Tissue inhibitor of metalloproteinase-3 expression affects clinicopathological features and prognosis of aflatoxin B1-related hepatocellular carcinoma

BACKGROUND The dysregulation of tissue inhibitor of metalloproteinase-3(TIMP3)was positively correlated with the progression of hepatocellular carcinoma(HCC).However,it is not clear whether TIMP3 expression is associated with the clinico-pathological features and prognosis of aflatoxin B1(AFB1)-related HCC(AHCC).A retrospective study,including 182 patients with AHCC,was conducted to explore the link between TIMP3 expression in cancerous tissues and the clinico-pathological characteristics and prognosis of AHCC.TIMP3 expression was detected by immunohistochemistry and its effects on the clinicopathological features and prognosis of AHCC were evaluated by Kaplan-Meier survival analysis and Cox regression survival analysis.Odds ratio,hazard ratio(HR),median overall survival time(MST),median tumor recurrence-free survival time(MRT),and corresponding 95%confidential interval(CI)was calculated to RESULTS Kaplan-Meier survival analysis showed that compared with high TIMP3 expression,low TIMP3 expression in tumor tissues significantly decreased the MST(36.00 mo vs 18.00 mo)and MRT(32.00 mo vs 16 mo)of patients with AHCC.Multivariate Cox regression survival analysis further proved that decreased expression of TIMP3 increased the risk of death(HR=2.85,95%CI:2.04-4.00)and tumor recurrence(HR=2.26,95%CI:1.57-3.26).Furthermore,decreased expression of TIMP3 protein in tissues with AHCC was significantly correlated with tumor clinicopatho-logical features,such as tumor size,tumor grade and stage,tumor microvessel density,and tumor blood invasion.Additionally,TIMP3 protein expression was also negatively associated with amount of AFB1-DNA adducts in tumor tissues.CONCLUSION These findings indicate that the dysregulation of TIMP3 expression is related to AHCC biological behaviors and affects tumor outcome,suggesting that TIMP3 may act as a prognostic biomarker for AHCC.

Clinicopathological significance of B-cell-specific Moloney murine leukemia virus insertion site 1 expression in gastric carcinoma and its precancerous lesion

AIM： To explore the relation between B-cell-specific Moloney murine leukemia virus insertion site 1 （Bmi-1） expression and the clinicopathological features of gastric carcinoma （GC）.METHODS： Immunohistochemistry was used to detect the expression of Bmi-1 and ki-67. Doublelabeling staining was used to display the distribution of Bcl-2^＋/ki-67 cells in 162 cases of GC and its matched normal mucosa and precancerous lesion.RESULTS： The positive rate of Bmi-1 expression in GC（52.5%） was significantly higher than that in normal gastric mucosa （21.6%, X^2 = 33.088, P 〈 0.05）. The Bmi-1 expression in GC was closely related with the Lauren＇s and Borrmann＇s classification and clinicalstage （X^2 = 4.400, 6.122 and 11.190, respectively, P〈 0.05）. The expression of ki-67 was related to the Borrmann＇s classification （X^2 = 13.380, P 〈 0.05）.Bcl-2 expression was correlated with the Lauren＇s classification （Z2 = 4.725, P 〈 0.05）, and the Bmi-1 expression both in GC （rk = 0.157, P 〈 0.05） and inintestinal metaplasia （rk = 0.270, P 〈 0.05）.CONCLUSION： Abnormal Bmi-1 expression in GCmay be involved in cell proliferation, apoptosis andcancerization. This marker can objectively indicate theclinicopathological characteristics of GC.

