Low PDCD4 Expression Is Associated With Poor Prognosis of Colorectal Carcinoma.

Programmed cell death 4 (PDCD4) is a tumor suppressor gene that inhibits tumor progression, invasion, and metastasis. Decreased PDCD4 expression is associated with poor prognosis in various types of cancers. We evaluated PDCD4 expression and its clinicopathologic correlation, including patient survival, in 289 surgically resected colorectal cancers. Low nuclear PDCD4 expression was identified in 177 (61.2%) cases and was associated with large tumor size, high pT classification, and the presence of lymphovascular and perineural invasion. The 5-year survival rate of patients with low nuclear PDCD4 expression was significantly lower than that of patients with high expression (72.2% vs. 93.3%, P<0.001). American Joint Committee on Cancer stage II and III colorectal cancer patients with low nuclear PDCD4 expression (76.9% and 67.2%, respectively) showed significantly worse overall survival than those with high expression (100% and 92.9%, P=0.002 and 0.032, respectively). Low nuclear PDCD4 expression was an independent poor prognostic factor in colorectal cancer patients (hazard ratio=3.556; 95% confidence interval, 1.739-7.271; P=0.001). Our study suggests that low PDCD4 expression is associated with aggressive behavior and can be used as a prognostic indicator of colorectal cancer patients.

VGLL4 with low YAP expression is associated with favorable prognosis in colorectal cancer.

The Hippo pathway is a tumor suppressive pathway regulating Yes-associated protein-TEA domain-containing sequence-specific transcription factor (YAP-TEAD) complex. VGLL (Vestigial-like) proteins are transcriptional cofactors competing with YAP for TEAD binding and interfering oncogenic activity of YAP-TEAD complex. We evaluated the expression of VGLL4, YAP, and TEAD4 and assessed their correlations with clinicopathologic factors and prognostic effects in 295 colorectal cancers. VGLL4 was positive in 164 (55.6%) cases and correlated with small tumor size, low pT classification, and absence of lymph node metastasis. YAP and TEAD4 were highly expressed in 138 (46.8%) cases and 144 (48.8%) cases, respectively, and high expressions were associated with presence of lymphovascular invasion and lymph node metastasis, or distant metastasis. VGLL4 expression was significantly correlated with low YAP expression (p < 0.001) and had significantly better overall survival than negative expression (p < 0.001). High YAP (HR, 2.108; 95% confidence interval, 1.239-3.584; p = 0.006) and TEAD4 (1.724; 1.021-2.912; p = 0.042) expressions were associated with poor overall survivals. The combined VGLL4pos YAPlow expression showed the best overall survival than other groups (p < 0.001). VGLL4 expression (0.381; 0.212-0.683; p = 0.001) and combined VGLL4pos YAPlow expression (0.227; 0.108-0.475; p < 0.001) were independent good prognostic factors in colorectal cancers. The expressions of VGLL4, YAP, and TEAD4 can be used as prognostic markers in colorectal cancer patients.

Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide, causing serious liver complications, including nonalcoholic steatohepatitis. Recent findings suggest that peripheral serotonin (5-hydroxytryptamine, 5HT) regulates energy homeostasis, including hepatic lipid metabolism. More specifically, liver-specific 5HT2A knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT2A antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT2A antagonists. Among the synthesized compounds, compound 14a showed good in vitro activity, good liver microsomal stability, 5HT subtype selectivity, and no significant inhibition of CYP and hERG. The in vitro and in vivo blood-brain barrier permeability study proved that 14a acts peripherally. Compound 14a decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT2A antagonists in NAFLD.

Anti-inflammatory effect of a novel synthetic compound 1-((4-fluorophenyl)thio)isoquinoline in RAW264.7 macrophages and a zebrafish model.

