Potential Role of PDGFRß-Associated THBS4 in Colorectal Cancer Development.

Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-ß (TGFß) signaling. Platelet-derived growth factor receptor ß (PDGFRß), which is a receptor tyrosine kinase and is also a downstream signal of TGFß, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFRß and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGFß treatment in the colon cancer cell line DLD-1. TGFß and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFRß blockade. We propose that the PDGFRß signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca2+-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFRß signaling due to increased TGFß and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.

Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma.

Neurotransmitters are reported to be involved in tumor initiation and progression. This study aimed to elucidate the prognostic value of γ-aminobutyric acid type A receptor δ subunit (GABRD) in colon adenocarcinoma (COAD) using the data from The Cancer Genome Atlas (TCGA) database. The GABRD mRNA expression levels in the COAD and normal tissues were compared using the Wilcoxon rank-sum test. The correlation between clinicopathologic characteristics and GABRD expression was analyzed by Wilcoxon rank-sum test or Kruskal-Wallis test and logistic regression. The prognostic value of GABRD mRNA expression in patients with COAD was determined using the Kaplan-Meier curve and Cox regression analysis. Finally, the molecular mechanisms of GABRD in COAD were predicted by gene set enrichment analysis (GSEA). The COAD tissues exhibited higher GABRD mRNA expression levels than the normal tissues. The logistic regression analysis revealed that GABRD mRNA expression was correlated with TNM stage, N stage, M stage, and microsatellite instability (MSI) status. The Kaplan-Meier survival curve and log-rank test revealed that patients with COAD exhibiting high GABRD mRNA expression were associated with poor overall survival (OS). The multivariate analysis indicated that increased GABRD mRNA expression was an independent prognostic factor and was correlated with a poor OS. The GSEA revealed that GABRD was involved in signaling pathways, including cell adhesion molecules, gap junction, melanogenesis, and mTOR signaling pathway, as well as the signaling pathways associated with basal cell carcinoma or bladder cancer development. In summary, enhanced GABRD mRNA expression may be a potential independent prognostic biomarker for COAD.

The Role of Primary Tumor Resection in Colorectal Cancer Patients with Asymptomatic, Synchronous, Unresectable Metastasis: A Multicenter Randomized Controlled Trial.

We aimed to assess the survival benefits of primary tumor resection (PTR) followed by chemotherapy in patients with asymptomatic stage IV colorectal cancer with asymptomatic, synchronous, unresectable metastases compared to those of upfront chemotherapy alone. This was an open-label, prospective, randomized controlled trial (ClnicalTrials.gov Identifier: NCT01978249). From May 2013 to April 2016, 48 patients (PTR, n = 26; upfront chemotherapy, n = 22) diagnosed with asymptomatic colorectal cancer with unresectable metastases in 12 tertiary hospitals were randomized (1:1). The primary endpoint was two-year overall survival. The secondary endpoints were primary tumor-related complications, PTR-related complications, and rate of conversion to resectable status. The two-year cancer-specific survival was significantly higher in the PTR group than in the upfront chemotherapy group (72.3% vs. 47.1%; p = 0.049). However, the two-year overall survival rate was not significantly different between the PTR and upfront chemotherapy groups (69.5% vs. 44.8%, p = 0.058). The primary tumor-related complication rate was 22.7%. The PTR-related complication rate was 19.2%, with a major complication rate of 3.8%. The rates of conversion to resectable status were 15.3% and 18.2% in the PTR and upfront chemotherapy groups. While PTR followed by chemotherapy resulted in better two-year cancer-specific survival than upfront chemotherapy, the improvement in the two-year overall survival was not significant.

NUDT7 Loss Promotes KrasG12D CRC Development.

Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal b-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7-/-) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7-/- and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7-/- colons. Upregulated levels of ß-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7-/- mice and downstream targets of ß-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7-/- mice. We observed an increased level of palmitic acid in the colon of Nudt7-/- mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of b-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.