CLINICOPATHOLOGICAL SIGNIFICANCE OF PTEN AND CASPASE-3 EXPRESSIONS IN BREAST CANCER

Objective To investigate the expressions of PTEN and Caspase-3 proteins in human breast carcinoma,and to evaluate their clinicopathological implications during the tumorigenesis and progression of breast cancer.Methods The expressions of PTEN and Caspase-3 proteins in 95 cases of breast cancer and 15 cases of benign breast diseases were investigated immunohistochemically.Correlations between the expression of PTEN protein,Caspase-3 protein,and clinicopathological features of breast cancers were analyzed.Results The loss expression rate of PTEN protein in tumor tissues was significantly higher than that in benign breast diseases(33.7% vs.0,P<0.01).Analysis of the clinicopathological features showed that PTEN expression level was negatively correlated with TNM stage,histological grade,axillary lymph node status,recurrence,and metastasis(P<0.05).The positive expression level of Caspase-3 was negatively correlated with TNM stage(P<0.01),but not related with histological grade,axillary lymph node status,recurrence,or metastasis(P>0.05).In addition,the expression of PTEN protein had significantly positive correlation with the expression of Caspase-3 protein in breast cancer(P<0.01).Conclusion The combination detection of PTEN and Caspase-3 may serve as an important index to estimate the pathobiological behavior and prognosis of breast cancer.

Mechanism and pathobiologic implications of CHFR promoter methylation in gastric carcinoma

AIM： TO investigate the aberrant methylation of CHFR promoter in human gastric cancer （GC） and its impact on the expression of CHFR mRNA and protein, as well as its correlation with clinical and histological features of human GC. METHODS： Methylation-specific polymerase chain reaction （MSPCR） was used to detect the methylation status of CHFR promoter in 20 primary GC samples and paired normal gastric mucosa. The CHFR mRNA and protein expressions were investigated both by RT-PCR and by Western blotting. The CHFR protein expression in 39 GC samples was immunohistochemically examined. RESULTS： The DNA methylation of the CHFR gene was found in 9 of the 20 GC samples （45%） and the down-regulation of CHFR mRNA and protein was significantly associated with the methylation status of the CHFR gene （P = 0.006）. In 20 samples of corresponding non-neoplastic mucosa, no DNA methylation of the CHFR gene was detected. The CHFR gene methylation in poorly differentiated GC samples was significantly higher than that in well-differentiated GC samples （P = 0.014）. Moreover, the negative CHFR protein expression rate in paraffin-embedded GC samples was 55.07% （38/69）, the positive rate in poorly differentiated GC samples was 36.73% （18/49）, which was significantly lower than 65.00% （13/20） in well-differentiated GC samples （X^2 = 4.586, P = 0.032）. CONCLUSION： Aberrant methylation of the CHFR gene may be involved in the carcinogenesis and development of GC, and is the predominant cause of down-regulation or loss of CHFR mRNA or protein expression. As aberrant methylation of CHFR promoter is correlated with tumor differentiation, it may help to predict the prognosis of GC and CHFR may become a novel target of gene therapy for GC in the future.

Prognostic significance of BMP and activin membrane-bound inhibitor in colorectal cancer

AIM： To investigate the clinical significance of BMP and activin membrane-bound inhibitor （BAMBI） which is a pseudoreceptor of transforming growth factorbeta （TGF-β） type 1 receptors and acts as a negative regulator of TGF-β signaling and expression aberrantly elevated in colorectal cancers （CRCs）. We studied BAMBI expression in CRCs. METHODS： We studied BAMBI expression in 183 surgically resected CRCs by immunochemical and immunoblotting analyses using a generated monoclonal anti-BAMBI antibody. Commercially available anti-β- catenin and anti-p53 antibodies were also applied for immunochemical analyses as a comparison control.RESULTS： Immunohistochemical analysis revealed that BAMBI expression was observed in 148 （80.8%）, and strong BAMBI expression was observed in 46% of the CRCs. Strong BAMBI expression was positively correlated with histological type, depth of invasion, lymph node metastases, and tumor node metastasis （TNM） stage （P 〈 0.05）. Clear associations were found between BAMBI and β-catenin （P = 0.035） and p53 （P =0.049） expression. In curatively resected CRC, 5-year recurrence-free survival was 51.9% （P = 0.037） for strong BAMBI expression compared to 79.8% for weak BAMBI expression. In the Cox＇s multivariate analysis, lymph node metastases （relative risk 6.685; P 〈 0.001） and depth of invasion （RR 14.0; P = 0.013） were significant indicators for recurrence, and strong BAMBI expression （RR 2.26; P = 0.057） tended to be significant. CONCLUSION： BAMBI was linked to a potentially aggressive tumor phenotype and predicted tumor recurrence and cancer-related death in CRC. BAMBI expression might be applicable in the routine clinical setting of CRC.

