression was observed more frequently in the intestinal phenotype (51 %) of GC than in other phenotypes (37 %) when defined by the expression patterns of mucin 5AC, mucin 6, mucin 2, and CD10. FKTN small interfering RNA treatment decreased GC cell proliferation. CONCLUSIONS: These results indicate that the expression of fukutin may be a key regulator for progression of GC with the intestinal mucin phenotype.

TSPAN8, identified by Escherichia coli ampicillin secretion trap, is associated with cell growth and invasion in gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common human cancers. Genes expressed only in cancer tissue, especially on the cell membrane, will be useful biomarkers for cancer diagnosis and therapeutics. METHODS: To identify novel genes encoding transmembrane protein specifically expressed in GC, we generated an Escherichia coli ampicillin secretion trap (CAST) library from diffuse-type GC cell line MKN-45. CAST is a survival-based signal sequence trap method that exploits the ability of mammalian signal sequences to confer ampicillin resistance to a mutant ß-lactamase lacking the endogenous signal sequence. RESULTS: By sequencing 1,536 colonies, we identified 23 genes encoding the transmembrane protein present in GC. Among these genes, TSPAN8 (also known as CO-029 and TM4SF3) gene, which encodes transmembrane protein tetraspanin 8, was emphasized as a candidate. Immunohistochemical analysis of tetraspanin 8 in human GC tissues revealed that 72 (34 %) of 210 GC cases were positive for tetraspanin 8, and microvessel density was significantly higher in tetraspanin 8-positive GC than in tetraspanin 8-negative GC. Furthermore, univariate and multivariate analyses revealed that tetraspanin 8 expression is an independent prognostic classifier of patients with GC. TSPAN8 knockdown by siRNA reduced the invasion of GC cell line. The reduction of invasiveness was retrieved by the tetraspanin 8-containing exosome. CONCLUSION: These results suggest that tetraspanin 8 is involved in tumor progression and is an independent prognostic classifier in patients with GC.

Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer.

The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. To elucidate the roles of miR-34 family in colon carcinogenesis, miR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR, and we examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status and Affymetrix microarray data. All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression that is consistent with the proposed regulation of miR-34a/b/c by TP53. To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique. The expression of miR-34b/c was increased significantly in stromal tissues, especially in cancer stroma, compared with epithelial tissue. In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer. MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.

Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer.

Scirrhous type gastric cancer is highly aggressive and has a poorer prognosis than many other types of gastric carcinoma, due to its characteristic rapid cancer cell infiltration and proliferation, extensive stromal fibrosis, and frequent peritoneal dissemination. The aim of the present study was to identify novel prognostic markers or therapeutic targets for scirrhous type gastric cancer. We reviewed a list of genes with upregulated expression in scirrhous type gastric cancer and compared their expression with that in normal stomach from our previous Escherichia coli (E. coli) ampicillin secretion-trap (CAST) analysis. We focused on the ZDHHC14 gene, which encodes zinc finger, DHHC-type containing 14 protein. qRT-PCR analysis of ZDHHC14 in 41 gastric cancer cases revealed that compared to mRNA levels in normal non-neoplastic gastric mucosa, ZDHHC14 mRNA was overexpressed in 27% of gastric cancer tissue samples. The overexpression of ZDHHC14 was significantly associated with depth of tumor invasion, undifferentiated histology and scirrhous pattern. The invasiveness of ZDHHC14-knockdown HSC-44PE and 44As3 gastric cancer cells was decreased in comparison with that of the negative control siRNA-transfected cells, together with downregulation of MMP-17 mRNA. Integrins α5 and ß1 were also downregulated in ZDHHC14-knockdown 44As3 cells. Forced expression of ZDHHC14 activated gastric cancer cell migration and invasion in vitro. These results indicate that ZDHHC14 is involved in tumor progression in patients with scirrhous type gastric cancer.

Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer.

Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.

Identification of novel transmembrane proteins in scirrhous-type gastric cancer by the Escherichia coli ampicillin secretion trap (CAST) method: TM9SF3 participates in tumor invasion and serves as a prognostic factor.