The compound, 1-((4-fluorophenyl)thio)isoquinoline (FPTQ), is a synthetic isoquinoline derivative. To test the anti-inflammatory effect of FPTQ, we used neutrophil-specific transgenic zebrafish Tg(mpx::EGFP)i114 line and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. We also used two different methods, involving tail transection and LPS stimulation in the zebrafish model. Neutrophils translocation in the zebrafish tail-transected model was inhibited by FPTQ. Neutrophil aggregation was also inhibited by FPTQ in the LPS-stimulated zebrafish model. Decreased mRNA expression of the pro-inflammatory cytokine genes, interleukin-1ß (il-1ß) and interleukin-6 (il-6), was found in zebrafish larvae injected with FPTQ. Additionally, production of nitric oxide was inhibited by FPTQ in RAW264.7 macrophage cells treated with LPS. Moreover, the mRNA expression of Il-1ß and Il-6 suppressed by FPTQ treatment in RAW264.7 macrophage cells, and an enzyme immunoassay showed that FPTQ suppressed the secretion of IL-1ß and IL-6 in RAW264.7 cells. These results demonstrate that FPTQ reduced inflammatory responses and, therefore, suggest that it may be effective as an anti-inflammatory agent.

Comparison of wound healing effects between Oncorhynchus keta-derived polydeoxyribonucleotide (PDRN) and Oncorhynchus mykiss-derived PDRN.

BACKGROUND: Polydeoxyribonucleotide (PDRN) influencing cellular growth and differentiation is recognized to promote wound healing by stimulating tissue repair. Although PDRN can be extracted from human placentas, PDRN medications have recently been extracted from the semen of trout (Oncorhynchus mykiss) and salmon (Oncorhynchus keta). The present study was designed to evaluate the wound healing effects of O. keta-derived PDRN for injection (Rejuvenex) and PDRN cream (Rejuvenex Cream) in comparison with those of O. mykiss-derived PDRN injection (Placentex). METHODS: Full-thickness skin defects were made on the back of mice (n=60). The mice were divided into the following four groups according to the dressing used for the wounds: O. mykiss-derived PDRN injection group, O. keta-derived PDRN injection group, O. keta-derived PDRN cream group, and normal saline soaked dressing group (control group). We analyzed the gross findings, wound sizes, histological findings, immunohistochemistry and enzyme-linked immunosorbent assays for the groups immediately after the treatment, and again after 4, 7, and 10 days of treatment. RESULTS: The wound healing effects were the greatest in the O. keta-derived PDRN injection and O. mykiss-derived PDRN injection groups, which showed similar scores, followed by the O. keta-derived cream and normal saline soaked dressing groups. CONCLUSION: The injection of PDRN extracted from O. keta was found to be as effective at healing full-thickness skin defects as the O. mykiss-derived PDRN injection, which is currently used in the clinic. Moreover, the O. keta-derived PDRN injection was also found to reduce the time required for wound healing.

Mutational Analysis of Extranodal NK/T-Cell Lymphoma Using Targeted Sequencing with a Comprehensive Cancer Panel.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, KMT2D, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested KMT2D as a novel driver gene in NKTCL. Mutations were also found in ARID1A, a chromatin remodeling gene, and TP53, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future.

Chondroid Syringoma on Face.

Chondroid syringoma is a rare mixed tumor of the skin which is composed of both mesenchymal and epithelial cells. Its incidence at less than 0.1% and is frequently located on the head and neck. Chondroid syringoma is easily confused with epidermal cysts. Since malignant forms of chondroid syringoma have been reported, accurate and timely diagnosis is important for proper management. We report clinical and histological features of chondroid syringoma in 5 patients treated at our institution. In most of the cases, chondroid syringoma presented as a round, firm, nodular or cystic lesion that had well marginated heterogeneity in sonography. Clinically, all of the lesions were removed by simple excision. Microscopically, all five tumors were well circumscribed and consisted of epithelial, myoepithelial, and stromal components. The epithelial component formed tubules lined by one or more rows of eosinophilic epithelial cells. The outer layer of tubules appeared to be flattened myoepithelial cells. The stroma is myxoid and contained spindle shaped myoepithelial cells. We expect that the clinical, sonographic, and histological data from our report may help clinicians who are confronted with various kinds of analogous facial lesions to decide the most proper management for their patients.

Cytokine expression of microscopic colitis including interleukin-17.