Chemoprevention of colorectal cancer by targeting obesity-related metabolic abnormalities

Obesity and its related metabolic disorders, including insulin resistance and chronic inflammation, increase the risk of colorectal cancer(CRC). This observation suggests that the metabolic abnormalities associated with obesity can be effective targets for preventing the development of CRC in obese individuals. In recent years, many studies using obese and diabetic animal models have been conducted to investigate the chemoprevention of CRC using pharmaceutical or nutritional interventions. Pitavastatin, a medicine used to treat hyperlipidemia, prevents the development of obesityrelated colorectal carcinogenesis by attenuating chronic inflammation. Anti-hypertensive medicines, such as captopril and telmisartan, also suppress the formation of colonic preneoplastic lesions in obese and diabetic mice. In addition, several phytochemicals, including green tea catechins, have been reported to improve metabolic disorders and prevent the development of various cancers, including CRC. Moreover, the administration of branched-chain amino acids, which improves protein malnutrition and prevents the progression of hepatic failure, is effective for suppressing obesityrelated colon carcinogenesis, which is thought to be associated with improvements in insulin resistance. In the present article, we summarize the detailed relationship between metabolic abnormalities and the development of CRC. This review also outlines recent evidence, in particular drawing from basic and clinical examinations using either pharmaceutical or nutritional intervention that suggests that targeting metabolic alterations may be an effective strategy for preventing the development of CRC in obese individuals.

Tuberous sclerosis patient with neuroendocrine carcinoma of the esophagogastric junction:A case report

BACKGROUND Tuberous sclerosis complex(TSC)is a rare inherited disease with non-cancerous tumor growths in the skin,brain,kidneys,heart,and lungs.The co-occurrence of neuroendocrine neoplasm(NEN)with TSC is even rarer.There have been few reports on the relationship between TSC and neuroendocrine tumors(NETs),and fewer on the relationship between TSC and neuroendocrine carcinoma(NEC),a subtype of NEN.This is the first reported case of NEC occurring at the esophagogastric junction in a patient with TSC.CASE SUMMARY A 46-year-old woman visiting our hospital for the treatment of TSC was admitted to the emergency department with tarry stools and dizziness.Computed tomography scans revealed thickness of the gastric cardia,multiple metastatic lesions of the liver,and enlarged lymph nodes near the lesser curvature of the stomach.Esophagogastroduodenoscopy revealed a type 3 tumor located from the esophagogastric junction to the fundus,and the pathological diagnosis by biopsy was NEC.The patient was treated with seven courses of cisplatin+irinotecan,followed by eight courses of ramucirumab+nab-paclitaxel,one course of nivolumab,and two courses of S-1+oxaliplatin.Twenty-three months after the first treatment,the patient died because of disease progression and deterioration of the general condition.CONCLUSION This case of NEC occurring in a patient with TSC indicates a difference in the occurrence of NETs and NECs.

Internal frontier:The pathophysiology of the small intestine

Even though the small intestine occupies a major portion of the abdominal space and is essential for life,in most pathology textbooks any chapter on small intestinal diseases,especially in human beings,is typically shorter than those for other gastrointestinal organs.Clinical and experimental investigations of the small intestine in various clinical situations,such as nutrition management,obesity interventions,and emergency care,have elucidated several important biological problems associated with the small intestine,the last frontier of gastroenterology.In this issue,a review by Professor Basson and his team at Michigan State University sheds light on the changes in the human small intestine under various conditions based on their clinical and surgical experience.With the advent of recent innovations in enteroscopy,a form of endoscopy used to examine deep within the small intestine,the issue that they highlighted,i.e.,mucosal adaptation and atrophy of the human small intestine,has emerged as a major and manageable challenge for gastroenterologists in general,including the readers of the World Journal of Gastroenterology.