OBJECTIVE: Scirrhous-type gastric cancer (GC) is highly aggressive and has a poor prognosis due to rapid cancer cell infiltration accompanied by extensive stromal fibrosis. The aim of this study is to identify genes that encode transmembrane proteins frequently expressed in scirrhous-type GC. METHODS: We compared Escherichia coli ampicillin secretion trap (CAST) libraries from 2 human scirrhous-type GC tissues with a normal stomach CAST library. By sequencing 2,880 colonies from scirrhous CAST libraries, we identified a list of candidate genes. RESULTS: We focused on the TM9SF3 gene because it has the highest clone count, and immunohistochemical analysis demonstrated that 46 (50%) of 91 GC cases were positive for TM9SF3, which was observed frequently in scirrhous-type GC. TM9SF3 expression showed a significant correlation with the depth of invasion, tumor stage and undifferentiated GC. There was a strong correlation between TM9SF3 expression and poor patient outcome, which was validated in two separate cohorts by immunostaining and quantitative RT-PCR, respectively. Transient knockdown of the TM9SF3 gene by siRNA showed decreased tumor cell-invasive capacity. CONCLUSION: Our results indicate that TM9SF3 might be a potential diagnostic and therapeutic target for scirrhous-type GC.

High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer.

Colon cancer (CC) is a leading cause of cancer mortality. Novel biomarkers are needed to identify CC patients at high risk of recurrence and those who may benefit from therapeutic intervention. The aim of this study is to investigate if miR-21 expression from RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue sections is associated with prognosis and therapeutic outcome for patients with CC. The expression of miR-21 was measured by quantitative reverse transcriptase-polymerase chain reaction in a Japanese cohort (stage I-IV, n = 156) and a German cohort (stage II, n = 145). High miR-21 expression in tumors was associated with poor survival in both the stage II/III Japanese (p = 0.0008) and stage II German (p = 0.047) cohorts. These associations were independent of other clinical covariates in multivariable models. Receipt of adjuvant chemotherapy was not beneficial in patients with high miR-21 in either cohort. In the Japanese cohort, high miR-21 expression was significantly associated with poor therapeutic outcome (p = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21 (p = 0.001). These results suggest that miR-21 is a promising biomarker to identify patients with poor prognosis and can be accurately measured in FFPE tissues. The expression of miR-21 may also identify patients who will benefit from adjuvant chemotherapy.

Expression of olfactomedin 4 and claudin-18 in serrated neoplasia of the colorectum: a characteristic pattern is associated with sessile serrated lesion.

AIMS: Olfactomedin 4 is a useful marker for stem cells in the intestine and is an independent prognostic molecule for survival in patients with colorectal cancer (CRC). Claudin-18, a component of tight junctions, correlates with poor survival in patients with CRC and is associated with the gastric phenotype. We investigated the possible usefulness of these molecules in serrated neoplasia of the colorectum. METHODS AND RESULTS: We performed immunohistochemical analysis of colorectal polyps, including hyperplastic polyps (HP), sessile serrated lesions (SSL), traditional serrated adenomas (TSA) and conventional adenomas (CA). We also investigated the association between expression of these molecules and clinicopathological parameters in serrated adenocarcinoma (SAC) and non-SAC of the colorectum. Olfactomedin 4 expression was not detected or was decreased in SSL compared with the other polyp types. Claudin-18 expression was higher in SSL than in the other types. Similarly, positivity for olfactomedin 4 in SAC was significantly lower than that in non-SAC, and positivity for claudin-18 in SAC was significantly higher than that in non-SAC. Furthermore, claudin-18-positive SAC showed more advanced N grade and stage than claudin-18-negative SAC. CONCLUSIONS: Reduced expression of olfactomedin 4 and ectopic expression of claudin-18 might be useful markers in the differential diagnosis of serrated polyps.

The search for secreted proteins in prostate cancer by the Escherichia coli ampicillin secretion trap: expression of NBL1 is highly restricted to the prostate and is related to cancer progression.

