MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway.

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is frequently activated in various human cancers and plays essential roles in their development and progression. Accumulating evidence suggests that dysregulated expression of microRNAs (miRNAs) is closely associated with cancer progression and metastasis. Here, we focused on miRNAs that could regulate genes related to the PI3K/AKT pathway in esophageal squamous cell carcinoma (ESCC). To identify upregulated miRNAs and their possible target genes in ESCC, we performed microarray-based integrative analyses of miRNA and mRNA expression levels in three human ESCC cell lines and a normal esophageal epithelial cell line. The miRNA microarray analysis revealed that miR-31-5p, miR-141-3p, miR-200b-3p, miR-200c-3p, and miR-205-5p were expressed at higher levels in the ESCC cell lines than the normal esophageal epithelial cell line. Bioinformatical analyses of mRNA microarray data identified several AKT/PI3K pathway-related genes as candidate targets of these miRNAs, which include tumor suppressors such as DNA-damage-inducible transcript 4 and pleckstrin homology domain leucine-rich repeat protein phosphatase-2 (PHLPP2). To validate the targets of relevant miRNAs experimentally, synthetic mimics of the miRNAs were transfected into the esophageal epithelial cell line. Here, we report that miR-141-3p suppress the expression of PHLPP2, a negative regulators of the AKT/PI3K pathway, as a target in ESCC.

RNA-Seq analysis of human cell lines established from normal and neoplastic esophageal squamous epithelium.

Esophageal cancer (EC) is the eighth most common cancer globally in 2012 and predominantly occurs in the man (Enzinger and Mayer, 2003; Conteduca et al., 2012). EC is classified mainly into two types, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, accounting for 60-70% and 20-30% of all EC cases, respectively. In a previous statistical study it was reported that the numbers of new EC cases and EC-related deaths worldwide in 2008 were estimated to be 482,300 and 406,800, respectively (Jemal et al., 2011). This high mortality rate is largely due to the characteristics of EC such as frequent distant/local metastasis and poor subjective symptoms leading to difficulty with early diagnosis. Patients affected with EC diagnosed at late stages mostly have unsatisfactory prognosis, even though various therapeutic options are available. Therefore, there is an urgent need to develop effective methods that enable the early detection of EC (Orringer, 1993), prompting us to search for novel biomarkers for EC. Here, we provide datasets from RNA-Seq analysis of Het-1A, a normal human esophageal squamous cell line (Stoner et al., 1991), and TE-1, TE-5, and TE-8, which are well-, poorly-, and moderately-differentiated ESCC-derived cell lines, respectively (Nishihira et al., 1993). The raw data of these experiments have been deposited at DNA Data Bank of Japan (DDBJ) under the accession IDs DRR084199, DRR084200, DRR084201, and DRR084202.

Right Inguinal Hernia Encompassing the Uterus, Right Ovary and Fallopian Tube in an Elderly Female: Case Report.

The uterus, ovary, and fallopian tube are rarely present in an inguinal hernia. We report on an operation to treat just such a rare condition for a right inguinal hernia. An 87-year-old Japanese woman was admitted with swelling in the right inguinal region and a purulent discharge from the vagina. Vital signs were stable, but the mobile mass was irreducible. Computed tomography of the abdomen indicated uterine tissue in a right inguinal hernia. We diagnosed an inguinal hernia with an incarcerated uterus and performed surgery on that basis. An incision approximately 6 cm long was made in the skin above the swollen area to open the inguinal sac, disclosing a tumor enveloped by a hernial sac. Opening the hernial sac revealed the prolapsed uterus, the fallopian tube, and the right ovary. Because no ischemic change was noted, the incarcerated uterus was returned to the abdominal cavity, and the hernial opening was closed with the onlay mesh technique. The posterior wall of the inguinal canal was found to have prolapsed laterally to the inferior epigastric artery, resulting in an external inguinal hernia. This case demonstrates that careful attention must be paid to inguinal hernias in female patients because the uterus, ovary, and fallopian tube may be involved.

Small cell carcinoma of the esophagus: a case report.

A case of esophageal small cell carcinoma successfully treated with combination therapy consisting of preoperative chemotherapy, radiation therapy, and surgical resection. A 76-year-old man presented with a small cell carcinoma measuring 6 cm in diameter in the middle third of the thoracic esophagus. After preoperative therapy, the gross tumor was completely resected. The patient eventually died of metastatic disease 25 months after diagosis. We discuss the treatment of esophageal small cell carcinoma.