Cancer chemoprevention through the induction of apoptosis by natural compounds

As cell and tissue homeostasis are mediated by the balance between proliferation and apoptosis, controlling this balance is important for cancer chemoprevention. Cancer chemoprevention can be achieved by the use of natural, synthetic or biologic compounds that reverse, suppress or prevent the development of epithelial malignancies. Natural compounds including flavonoids are able to reduce oxidative stress, which is the most likely mechanism mediating the protective effects against cancer development. In addition, in vitro and in vivo studies have suggested that flavonoids, such as (-)-epigallocatechin-3-gallete (EGCG), quercetin, and curcumin, act by induction of apoptosis. Several natural compounds inhibit cell proliferation and angiogenesis. Certain natural products have been shown to inhibit the activation of nuclear factor kappa B (NF-κB) and Akt signaling pathways, both of which are known to maintain a homeostatic balance between cell survival and apoptosis. Understanding the mechanism of these natural products will contribute to the development of more specific preventive strategies against cancer development. Here we focus on the ability of natural cancer chemopreventive agents to induce apoptosis, and attempt to provide evidence for the preventive and therapeutic effects of natural compounds, EGCG, quercetin, and curcumin, in a succinct manner highlightingκand Akt signaling pathways in vivo.

Visualization of sphingolipids and phospholipids in the fundic gland mucosa of human stomach using imaging mass spectrometry

AIM:To analyze the lipid distribution in gastric mucosae.METHODS:Imaging mass spectrometry(MS)is a useful tool to survey the distribution of biomolecules in surgical specimens.Here we used the imaging MS apparatus named i MScope to identify the dominant molecules present in the human gastric mucosa near the fundic glands.Five gastric specimens were subjected to iM Scope analysis.These specimens were also analyzed by immunohistochemistry using MUC5 AC,H(+)-K(+)-ATPaseβ Claudin18 antibodies.RESULTS:Three major molecules with m/z 725.5,780.5,and 782.5 detected in the gastric mucosa were identified as sphingomyelin(SM)(d18:1/16:0),phosphatidylcholine(PC)(16:0/18:2),and PC(16:0/18:1),respectively,through MS/MS analyses.Using immunohistological staining,SM(d18:1/16:0)signals were mainly colocalized with the foveolar epithelium marker MUC5 AC.In contrast,PC(16:0/18:2)signals were observed in the region testing positive for the fundic gland marker H(+)-K(+)-ATPaseβ.PC(16:0/18:1)signals were uniformly distributed throughout the mucosa.CONCLUSION:Our basic data will contribute to the studies of lipid species in physical and pathological conditions of the human stomach.

Clinicopathological significance and relations of Caspase-3 expression, cell proliferation and apoptosis in gastric cancer and the precancerous lesions

Objective： We investigated the relationship between the expression of Caspase-3, cell proliferation and apoptosis in gastric cancer and their precancerous lesions, to explore the tumorigenesis of the stomach mucosa. Methods： Caspase- 3 expression in 13 normal gastric mucosa, 6 chronic atrophic gastritis （CAG）, 31 intestinal metaplasia （IM）, 114 dysplasia （DYS） and 20 gastric carcinomas were investigated immunohistochemically. Cell proliferation was evaluated with anti-Ki-67 immunostaining and apoptosis was evaluated using DNA fragmentation in situ by TdT-mediated dUTP biotin nick end labeling （TUNEL） method. Results： Caspase-3 mild-moderately positive expression was observed in most of normal superficial epithelia, its positively polar distribution in normal mucosa, CAG, IM, DYS and gastric carcinomas changed as seen in TU- NEL, and so did the positive rate. Caspase-3 protein expression showed significantly positive correlation with the number of apoptotic cells labeled with TUNEL （correlation coefficient r = 0,94; P 〈 0101）. Ki-67 expression showed a negative but not significant correlation trend with Caspase-3 （correlation coefficient r = -0.23; P 〉 0.05）. Conclusion： Caspase-3 protein expression was up-regulated from CAG to IM and mild-moderate atypical dysplasia, but down-regulated in severe dysplasia and gastric carcinoma, indicating that inactivity or reduced expression of Caspase-3 is closely correlated with carcinogenesis of the stomach mucosa.