AIMS: Genes expressed only in cancer tissue or specific organs will be useful molecular markers. To identify genes that encode secreted proteins present in prostate cancer (PCa), we generated Escherichia coli ampicillin secretion trap (CAST) libraries from PCa and normal prostate (NP). METHODS AND RESULTS: We identified 15 candidate genes that encode secreted proteins present in PCa and NP. Quantitative RT-PCR analysis revealed that MSMB, NBL1 and AZGP1 were expressed with much higher specificity in PCa and NP than in 14 other kinds of normal tissue. We focused on NBL1, which was originally identified as a putative tumor suppressor gene. Western blot analysis revealed that NBL1 protein was highly expressed in both cell lysate and culture media of the DU145 PCa cell line. Immunohistochemical analysis showed that NBL1 expression was highly detected in and restricted to NP and PCa and was significantly down-regulated in PCa. NBL1 expression was significantly reduced according to the tumor stage, Gleason grade and preoperative prostate-specific antigen (PSA) value. CONCLUSION: NBL1 is a secreted protein that is highly restricted to the prostate. Underexpression of NBL1 correlated with PCa progression. NBL1 might be a candidate tumor marker for PCa in addition to PSA.

MicroRNA-155 is a predictive marker for survival in patients with clear cell renal cell carcinoma.

OBJECTIVES: To investigate the clinical significance of micro-ribonucleic acid-155 in clear cell renal cell carcinoma, in particular focusing on the association of expression levels of micro-ribonucleic acid-155 with clinicopathological factors, cancer-specific survival and therapeutic outcomes in clear cell renal cell carcinoma patients. METHODS: Quantitative reverse transcription polymerase chain reaction of micro-ribonucleic acid-155 was carried out on 137 clear cell renal cell carcinoma cases, containing 77 matched pairs of clear cell renal cell carcinoma and normal adjacent kidney tissues from the same patients. RESULTS: Significant overexpression of micro-ribonucleic acid-155 was found in clear cell renal cell carcinoma compared with normal kidney tissue. Expression of micro-ribonucleic acid-155 was not associated with prognosis in all stage groups. However, in 43 patients with stage III and IV clear cell renal cell carcinoma, low expression levels of micro-ribonucleic acid-155 correlated with a poor prognosis. Regarding cancer-free survival of 26 patients with stage III and IV clear cell renal cell carcinoma who received curative resection and cancer-specific survival of 31 patients who received postoperative therapy with interferon-α after radical nephrectomy, low expression levels of micro-ribonucleic acid-155 correlated with poor clinical outcomes in these two groups. CONCLUSIONS: Low expression of micro-ribonucleic acid-155 represents a valuable marker of poor clinical outcomes in patients with stage III and IV clear cell renal cell carcinoma.

Infantile adenomyoma subclinically excreted into the patient's diaper.

Adenomyoma is a rare condition of the gastrointestinal tract, consisting of glandular structures lined by columnar or cuboidal epithelium and surrounded by smooth muscle bundles. The vast majority of adenomyomas of gastrointestinal tract have been reported to be located at the propyloric segment of the stomach and their localization in the bowel of infantile patients is considered rare. A review of the literature showed that 13 cases of infantile adenomyoma in the bowel have been reported. In the previous cases, intussusception was the most common complication of adenomyoma in the bowel and all cases underwent laparotomy. Here we describe an extremely rare case of infantile adenomyoma subclinically eliminated in the diaper. In addition, we performed immunohistochemical analysis to speculate on the origin of the adenomyoma.