MSI status is associated with distinct clinicopathological features in BRAF mutation colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Microsatellite stable (MSS) BRAF p.V600E mutation colorectal cancer (BRAF-CRC) has a poor prognosis, whereas microsatellite instability (MSI) in BRAF-CRC is associated with a favorable prognosis. Although usually considered a single clinical entity, the MSI BRAF-CRC subtype shows some distinct characteristics in comparison with the MSS BRAF-CRC subtype. METHODS: We conducted a meta-analysis to investigate the influence of clinicopathological features on MSI status in BRAF-CRC. We searched publications up to March 2019 from PubMed, Embase, and the Cochrane Library. The effect of MSI status on outcome parameters was assessed using odds ratios (ORs) with 95% confidence intervals (CIs) and fixed- or random-effects models according to the heterogeneity. RESULTS: After reviewing 2839 reports, 16 eligible studies including 1381 patients with BRAF-CRC met the criteria. The MSI BRAF-CRC subtype was associated with older age, female sex (OR = 1.70; 95% CI = 1.35-2.14; P < 0.00001), proximal tumor location (OR = 5.10; 95% CI = 3.70-7.03; P < 0.00001), early TNM stage (OR = 5.28; 95% CI = 3.93-7.09; P < 0.00001), and poor differentiation (OR = 2.29; 95% CI = 1.60-3.28; P < 0.00001). CONCLUSIONS: MSI was significantly correlated with distinct favorable clinicopathological characteristics in BRAF-CRC. These results suggest that MSI status should be considered as a stratification factor for better management of the BRAF-CRC.

Reduced microRNA 375 in colorectal cancer upregulates metadherin-mediated signaling.

BACKGROUND: The human microRNA 375 (MIR375) is significantly downregulated in human colorectal cancer (CRC) and we have previously shown that MIR375 is a CRC-associated miRNA. The metadherin (MTDH) is a candidate target gene of MIR375. AIM: To investigate the interaction and function between MIR375 and MTDH in human CRC. METHODS: A luciferase reporter system was used to confirm the effect of MIR375 on MTDH expression. The expression levels of MIR375 and the target genes were evaluated by quantitative RT-PCR (qRT-PCR), western blotting, or immunohistochemistry. RESULTS: MTDH expression was found to be upregulated in human CRC tissues compared to that in healthy controls. We show that MIR375 regulates the expression of many genes involved in the MTDH-mediated signal transduction pathways [BRAF-MAPK and phosphatidylinositol-4,5-biphosphate-3-kinase catalytic subunit alpha (PIK3CA)-AKT] in CRC cells. Upregulated MTDH expression levels were found to inhibit NF-κB inhibitor alpha, which further upregulated NFKB1 and RELA expression in CRC cells. CONCLUSION: Our findings suggest that suppressing MIR375 expression in CRC regulates cell proliferation and angiogenesis by increasing MTDH expression. Thus, MIR375 may be of therapeutic value in treating human CRC.

MicroRNA 452 Regulates Cell Proliferation, Cell Migration, and Angiogenesis in Colorectal Cancer by Suppressing VEGFA Expression.

The human microRNA 452 (MIR452) was identified as a colorectal cancer (CRC)-associated micro RNA (miRNA) by miRNA expression profiling of human CRC tissues versus normal colorectal tissues. It was significantly up-regulated in human CRC tissues. However, the functional mechanisms of MIR452 and its target genes in CRC remain unclear. We identified 27 putative MIR452 target genes, and found that the vascular endothelial growth factor A (VEGFA) was a direct target gene of MIR452. Both cellular and extracellular VEGFA levels were significantly downregulated in CRC cells upon their transfection with MIR452 or siVEGFA. VEGFA expression was frequently downregulated in human CRC tissues in comparison with that in their healthy counterparts. We showed that MIR452 regulated the expression of genes in the VEGFA-mediated signal transduction pathways vascular endothelial growth factor receptor 1 (VEGFR2)-mitogen-activated protein kinase (MAPK) and VEGFR2-SRC proto-oncogene non-receptor tyrosine kinase (SRC) in CRC cells. Immunohistological analyses of xenografted MIR452-overexpressing CRC cells in mice showed that MIR452 regulated cell proliferation and angiogenesis. Furthermore, aortic ring angiogenesis assay in rats clearly showed that the number of microvessels formed was significantly reduced by MIR452 transfection. Our findings suggest that MIR452 regulates cell proliferation, cell migration, and angiogenesis by suppressing VEGFA expression in early CRC progression; therefore, MIR452 may have therapeutic value in relation to human CRC.

Comparison of Short-term Outcomes of Laparoscopic-Assisted Colon Cancer Surgery Using a Joystick-Guided Endoscope Holder (Soloassist II) or a Human Assistant.