Impaired suppressive activities of human MUTYH variant proteins against oxidative mutagenesis

AIM:To investigate the suppressive activity of MUTYH variant proteins against mutations caused by oxidative lesion,8-hydroxyguanine(8OHG),in human cells.METHODS:p.R154H,p.M255V,p.L360P,and p.P377L MUTYH variants,which were previously found in patients with colorectal polyposis and cancer,were selected for use in this study.Human H1299 cancer cell lines inducibly expressing wild-type(WT) MUTYH(type 2) or one of the 4 above-mentioned MUTYH variants were established using the piggyBac transposon vector system,enabling the genomic integration of the transposon sequence for MUTYH expression.MUTYH expression was examined after cumate induction using Western blotting analysis and immunofluorescence analysis.The intracellular localization of MUTYH variants tagged with FLAG was also immunofluorescently examined.Next,the mutation frequency in the supF of the shuttle plasmid pMY189 containing a single 8OHG residue at position 159 of the supF was compared between empty vector cells and cells expressing WT MUTYH or one of the 4 MUTYH variants using a supF forward mutation assay.RESULTS:The successful establishment of human cell lines inducibly expressing WT MUTYH or one of the 4 MUTYH variants was concluded based on the detection of MUTYH expression in these cell lines after treatment with cumate.All of the MUTYH variants and WT MUTYH were localized in the nucleus,and nuclear localization was also observed for FLAG-tagged MUTYH.The mutation frequency of supF was 2.2 × 10-2 in the 8OHG-containing pMY189 plasmid and 2.5 × 10-4 in WT pMY189 in empty vector cells,which was an 86-fold increase with the introduction of 8OHG.The mutation frequency(4.7 × 10-3) of supF in the 8OHG-containing pMY189 plasmid in cells overexpressing WT MUTYH was significantly lower than in the empty vector cells(P < 0.01).However,the mutation frequencies of the supF in the 8OHG-containing pMY189 plasmid in cells overexpressing the p.R154H,p.M255V,p.L360P,or p.P377L MUTYH variant were 1.84 × 10-2,1.55 × 10-2,1.91 × 10-2,and 1.96 × 10-2,respectively,meaning that no significant difference was observed in the mutation frequency between the empty vector cells and cells overexpressing MUTYH mutants.CONCLUSION:The suppressive activities of p.R154H,p.M255V,p.L360P,and p.P377L MUTYH variants against mutations caused by 8OHG are thought to be severely impaired in human cells.

Significance and relationship between Yes-associated protein and survivin expression in gastric carcinoma and precancerous lesions

AIM:To analyze the differences and relevance of Yes-associated protein (YAP) and survivin, and to explore the correlation and signifi cance of their expression in gastric carcinoma and precancerous lesions.METHODS: The PV9000 immunohistochemical method was used to detect the expression of YAP and survivin in 98 cases of normal gastric mucosa, 58 intestinal metaplasia (IM), 32 dysplasia and 98 gastric carcinoma.RESULTS: The positive rates of YAP in dysplasia (37.5%) and gastric carcinoma (48.0%) were significantly higher than that in normal gastric mucosa (13.3%), P<0.01. The positive rates of survivin in IM (53.4%), dysplasia (59.4%) and gastric carcinoma (65.3%) were significantly higher than in normal gastric mucosa (11.2%), P<0.01. Survivin expression gradually increased from 41.7% in well differentiated adenocarcinoma through 58.3% in moderately differentiated adenocarcinoma to 75.6% in poorly differentiated adenocarcinoma, with significant Rank correlation, rk=0.279, P<0.01. The positive rate of survivin in gastric carcinoma of diffused type (74.6%) was significantly higher than that in intestinal type (51.3%), P<0.05. In gastric carcinoma with lymph node metastasis (76.9%), the positive rate of survivin was signifi cantly higher than that in the group without lymph node metastasis (41.2%), P<0.01. In 98 cases of gastric carcinoma, the expression of YAP and of survivin were positively correlated, rk=0.246, P<0.01.CONCLUSION: YAP may play an important role as a carcinogenic factor and may induce survivin expression. Detecting both markers together may help in early diagnosis of gastric carcinoma.