Giant appendiceal mucocele: report of a case.

Mucoceles of the appendix are a group of mucus-filled lesions causing obstructive dilation of the ileocecal appendix. We report a rare case of giant appendiceal mucocele. A 48-year-old woman, with no discomfort, was admitted to our hospital after a mass was detected in the right lower quadrant of the abdomen. The patient underwent right hemicolectomy on the basis of the clinical diagnosis of a possible appendiceal tumor. The final pathologic diagnosis was mucocele of the appendix.

Hepatic pedicle clamping does not worsen survival after hepatic resection for colorectal liver metastasis: results from a systematic review and meta-analysis.

BACKGROUND: Hepatic pedicle clamping (HPC) has been demonstrated to be effective for short-term outcomes during hepatic resection. However, HPC-induced hepatic ischemia/reperfusion injury can accelerate the outgrowth of hepatic micrometastases in experimental studies. The conclusive evidence regarding effects of HPC on long-term patient outcomes after hepatic resection for colorectal liver metastasis (CRLM) has not been determined. METHODS: A comprehensive electronic literature search was performed to identify studies evaluating the oncological effects of HPC after hepatic resection for CRLM. The main outcome measures were intrahepatic recurrence (IHR), disease-free survival (DFS), and overall survival (OS). A meta-analysis was performed using the random-effects models to compute odds ratio (OR) along with 95% confidence intervals (CI). RESULTS: Four studies, with a total of 2,114 patients (73.7% HPC, 26.3% non-HPC), matched the inclusion criteria. Meta-analyses revealed that IHR (OR 0.88; 95% CI 0.69-1.11; P = 0.27), DFS (OR 0.88; 95% CI 0.70-1.10; P = 0.27) and OS (OR 0.99; 95% CI 0.79-1.24; P = 0.90) did not differ significantly between the HPC and non-HPC groups. CONCLUSIONS: This meta-analysis provides persuasive evidence that HPC during hepatic resection for CRLM has no significant adverse oncological outcomes. HPC should be considered an option during parenchymal liver resection from current available evidence.

Combination of protein coding and noncoding gene expression as a robust prognostic classifier in stage I lung adenocarcinoma.

Prognostic tests for patients with early-stage lung cancer may provide needed guidance on postoperative surveillance and therapeutic decisions. We used a novel strategy to develop and validate a prognostic classifier for early-stage lung cancer. Specifically, we focused on 42 genes with roles in lung cancer or cancer prognosis. Expression of these biologically relevant genes and their association with relapse-free survival (RFS) were evaluated using microarray data from 148 patients with stage I lung adenocarcinoma. Seven genes associated with RFS were further examined by quantitative reverse transcription PCR in 291 lung adenocarcinoma tissues from Japan, the United States, and Norway. Only BRCA1, HIF1A, DLC1, and XPO1 were each significantly associated with prognosis in the Japan and US/Norway cohorts. A Cox regression-based classifier was developed using these four genes on the Japan cohort and validated in stage I lung adenocarcinoma from the US/Norway cohort and three publicly available lung adenocarcinoma expression profiling datasets. The results suggest that the classifier is robust across ethnically and geographically diverse populations regardless of the technology used to measure gene expression. We evaluated the combination of the four-gene classifier with miRNA miR-21 (MIR21) expression and found that the combination improved associations with prognosis, which were significant in stratified analyses on stage IA and stage IB patients. Thus, the four coding gene classifier, alone or with miR-21 expression, may provide a clinically useful tool to identify high-risk patients and guide recommendations regarding adjuvant therapy and postoperative surveillance of patients with stage I lung adenocarcinoma.

SnoN/SKIL modulates proliferation through control of hsa-miR-720 transcription in esophageal cancer cells.

It is now evident that changes in microRNA are involved in cancer progression, but the mechanisms of transcriptional regulation of miRNAs remain unknown. Ski-related novel gene (SnoN/SKIL), a transcription co-factor, acts as a potential key regulator within a complex network of p53 transcriptional repressors. SnoN has pro- and anti-oncogenic functions in the regulation of cell proliferation, senescence, apoptosis, and differentiation. We characterized the roles of SnoN in miRNA transcriptional regulation and its effects on cell proliferation using esophageal squamous cell carcinoma (ESCC) cells. Silencing of SnoN altered a set of miRNA expression profiles in TE-1cells, and the expression levels of miR-720, miR-1274A, and miR-1274B were modulated by SnoN. The expression of these miRNAs resulted in changes to the target protein p63 and a disintegrin and metalloproteinase domain 9 (ADAM9). Furthermore, silencing of SnoN significantly upregulated cell proliferation in TE-1 cells, indicating a potential anti-oncogenic function. These results support our observation that cancer tissues have lower expression levels of SnoN, miR-720, and miR-1274A compared to adjacent normal tissues from ESCC patients. These data demonstrate a novel mechanism of miRNA regulation, leading to changes in cell proliferation.