PURPOSE: This study aimed to compare the short-term outcomes of laparoscopic-assisted colon cancer surgery in the Soloassist II-assisted (SA) group and in the human-assisted (HA) group. METHODS: A total of 76 patients with colon cancer who underwent laparoscopic-assisted right hemicolectomy and anterior resection performed by a single surgeon between January 2017 and May 2018 were recruited from the consecutively enrolled registry and retrospectively analyzed. RESULTS: Of 76 patients, 43 underwent surgery with human assistance and 33 underwent surgery using the Soloassist II system. The clinicopathologic characteristics were not statistically different between the 2 groups. In both HA and SA groups, no statistical difference was observed between operation time (220.23 ± 47.83 minutes vs. 218.03 ± 38.22 minutes, P = 0.829), total number of harvested lymph nodes (20.42 ± 10.86 vs. 20.24 ± 8.21, P = 0.938), and other parameters of short-term outcomes (length of hospital stay, blood loss, open conversion, time to flatus, time to soft diet, and complication events). Subgroup analyses did not show statistical differences. CONCLUSION: Soloassist II can reduce the participation of a human assistant during surgery and is not inferior to human assistance in laparoscopic-assisted colon cancer surgery. Thus, it is a feasible instrument in laparoscopic-assisted colon cancer surgery that can provide positive short-term outcomes.

Primary Undifferentiated Pleomorphic Sarcoma of the Colon Mesentery.

An undifferentiated pleomorphic sarcoma (UPS), also known as a malignant fibrous histiocytoma in the past, commonly involves the soft tissue of the extremities and the retroperitoneum. However, a primary UPS of the colon mesentery is very rare. A 69-year-old male patient visited our outpatient department for treatment of an enlarged, palpable mass in the right lower quadrant (RLQ). Computed tomography showed a 15-cm multilobulated, heterogeneous, enhanced mass in the RLQ, which we suspected originated from the colon. He underwent a right hemicolectomy, and the pathologic result was a colon mesenteric UPS. We report a rare case of a primary UPS of the colon mesentery and discuss the characteristics of this neoplasm in reference to the literature.

Efficacy and Safety of Laparoscopic Hartmann Colostomy Reversal.

PURPOSE: Hartmann operation is widely recognized as a useful procedure, especially in emergencies involving the rectosigmoid colon. One of the surgeon's foremost concerns after Hartmann operation is future colostomy reversal, as colostomy reversal after a Hartmann procedure is associated with relatively high morbidity and mortality. Laparoscopic surgical techniques continue to prove useful for an ever-increasing variety of indications. We analyzed the outcomes of laparoscopic Hartmann colostomy reversals at our center. METHODS: We retrospectively analyzed the hospital records of 170 patients who had undergone Hartmann operation between January 2010 and June 2017 at Wonkwang University Hospital. Among 68 Hartmann colostomy reversals, we evaluated and compared the outcomes of 3 groups of patients: 29 patients in the open colostomy reversal group (OG) who had undergone laparotomies for Hartmann reversals, 19 patients in the conversion group (CG) whose laparoscopic procedures had required conversion to a laparotomy, and 20 patients in the laparoscopy group (LG). RESULTS: The overall reversal rate for Hartmann colostomies was 40.5% during this time period. The duration of hospital stay was significantly shorter among LG patients (10.15 ± 2.94 days) than among OG patients (16 ± 9.5 days). The overall complication rate among OG patients was higher than that among LG patients (adjusted odds ratio, 8.78; P = 0.01). The most common complication was postoperative ileus (19.1%). CONCLUSION: If no contraindications to laparoscopy exist, surgeons should favor a laparoscopic reversal of Hartmann operation over an open reversal.

Korean Society of Coloproctology (KSCP) trial of cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: a multicenter, randomized controlled trial (KONCLUDE).

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced rectal cancer with improved local control. However, systemic recurrence despite neoadjuvant CRT remained unchanged. The only significant prognostic factor proven to be important was pathologic complete response (pCR) after neoadjuvant CRT. Several efforts have been tried to improve survival of patients who treated with neoadjuvant CRT and to achieve more pCR including adding cytotoxic chemotherapeutic agents, chronologic modification of chemotherapy schedule or adding chemotherapy during the perioperative period. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase pCR rate, subsequently could show better oncologic outcomes. METHODS: Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to undergo TME followed by 8 cycles of adjuvant chemotherapy (control arm) or receive 3 cycles of consolidation chemotherapy before TME, and receive 5 cycles of adjuvant chemotherapy (experimental arm). The primary endpoints are pCR and 3-year disease-free survival (DFS), and the secondary endpoints are radiotherapy-related complications, R0 resection rate, tumor response rate, surgery-related morbidity, and peripheral neuropathy at 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in pCR (15 to 30%) and in 3-year DFS (65 to 80%), compared with the control arm. The accrual period is 2 years and the follow-up period is 3 years. Based on the superiority design, one-sided log-rank test with α-error of 0.025 and a power of 80% was conducted. Allowing for a drop-out rate of 10%, 358 patients (179 per arm) will need to be recruited. Patients will be followed up at every 3 months for 2 years and then every 6 months for 3 years after the last patient has been randomized. DISCUSSION: KONCLUDE trial aims to investigate whether consolidation chemotherapy shows better pCR and 3-year DFS than adjuvant chemotherapy alone for the patients who received neoadjuvant CRT for locally advanced rectal cancer. This trial is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer. TRIAL REGISTRATION: Clinicaltrials.gov NCT02843191 (First posted on July 25, 2016).