Single skip metastasis in sentinel lymph node: In an early gastric cancer

Lymph node status is considered a key prognostic and predictive factor in patients with gastric cancer(GC).Although there is a practical approach to the intraoperative detection of sentinel lymph nodes(SLNs),such a procedure is not included in the European surgical protocol.In this report,we present a practical approach to SLN mapping in a representative case with early gastric cancer(EGC).A 74-year-old female was hospitalized with an endoscopically observed,superficially ulcerated tumor located in the antral region.Subtotal gastrectomy with D2 lymphadenectomy and SLN mapping was performed by injecting methylene blue dye into the peritumoral submucosal layer.An incidentally detected blue-stained lymph node located along the middle colic artery was also removed.This was detected 40 min after injection of the methylene blue.Histopathologic examination showed a p T1b-staged well-differentiated HER-2-negative adenocarcinoma.All of the 41 LNs located at the first,third,and fifth station of the regional LN compartments were found to be free of tumor cells.The only lymph node with metastasis was located along the middle colicartery and was considered a non-regional lymph node.This incidentally identified skip metastasis indicated stage Ⅳ GC.A classic chemotherapy regimen was given,and no recurrences were observed six months after surgery.In this representative case,low-cost SLN mapping,with a longer intraoperative waiting time,totally changed the stage of the tumor in a patient with EGC.

Kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice

BACKGROUND Inflammatory bowel disease,such as Crohn’s disease and ulcerative colitis,is characterized by chronic intestinal inflammation leading to intestinal mucosal damage.Inflammatory bowel disease causes dysregulation of mucosal T cell responses,especially the responses of CD4+T cells.Previously,we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate(TNBS)-induced colitis.Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan(Trp)and immunomodulatory Trp metabolites,the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear.AIM To investigate role of kynurenine 3-monooxygenase(KMO)in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis.METHODS Colitis was induced in eight-week-old male KMO+/+or KMO−/−mice of C57BL/6N background using TNBS.Three days later,the colon was used for hematoxylin-eosin staining for histological grading,immunohistochemical or immunofluorescence staining for KMO,cytokines,and immune cells.Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR,and kynurenine(Kyn)pathway metabolites were measured by high-performance liquid chromatography.The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry.RESULTS KMO expression levels in the colonic mononuclear phagocytes,including dendritic cells and macrophages increased upon TNBS induction.Notably,KMO deficiency reduced TNBS-induced colitis,resulting in an increased frequency of Foxp3+regulatory T cells and increased mRNA and protein levels of antiinflammatory cytokines,including transforming growth factor-βand interleukin-10.CONCLUSION Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+regulatory T cells by producing Kyn.Thus,Kyn may play a therapeutic role in colon protection during colitis.

SGF29 and Sry pathway in hepatocarcinogenesis

Deregulated c-Myc expression is a hallmark of many human cancers. We have recently identified a role of mammalian homolog of yeast SPT-ADA-GCN5-acetyltransferas(SAGA) complex component, SAGAassociated factor 29(SGF29), in regulating the c-Myc overexpression. Here, we discuss the molecular nature of SFG29 in SPT3-TAF9-GCN5-acetyltransferase complex, a counterpart of yeast SAGA complex, and the mechanism through which the elevated SGF29 expression contribute to oncogenic potential of c-Myc in hepatocellularcarcinoma(HCC). We propose that the upstream regulation of SGF29 elicited by sexdetermining region Y(Sry) is also augmented in HCC. We hypothesize that c-Myc elevation driven by the deregulated Sry and SGF29 pathway is implicated in the male specific acquisition of human HCCs.