Determination of urinary trypsin inhibitor provides insight into postoperative complications in patients following esophagectomy.

The urinary trypsin inhibitor (UTI) is responsible for most of the antitryptic activity in urine and is excreted in increased amounts in urine under certain pathological conditions such as cancer and bacterial infections. Our aim in this study was to better understand the mechanisms responsible for the increase in UTI excretion on surgical stress and thus to better appreciate the information provided by inflammatory mediators. Thirty-one consecutive patients who underwent radical esophagectomy for esophageal cancer were investigated in this study. We determined serum UTI and polymorphonuclear cell elastase (PMNE), urine UTI and evaluated the effectiveness of preoperative administration of methylprednisolone on the postoperative clinical course and adverse inflammatory reactions. The results revealed that urine UTI and serum PMNE levels in the steroid group were significantly lower than those in the non-steroid group. In addition, UTI levels correlated positively with serum levels of aminotransferases. More importantly, the maximum level of urine UTI in patients without complications was lower than that in patients with complications. These results suggest that urine UTI provides useful information concerning postoperative clinical course, and that preoperative administration of methylprednisolone may contribute to decrease postoperative complications following esophagectomy.

Surgical wound management made easier and more cost-effective.

Evidence-based guidelines for the prevention of surgical site infection (SSI) have been published by the U.S. Centers for Disease Control and Prevention (CDC). According to these guidelines, a wound should usually be covered with a sterile dressing for 24 to 48 h when a surgical incision is closed primarily. However, it is not recommended that an incision be covered by a dressing beyond 48 h. In this study, patients were stratified into two groups for analysis: patients whose surgical wound was sterilized and whose gauze was changed once daily until postoperative day 7 (7POD; group A); and patients whose surgical wound was sterilized and whose gauze was changed once daily until 2POD (group B). We evaluated the incidence of SSI, nursing hours and cost implications. The results showed that there was no significant difference in SSI occurrence between the two groups (group A, 10% vs. group B, 7.3%). By contrast, the average nursing time differed by 2.8 min (group A, 3.8 min vs. group B, 0.9 min). The material costs per patient were also reduced by $14.70 (group A, $61.80 vs. group B, $47.10). In conclusion, we applied our knowledge of the evidence-based CDC guidelines to determine whether 48-h wound management can be made easier, more uniform and more cost-effective compared to conventional wound management. The results of the present study showed that surgical wound management methods can be more convenient and inexpensive.

Pyogenic liver abscess caused by direct invasion of esophageal squamous cell carcinoma to the liver: report of a case.

We report a case of esophageal squamous cell carcinoma (ESCC) directly invading the liver and causing a pyogenic liver abscess. The patient was a 66-year-old man who presented with dysphagia. Esophagography, endoscopic study, and computed tomography (CT) showed a mass lesion in the lower third of the esophagus. A high fever developed on hospital day 17 and another CT scan revealed a liver abscess, 50 × 45 mm, in the left lateral lobe of the liver. Although imaging demonstrated a liver abscess continuous with the tumor, we performed percutaneous transhepatic drainage, followed thereafter by distal esophagectomy and total gastrectomy with a left lateral segmental resection of the liver. The pathological findings confirmed a diagnosis of ESCC with direct invasion (T4N1M0, stage IVa in the TNM classification). The patient had an uneventful postoperative recovery. Microscopic examination of the resected specimen revealed the expansive growth of tumor cells into the hepatocellular tissues. To our knowledge, this is the first report of the direct invasion of esophageal cancer to the liver causing a pyogenic liver abscess; however, it should be borne in mind when a patient with esophageal cancer becomes febrile.

Real-time PCR-based analysis of the human bile microRNAome identifies miR-9 as a potential diagnostic biomarker for biliary tract cancer.