MicroRNA 375 regulates proliferation and migration of colon cancer cells by suppressing the CTGF-EGFR signaling pathway.

MicroRNA 375 (MIR375) is significantly down regulated in human colorectal cancer (CRC) tissues; we have previously identified MIR375 as a colon cancer associated microRNA (miRNA). We identified putative MIR375 target genes by comparing the mRNA microarray analysis data of MIR375-overexpressing cells with the candidate MIR375 target genes predicted by public bioinformatic tools. We investigated that the connective tissue growth factor (CTGF) is a direct target gene of MIR375. Expression of CTGF, a ligand of epidermal growth factor receptor (EGFR), was markedly enhanced in human CRC tissues in comparison with the corresponding normal colon tissues. We demonstrated that the expression levels of molecules in EGFR signaling pathways were regulated by MIR375 in colorectal cells. Using immunohistochemistry and the xenograft of MIR375-overexpressing colorectal cells in mice, we showed that MIR375 regulates cell growth and proliferation, angiogenesis, cell migration, cell cycle arrest, apoptosis, and necrosis in colon cells. Furthermore, results of MIR375 overexpression and cetuximab treatment indicated that the apoptosis and necrosis in colon cells were synergistically enhanced. Our results suggest that the down-regulation of MIR375 modulates EGFR signaling pathways in human colorectal cells and tissues by increasing CTGF expression; therefore, MIR375 may have a therapeutic value in relation to human CRC.

Comparative expression patterns and diagnostic efficacies of SR splicing factors and HNRNPA1 in gastric and colorectal cancer.

BACKGROUND: Serine/arginine-rich splicing factors (SRSFs) and HNRNPA1 have oncogenic properties. However, their proteomic expressions and practical priority in gastric cancer (GC) and colorectal cancer (CRC) are mostly unknown. To apply SFs in clinics, effective marker selection and characterization of properties in the target organ are essential. METHODS: We concurrently analyzed SRSF1, 3, and 5-7, and HNRNPA1, together with the conventional tumor marker carcinoembryonic antigen (CEA), in stomach and colorectal tissue samples (n = 420) using semiquantitative immunoblot, subcellular fractionation, and quantitative real-time polymerase chain reaction methods. RESULTS: In the semiquantitative immunoblot analysis, HNRNPA1 and SRSF7 levels were significantly higher in GC than in gastric normal mucosa, and SRSF7 levels were higher in intestinal-type compared with diffuse-type of gastric adenocarcinoma. Of the SFs, only HNRNPA1 presented greater than 50 % upregulation (cancer/normal mucosa > 2-fold) incidences and CEA-comparable, acceptable (>70 %) detection accuracy (74 %) for GC. All SF protein levels were significantly higher in CRC than in colorectal normal mucosa, and HNRNPA1 levels were higher in low-stage CRC compared with high-stage CRC. Among the SFs, HNRNPA1 and SRSF3 presented the two highest upregulation incidences (88 % and 74 %, respectively) and detection accuracy (90 % and 84 %, respectively) for CRC. The detection accuracy of HNRNPA1 was comparable to that of CEA in low (≤ II)-stage CRC but was inferior to that of CEA in high (>II)-stage CRC. Extranuclear distributions of HNRNPA1 and SRSF6 (cytosol/microsome) differed from those of other SRSFs (membrane/organelle) in both cancers. In an analysis of the six SF mRNAs, all mRNAs presented unacceptable detection accuracies (≤70 %) in both cancers, and all mRNAs except SRSF6 were disproportionate to the corresponding protein levels in GC. CONCLUSION: Our results provide a comprehensive insight into the six SF expression profiles in GC and indicate that, among the SFs, HNRNPA1, but not HNRNPA1 mRNA, is the most effective, novel GC marker. Regardless of the good to excellent detection accuracy of SRSF3 and HNRNPA1 in CRC, the SFs have lower practical priority than CEA, especially for high-stage CRC detection.