Liver-intestine cadherin induction by epidermal growth factor receptor is associated with intestinal differentiation of gastric cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide. The epidermal growth factor receptor (EGFR) molecule is very important in GC progression. To examine the correlation between EGFR and GC-related genes, we analyzed gene expression profiles of HT-29 cells treated with EGFR ligands and identified six genes upregulated by epidermal growth factor (EGF) and transforming growth factor (TGF)-α treatment. Among these, we focused on cadherin 17 (CDH17) encoding liver-intestine cadherin (LI-cadherin). Expression of LI-cadherin was induced by both EGF and TGF-α, as detected by quantitative RT-PCR and Western blot analysis. A luciferase assay showed that LI-cadherin promoter activity was enhanced by EGF or TGF-α in both HT-29 cells and MKN-74 GC cells. Immunohistochemical analysis of 152 GC cases showed that out of 58 LI-cadherin-positive cases, 24 (41%) cases were also positive for EGFR, whereas out of 94 LI-cadherin-negative cases, only 9 (10%) cases were positive for EGFR (P < 0.0001). Double-immunofluorescence staining revealed that EGFR and LI-cadherin were coexpressed. Significant correlation was found between LI-cadherin expression and advanced T grade and N grade. Both EGFR and LI-cadherin expression were more frequently found in GC cases with an intestinal mucin phenotype than in cases with a gastric mucin phenotype. These results indicate that, in addition to the known intestinal transcription factor caudal type homeobox 2, EGFR activation induces LI-cadherin expression and participates in intestinal differentiation of GC.

Upregulation of HOXA10 in gastric cancer with the intestinal mucin phenotype: reduction during tumor progression and favorable prognosis.

Gastric cancer (GC) is one of the most common malignancies worldwide. Better knowledge of the changes in gene expression that occur during gastric carcinogenesis may lead to improvements in diagnosis, treatment and prevention. In this study, we screened for genes upregulated in GC by comparing gene expression profiles from microarray and serial analysis of gene expression and identified the HOXA10 gene. The aim of the present study was to investigate the significance of HOXA10 in GC. Immunohistochemical analysis demonstrated that 221 (30%) of 749 GC cases were positive for HOXA10, whereas HOXA10 was scarcely expressed in non-neoplastic gastric mucosa except in the case of intestinal metaplasia. Next, we analyzed the relationship between HOXA10 expression and clinicopathological characteristics. HOXA10 expression showed a significant inverse correlation with the depth of invasion and was observed more frequently in the differentiated type of GC than in the undifferentiated type of GC. HOXA10 expression was associated with GC with the intestinal mucin phenotype and correlated with CDX2 expression. Furthermore, the prognosis of patients with positive HOXA10 expression was significantly better than in the negative expression cases. 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and wound healing assay revealed that knockdown of HOXA10 in GC cells by short interfering RNA transfection significantly increased viability and motility relative to the negative control, indicating that HOXA10 expression inhibits cell growth and motility. These results suggest that expression of HOXA10 may be a key regulator for GC with the intestinal mucin phenotype.

Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide. Recently, cancer stem cells (CSCs) in tumors were found to possess the ability to sustain tumor self-renewal, initiate tumor progression, and possibly also contribute to cancer metastasis. We immunohistochemically examined expression and distribution of representative CSC markers ALDH1, CD44, and CD133 in primary tumors and lymph node metastasis of GC. Among 190 GC primary tumors, 104 (55%) were positive for ALDH1, 117 (62%) were positive for CD44, and 18 (9%) were positive for CD133. Expression of these three CSC markers was significantly associated with advanced clinicopathologic factors. Patients with CD44- and CD133-positive GC had a poorer survival rate than patients with CD44- and CD133-negative GC (CD44: P < 0.001, CD133: P= 0.006). Univariate and multivariate Cox proportional hazards analysis revealed tumor node metastasis stage, CD44 expression, and CD133 expression to be independent predictors of survival in patients with GC. Comparison of CSC markers in primary and metastatic sites showed ALDH1 positivity to be significantly higher in diffuse-type lymph node metastasis than in the primary tumor (P < 0.001). These results indicate that these CSC markers are important in tumor invasion and metastasis and may be good markers indicating long-term survival in patients with GC.

Cytokeratin 7 is a predictive marker for survival in patients with esophageal squamous cell carcinoma.