Biliary tract cancer (BTC) is often difficult to diagnose definitively, even through histological examination. MicroRNAs (miRNAs) regulate a variety of physiological processes. In recent years, it has been suggested that profiles for circulating miRNAs, as well as those for tissue miRNAs, have the potential to be used as diagnostic biomarkers for cancer. The aim of this study was to confirm the existence of miRNAs in human bile and to assess their potential as clinical biomarkers for BTC. We sampled bile from patients who underwent biliary drainage for biliary diseases such as BTC and choledocholithiasis. PCR-based miRNA detection and miRNA cloning were performed to identify bile miRNAs. Using high-throughput real-time PCR-based miRNA microarrays, the expression profiles of 667 miRNAs were compared in patients with malignant disease (n = 9) and age-matched patients with the benign disease choledocholithiasis (n = 9). We subsequently characterized bile miRNAs in terms of stability and localization. Through cloning and using PCR methods, we confirmed that miRNAs exist in bile. Differential analysis of bile miRNAs demonstrated that 10 of the 667 miRNAs were significantly more highly expressed in the malignant group than in the benign group at P<0.0005. Setting the specificity threshold to 100% showed that some miRNAs (miR-9, miR-302c*, miR-199a-3p and miR-222*) had a sensitivity level of 88.9%, and receiver-operating characteristic analysis demonstrated that miR-9 and miR-145* could be useful diagnostic markers for BTC. Moreover, we verified the long-term stability of miRNAs in bile, a characteristic that makes them suitable for diagnostic use in clinical settings. We also confirmed that bile miRNAs are localized to the malignant/benign biliary epithelia. These findings suggest that bile miRNAs could be informative biomarkers for hepatobiliary disease and that some miRNAs, particularly miR-9, may be helpful in the diagnosis and clinical management of BTC.

Successful treatment of a spontaneous esophageal rupture in an elderly patient: a case report.

An 80-year-old woman was admitted to our hospital with severe chest and back pains after vomiting. Computed tomography (CT) of the chest revealed left-sided pneumothorax and pleural effusion. Some food was drained from an inserted chest tube, and we diagnosed spontaneous esophageal rupture (Boerhaave's syndrome). A left thoracotomy was performed 7 hours after the onset of symptoms. A 3-cm perforation was discovered in the lateral wall of the distal esophagus. The perforation was repaired with a primary two-layered closure and covered with pericardial fat. The patient had a good postoperative course and was discharged 1 month after surgery. This case suggests the importance of early surgical treatment, even in elderly patients with spontaneous esophageal rupture.

Incisional bladder hernia with temporary bowel incarceration: report of a case.

Abdominal hernias are not rare in women, but incisional bladder hernias are rare. The incisional hernia is a condition caused by protrusion of the abdominal viscera through the abdominal fascia. The presenting symptoms in the cases reported included suprapubic discomfort, irritative voiding symptoms, and urinary incontinence. We present a case of bladder herniation with temporary bowel incarceration through a lower midline incision, which followed operative intervention. The temporary bowel herniation was managed conservatively because the impairment of the blood supply was not severe.

Overexpression of PIK3CA is associated with lymph node metastasis in esophageal squamous cell carcinoma.

The genomic region containing PIK3CA was found to be amplified in esophageal squamous cell carcinoma (ESCC) tissue. PIK3CA at 3q26, which encodes the p110alpha catalytic subunit of phosphatidylinositol (PI) 3-kinase, is a unique intracellular signal transducer characterized by its lipid substrate specificity. In order to characterize PIK3CA in ESCC, we investigated hot-spot mutations in exons 1, 9 and 20, the copy number gain, the expression levels of mRNA and protein. Analysis in exon 9 of the PIK3CA gene revealed mutation in 7.7% (4 of 52) of ESCC samples. No mutation was detected in either exon 1 or exon 20. Copy number amplifications of PIK3CA were found in 12 of the 45 patients (26.7%). PIK3CA mRNAs were examined in 37 ESCC patients as determined by quantitative RT-PCR and the mean mRNA level of PIK3CA in ESCC tissues was 2.61-fold higher compared with that in corresponding non-tumorous esophageal epithelia (P<0.001). Immunohistochemically, positive immunoreaction for PIK3CA was detectable in 33 of 66 (50.0%) ESCC cases, while it was not detectable in the remaining 33 cases. Furthermore, comparing the cases with negative staining with those with positive staining for PIK3CA, the presence of node metastasis was significantly correlated with those with positive staining (P<0.05). This study is the first report providing comprehensive analysis of PIK3CA expression in ESCC. These results indicate that PIK3CA may play a crucial role in the development of ESCC and serve as an indicator for lymph node metastasis.

Expression of Akt and Mdm2 in human esophageal squamous cell carcinoma.