The role of primary tumor resection in colorectal cancer patients with asymptomatic, synchronous unresectable metastasis: Study protocol for a randomized controlled trial.

BACKGROUND: Approximately 20 % of all patients with colorectal cancer are diagnosed as having Stage IV cancer; 80 % of these present with unresectable metastatic lesions. It is controversial whether chemotherapy with or without primary tumor resection (PTR) is effective for the treatment of patients with colorectal cancer with unresectable metastasis. Primary tumor resection could prevent tumor-related complications such as intestinal obstruction, perforation, bleeding, or fistula. Moreover, it may be associated with an increase in overall survival. However, surgery delays the use of systemic chemotherapy and affects the systemic spread of malignancy. METHODS/DESIGN: Patients with colon and upper rectal cancer patients with asymptomatic, synchronous, unresectable metastasis will be included after screening. They will be randomized and assigned to receive chemotherapy with or without PTR. The primary endpoint measure is 2-year overall survival rate and the secondary endpoint measures are primary tumor-related complications, quality of life, surgery-related morbidity and mortality, interventions with curative intent, chemotherapy-related toxicity, and total cost until death or study closing day. The authors hypothesize that the group receiving PTR following chemotherapy would show a 10 % improvement in 2-year overall survival, compared with the group receiving chemotherapy alone. The accrual period is 3 years and the follow-up period is 2 years. Based on the inequality design, a two-sided log-rank test with α-error of 0.05 and a power of 80 % was conducted. Allowing for a drop-out rate of 10 %, 480 patients (240 per group) will need to be recruited. Patients will be followed up at every 3 months for 3 years and then every 6 months for 2 years after the last patient has been randomized. DISCUSSION: This randomized controlled trial aims to investigate whether PTR with chemotherapy shows better overall survival than chemotherapy alone for patients with asymptomatic, synchronous unresectable metastasis. This trial is expected to provide evidence so support clear treatment guidelines for patients with colorectal cancer with asymptomatic, synchronous unresectable metastasis. TRIAL REGISTRATION: Clinicaltrials.gov NCT01978249 .

Association between genetic polymorphisms in cortactin and susceptibility to gastric cancer.

PURPOSE: Overexpression of cortactin (CTTN) in human tumors has been proposed to result in increased cell migration and metastatic potential. Here, we determined the frequencies of CTTN g.-9101C>T, g.-8748C>T, and g.72C>T polymorphisms in apparently healthy subjects and gastric cancer patients, respectively, and the influence of the CTTN polymorphisms on gastric cancer susceptibility. METHODS: Blood samples were collected from 267 patients and 533 controls. CTTN g.-8748C>T and g.-9101C>T polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism; the g.72C>T polymorphism was determined using the TaqMan method. RESULTS: Genotype frequencies of the CTTN g.-9101C>T polymorphism were 97.5% (TT), 2.5% (TC), and 0% (CC) in the patient group, and 98.6% (TT), 1.4% (TC), and 0% (CC) in the control group. Genotype frequencies of the CTTN g.-8748C>T polymorphism were 93.3% (TT), 6.8% (TC), and 0% (CC) in the patient group, and 94.2% (TT), 5.8% (TC), and 0% (CC) in the control group. Genotype frequencies of the CTTN g.72C>T polymorphism were 82.4% (CC), 17.2% (CT), and 0.4% (TT) in the patient group, and 78.0% (CC), 20.1% (CT), and 1.9% (TT) in the control group. Genotype and allele frequencies of the CTTN g.-9101C>T polymorphism differed significantly between the advanced gastric cancer and control groups. Patients with advanced gastric cancer, possessing the TC genotype, had a significantly poorer prognosis than the group with the TT genotype. CONCLUSION: The CTTN g.-9101C>T polymorphism might influence advanced gastric cancer susceptibility. However, the role of the CTTN g.-9101C>T, g.-8748C>T, and g.72C>T polymorphisms requires careful interpretation and confirmation through larger studies.

[Appendiceal neuroendocrine tumor with lymph node metastasis in a teenager].