BACKGROUND: Patients diagnosed with stage II and III esophageal squamous cell carcinoma (ESCC) have variable prognosis. This group would benefit greatly from the discovery of prognostic markers that are capable of identifying individuals for whom adjuvant treatment would be advantageous. The aim of this study was to investigate the impact of immunohistochemically detected cytokeratin 7 (CK7) expression on disease-free survival, overall survival (OS), or therapeutic outcome in patients with ESCC. METHODS: Immunohistochemical analysis of CK7 was performed on 225 surgically resected specimens of stage 0-III ESCC. RESULTS: In total, 20 (9%) of 225 ESCC cases were positive for CK7. In stage 0-III ESCC patients, CK7 expression was statistically significantly associated with OS, independent of clinical covariates, including tumor, node, metastasis system stage. In stage II and III ESCC patients (n = 124), CK7 expression was significantly associated with poorer OS (P = 0.0377). Furthermore, in stage II and III ESCC patients who did not receive adjuvant chemotherapy (n = 73), CK7 expression was significantly associated with poorer OS (P = 0.0003). CK7 expression was not associated with therapeutic outcome in patients with stage II and III ESCC who received adjuvant chemotherapy. In patients with CK7-positive ESCC (n = 16), receipt of adjuvant chemotherapy tended to be beneficial for patients with stage II and III ESCC (P = 0.0654). CONCLUSIONS: Immunohistochemical analysis of CK7 will help to identify high-risk patients.

Molecular pathology of gastric cancer: research and practice.

Recent advances in the understanding of molecular stomach carcinogenesis are reviewed. As to molecular events in individual mucin phenotypes of gastric cancer, the CDX2-Reg IV-SOX9 pathway is associated with the intestinal mucin phenotype, while OLFM4 and CLDN18 are novel markers for the gastric phenotype. microRNAs play an important role in epigenetic deregulation in gastric cancer. Many microRNAs are up-regulated and down-regulated, and some of these are associated with histological differentiation and cancer progression. Reduced miR-200 may participate in the genesis of diffuse type gastric cancer by reducing E-cadherin expression. Genetic polymorphism is a crucial endogenous cause and a fundamental factor of cancer risk. PSCA polymorphism alters the susceptibility to diffuse type gastric cancer through modulation of cell proliferation activity. Cancer stem cells possess the capacity for self-renewal and cause the heterogeneous lineages of cancer cells. Cancer stem cells also show resistance to anti-tumor chemotherapy. Only a minor population of gastric cancer cells reveals the properties of cancer stem cells, and CD44 is one of the markers for gastric cancer stem cells. The origin of gastric cancer stem cells remains to be elucidated.

Desmocollin 2 is a new immunohistochemical marker indicative of squamous differentiation in urothelial carcinoma.

AIMS: Urothelial carcinoma (UC) with squamous differentiation tends to present at higher stages than pure UC. To distinguish UC with squamous differentiation from pure UC, a sensitive and specific marker is needed. Desmocollin 2 (DSC2) is a protein localized in desmosomal junctions of stratified epithelium, but little is known about its biological significance in bladder cancer. We examined the utility of DSC2 as a diagnostic marker. METHODS AND RESULTS: We analysed the immunohistochemical characteristics of DSC2, and studied the relationship of DSC2 expression with the expression of the known markers uroplakin III (UPIII), cytokeratin (CK)7, CK20, epidermal growth factor receptor (EGFR), and p53. DSC2 staining was detected in 24 of 25 (96%) cases of UC with squamous differentiation, but in none of 85 (0%) cases of pure UC. DSC2 staining was detected only in areas of squamous differentiation. DSC2 expression was mutually exclusive of UPIII expression, and was correlated with EGFR expression. Furthermore, DSC2 expression was correlated with higher stage (P = 0.0314) and poor prognosis (P = 0.0477). CONCLUSIONS: DSC2 staining offers high sensitivity (96%) and high specificity (100%) for the detection of squamous differentiation in UC. DSC2 is a useful immunohistochemical marker for separation of UC with squamous differentiation from pure UC.