Maspin subcellular expression in wild-type and mutant TP53 gastric cancers

BACKGROUND Although the role of p53 in the evolution and prognosis of gastric cancer(GC)has been extensively examined,the exact mechanism of action is incompletely understood.In the last years,p53-target genes were supposed to be involved in the p53 pathway.One of them is the tumor-suppressor gene Maspin,which codifies the protein with the same name.Maspin activity depends on its subcellular localization.To our knowledge,the possible role of TP53 gene in Maspin subcellular localization,in GC cells,has not yet been studied in a large number of human samples.AIM To evaluate the possible role of wild-type and mutated p53 in Maspin subcellular localization.METHODS The present study included 266 consecutive patients with GC in which TP53 gene status,and mutations in exons 2 to 11,respectively,were analyzed and correlated with immunohistochemical expression of p53 and Maspin.RESULTS None of the 266 cases showed mutations in exon 9.The rate of TP53 mutations was 33.83%.The mutation rate was slightly higher in distally-located GCs,with a lower degree(≤5 buds/high power fields)of dyscohesivity(P<0.01).The wildtype cases had a longer survival,compared with mutant GCs,especially in patients without lymph node metastases,despite the high depth of tumor infiltration(P=0.01).The Dukes-MAC-like staging system was proved to have the most significant independent prognostic value(P<0.01).The statistical correlations proved that TP53 gene mutations in exon 7 might induce knockdown of Maspin,but wild-type p53 can partially restore nuclear Maspin expression and decrease the metastatic potential of gastric adenocarcinoma cells.CONCLUSION Downregulated Maspin might be induced by mutations in exon 7 of the TP53 gene but wild-type p53 can partially restore nuclear Maspin expression.These findings should be proved in experimental studies.

Rapidly enlarged inflammatory hepatocellular adenoma: A case report

We present a rare case of rapidly enlarging inflamematory hepatocellular adenoma (IHCA) in a 60-year-old Japanese man. Screening abdominal computed tomography (CT) for the fatty liver patient revealed a 1.7-cm liver mass in the anterior segment of the liver. After 19 months, the lesion had rapidly enlarged to 6 cm in diameter and the patient was referred to our hospital. On perflubutane microbubble contrast-enhanced ultrasonography, the tumor showed a characteristic centripetal filling pattern in the vascular phase. We performed hepatic anterior segment resection because we could not rule out malignant tumor. Histopathological examination showed hyperplasia of mildly atypical hepatocytes and sinusoidal dilatation with marked inflammatory cell infiltration. Immunohistological staining revealed positive staining for serum amyloid A and C-reactive protein;therefore, we diagnosed this tumor as IHCA. The patient remains alive 42 months after operation without evidence of recurrence.

Are there markers for exceptional responders available for attending pathologists?

In the records of the recent rampant clinical trials,people have noticed there is a fraction,though small,who have ex tremely good responses to the drugs.The definition of this population"Cancer exceptional responder"is proposed and feasibility study has been launched[1].Definition there is not par ticularly hard ones.Classical example is one of 14 bladder cancer patients who participated in Everolimus phase 2 trial,had complete response,and subsequent analysis of DNA of those patients revealed that they had inactivation mutations in TSC1 and NF2,both of which were mTOR regulators[2].

Esophageal Carcinogenesis

Esophageal cancer is the sixth leading cause of cancer death and remains one of the least survivable cancers. Esophageal cancers show wide variations in incidence in different population, suggesting that environmental or lifestyle risk factors could be controlled to reduce risk of these diseases. There are two major histopathologic types (squamous cell carcinoma and adenocarcinoma) of esophageal epithelial malignancy. Recently, the rate of adenocarcinoma is increasing in developed countries: in the United States, 50% or more is adenocarcinoma and, in about 70%, the increase especially in a white male serves as adenocarcinoma. Esophageal adenocarcinoma develops in the lower esophagus. In contrast, in Japan, the increase in adenocarcinoma is not clear and most (90%) of esophageal cancers are squamous cell carcinoma. Such squamous cell carcinoma occurs onto the middle part esophagus mostly, and 60% or more of the whole esophagus cancer also develops in the middle and upper parts. These differences also influence the treatment results. The scope of this article is to discuss carcinogenesis in the esophagus by giving an overview about its histopathological characteristics and molecular mechanisms.