Neuroendocrine tumor (NET) is a cancer-like tumor that occurs mostly in the gastrointestinal system. Within the gastrointestinal tract, NET most commonly occurs in the rectum whereas appendix is very rarely involved. In most cases of appendiceal NET, it is found at a relatively early stage compared to other NETs because appendiceal NET frequently presents with acute appendicitis because appendiceal NET frequently presents with acute appendicitis even when the size is smaller than 1 cm. Therefore, it is very rare for lymph node metastasis to occur in a young adult. Herein, we report a rare case of grade 1 appendiceal NET with lymph node metastasis which developed in a teenage male.

MicroRNA 196B regulates FAS-mediated apoptosis in colorectal cancer cells.

Using miRNA microarray analysis, we identified 31 miRNAs that were significantly up-regulated or down-regulated in colon cancer tissues. We chose MIR196B, which was specifically up-regulated in colon cancer, for further study. We identified 18 putative MIR196B target genes by comparing between the mRNAs down-regulated in MIR196B-overexpressed cells and the assumed MIR196B target genes predicted by public bioinformatics tools. The association between MIR196B and FAS was verified in this study. FAS expression was constitutively elevated in normal human colorectal tissues. However, its expression was often reduced in human colorectal cancer. The decrease in FAS expression could be responsible for the reduction of apoptosis in colorectal cancer cells. In colorectal cancer tissue, we showed that MIR196B up-regulation was mutually followed by down regulation of FAS expression. We also showed that MIR196B directly repressed FAS expression in colorectal cells. Furthermore, anti-MIR196B up-regulated FAS expression and increased apoptosis in colorectal cancer cell lines. Our results suggest that the up-regulation of MIR196B modulates apoptosis in colorectal cancer cells by partially repressing FAS expression and that anti-MIR196B could be a potential candidate as an anti-cancer drug in colorectal cancer therapy.

Necrotizing Fasciitis Arising From an Enterocutaneous Fistula in a Case of an Appendiceal Mucocele.

An appendiceal mucocele (AM) is a rare tumorous condition of the appendix. Many patients with AM are admitted to the hospital with abdominal pain or discomfort, and many cases are found incidentally. Although the rate of complications in patients with AM is very low, if left untreated, a mucocele may rupture and produce a potentially fatal entity known as pseudomyxoma peritonei. In this paper, we report a case of an 80-year-old man with necrotizing fasciitis arising from an enterocutaneous fistula caused by AM.

Targeted next-generation sequencing at copy-number breakpoints for personalized analysis of rearranged ends in solid tumors.

BACKGROUND: The concept of the utilization of rearranged ends for development of personalized biomarkers has attracted much attention owing to its clinical applicability. Although targeted next-generation sequencing (NGS) for recurrent rearrangements has been successful in hematologic malignancies, its application to solid tumors is problematic due to the paucity of recurrent translocations. However, copy-number breakpoints (CNBs), which are abundant in solid tumors, can be utilized for identification of rearranged ends. METHOD: As a proof of concept, we performed targeted next-generation sequencing at copy-number breakpoints (TNGS-CNB) in nine colon cancer cases including seven primary cancers and two cell lines, COLO205 and SW620. For deduction of CNBs, we developed a novel competitive single-nucleotide polymorphism (cSNP) microarray method entailing CNB-region refinement by competitor DNA. RESULT: Using TNGS-CNB, 19 specific rearrangements out of 91 CNBs (20.9%) were identified, and two polymerase chain reaction (PCR)-amplifiable rearrangements were obtained in six cases (66.7%). And significantly, TNGS-CNB, with its high positive identification rate (82.6%) of PCR-amplifiable rearrangements at candidate sites (19/23), just from filtering of aligned sequences, requires little effort for validation. CONCLUSION: Our results indicate that TNGS-CNB, with its utility for identification of rearrangements in solid tumors, can be successfully applied in the clinical laboratory for cancer-relapse and therapy-response monitoring.

Chronic gastric anisakiasis provoking a bleeding gastric ulcer.

Gastric anisakiasis is a parasitic disease caused by the gastric mucosal penetration of the Anisakis larvae ingested with raw fish. Acute gastric anisakiasis is diagnosed by the endoscopic visualization of Anisakis larvae along with mucosal edema, erythema, hemorrhage, and/or an ulcer, whereas chronic anisakiasis is often observed as a localized tumor commonly occurring in the submucosal layer, and is characterized by eosinophilic granuloma with edema and embedded Anisakis larvae on pathological examination of surgical specimens. We report here a case of chronic gastric anisakiasis provoking a bleeding gastric ulcer, which is a rare clinical manifestation of this condition.