The Akt-Mdm2 pathway plays an important role in carcinogenesis in a variety of malignant tumors. However, the Akt-Mdm2 pathway in esophageal squamous cell carcinoma (ESCC) has not been fully studied. We investigated the proteins and mRNA expression of Akt and Mdm2 to elucidate the roles of these proteins in ESCC. We also examined the effect of Akt knockdown on Mdm2 expression in ESCC cells. ESCC tissue samples were obtained from 23 individuals who underwent surgical resection with no preoperative treatment. Akt1-3 and Mdm2 gene and protein expression were analyzed. The effect of siRNA-mediated Akt knockdown on Mdm2 expression was also studied, using ESCC cell lines. Akt1 and Mdm2 immunoreactivity was detected in 77.8 and 66.7% of tumor specimen from ESCC patients, respectively. Akt1 and Mdm2 mRNA expressions were correlated and significantly elevated in tumor tissue (p<0.0001 and p<0.05, respectively). The siRNA-targeted reduction of each Akt isoform reduced Mdm2 protein expression. The overexpression of Akt1 and Mdm2 may be related to esophageal carcinogenesis. Furthermore, Akt expression regulates Mdm2 expression, which may in turn regulate the function of wild-type p53. These results may provide the basis for future preventative or clinical therapies for esophageal cancer.

Adult intussusception caused by an intestinal lipoma: report of a case.

Intussusception in adults represents only 5% of all cases and is usually caused by a small bowel lesion acting as the apex of the intussusception. We report an unusual case of intussusception in man caused by a lipomatous lesion located in the ileum acting as the lead point. After repeated admissions to our hospital for ileus, the possibility of intussusception was finally raised by a computed tomographic scan of the abdomen. The patient underwent primary resection of the intussuscepted intestine, which resulted in a long-lasting resolution of the symptoms. The resected specimen contained a round tumor measuring 27 x 27 x 40 mm which was diagnosed histopathologically as an intestinal lipoma. This case highlights the uncommon causation of adult intussusception by an intestinal lipoma.

So-called carcinosarcoma of the esophagus: report of a case.

The carcinosarcoma of the esophagus is a rare malignant neoplasm consisting of both carcinomatous and sarcomatous components. A case of so-called carcinosarcoma of the esophagus is described herein. A 69-year-old man presented with dysphagia and was admitted to our hospital. Imaging studies revealed a localized ulcerative tumor in the middle intrathoracic esophagus without any invasion or metastasis. The patient was initially thought to have squamous cell carcinoma and underwent subtotal esophagectomy with lymphadenectomy. Final diagnosis of the tumor was so-called carcinosarcoma of the esophagus. The patient had an uneventful postoperative course and showed no evidence of recurrence or metastasis in the 4-year postoperative period.

SnoN overexpression is predictive of poor survival in patients with esophageal squamous cell carcinoma.

BACKGROUND: Earlier studies have identified the minimal overlapping region of amplification at 3q26 in esophageal squamous cell carcinoma (ESCC) by comparative genomic hybridization (CGH) analysis. These include PIK3CA which encodes the p110alpha catalytic subunit of phosphatidylinositol (PI) 3-kinase, a telomerase RNA component (TERC), a squamous cell carcinoma-related oncogene (SCCRO), ecotropic viral integration site-1 (EVI-1), and a Ski-related novel oncogene (SnoN). In the present study, we investigated the mRNA levels of four candidate genes (TERC, SCCRO, EVI-1, and SnoN) to determine whether genes other than PIK3CA are targets for amplification at 3q26 in ESCC. And also, we examined SnoN expression in ESCC samples. METHODS: Fifty-nine representative cases with ESCC were selected from our archives. We performed quantitative RT-PCR of four candidate genes (TERC, SCCRO, EVI-1, and SnoN) and immunohistochemistry for SnoN. Finally, we correlated these findings with the clinicopathological characteristics to determine their interrelationship. RESULTS: Among the four genes we tested, only SnoN mRNA was consistently overexpressed in primary ESCC, compared with those in corresponding nontumorous esophageal epithelia (P < 0.001). Immunoreactive SnoN was detectable in 31 of 59 (52.5%) esophageal squamous cell carcinoma specimens. The levels of SnoN expression were found to correlate with the depth of invasion and recurrence (P < 0.05). Furthermore, patients with positive staining for SnoN displayed more unfavorable outcomes than patients with negative staining (P < 0.05). CONCLUSION: SnoN is likely to be the target of the amplification at 3q26 in ESCC and plays an important role in the development of ESCC, influencing disease-specific survival.