BACKGROUND/AIMS: Microscopic colitis is characterized by chronic watery diarrhea with specific pathological changes that can be diagnosed by microscopic examination. We performed immunohistochemical analysis of proinflammatory cytokines to investigate the pathogenic mechanism of microscopic colitis. METHODS: This study consisted of six patients with lymphocytic colitis, six patients with collagenous colitis, and six patients with functional diarrhea but normal pathology. We performed an immunohistochemical analysis of the colonic mucosal biopsies to assess the expression of cyclo-oxygenase-2, interleukin-17, nuclear factor-κB, interferon-γ, inducible nitric oxide synthase, and tumor necrosis factor-α. We compared the quantity score of immunohistochemical staining among the groups. RESULTS: The microscopic colitis group showed significantly higher expression of cyclo-oxygenase-2, interleukin-17, nuclear factor-κB, and interferon-γ compared with the control group. Cytokine expression was similar between collagenous colitis and lymphocytic colitis. However, the expression of cyclo-oxygenase-2 was higher in collagenous colitis. CONCLUSIONS: Proinflammatory cytokines, including interleukin-17 and interferon-γ, are highly expressed in microscopic colitis. The expression of cyclo-oxygenase-2 was higher in collagenous colitis than in lymphocytic colitis. This study is the first on interleukin-17 expression in microscopic colitis patients.

A rare case of primary hyperparathyroidism associated with primary aldosteronism, Hürthle cell thyroid cancer and meningioma.

Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of endocrine and non-endocrine tumors. There are also a considerable number of atypical MEN1 syndrome. In this case, a 68-yr-old woman was referred to the Department of Endocrinology for hypercalcemia. Five years ago, she had diagnosed as primary hyperaldosteronism and now newly diagnosed as parathyroid hyperplasia with laboratory and pathologic findings. Hürthle-cell thyroid cancer was also resected during the parathyroid exploration and small meningioma was found on brain MRI. Her general condition has markedly improved and her adrenal mass and meningioma are being closely observed now. We could find the loss of heterozygosity of the MEN1 locus in parathyroid glands, suggesting a MEN1-related tumor, but not a germline mutation. Considering a variety of phenotypic expression and a limitation of current molecular analysis, periodic follow up will be needed in patients with a MEN1-like phenotype.

A clinical and histopathological study of 122 cases of dermatofibroma (benign fibrous histiocytoma).

BACKGROUND: Many variants of dermatofibromas have been described, and being aware of the variants of dermatofibromas is important to avoid misdiagnosis. OBJECTIVE: We wanted to evaluate the clinical and pathologic characteristics of 122 cases of dermatofibromas. METHODS: We retrospectively reviewed the medical records and 122 biopsy specimens of 92 patients who were diagnosed with dermatofibroma in the Department of Dermatology at Eulji Hospital of Eulji University between January 2000 and March 2010. RESULTS: Nearly 80% of the cases occurred between the ages of 20 and 49 years, with an overall predominance of females. Over 70% of the lesions were found on the extremities. The most common histologic variant was a fibrocollagenous dermatofibroma (40.1%). Other variants included histiocytic (13.1%), cellular (11.5%), aneurysmal (7.4%), angiomatous (6.5%), sclerotic (6.5%), monster (4.9%), palisading (1.6%) and keloidal dermatofibromas (0.8%). There were 9 dermatofibromas (7.3%) that were the mixed type with two co-dominant histologic features. CONCLUSION: The results of this study are consistent with previous reports on the clinical features of dermatofibromas. However, we observed several characteristic subtypes of dermatofibroma and we compared the frequency of the histologic subtypes.

A Case of Tubular Apocrine Adenoma with Syringocystadenoma Papilliferum that Developed in a Nevus Sebaceus.

Tubular apocrine adenoma (TAA) is a very rare sweat gland tumor. TAA and syringocystadenoma papilliferum (SCAP) rarely develop together in a nevus sebaceus (NS). Herein, we report on a 40-year-old Korean woman with TAA associated with SCAP that developed in a NS located on the scalp.

Inflammatory myoglandular polyps causing hematochezia.

We report herein three cases of inflammatory myoglandular polyp (IMGP) presenting as hematochezia. The polyps had pedunculated, red, and smooth features, and were 12, 12, and 15 mm in diameter and located in the sigmoid colon, transverse colon, and rectum, respectively. Endoscopic polypectomies were performed. Histologic examination of the recovered specimens revealed inflammatory granulation in the lamina propria mucosa, proliferation of smooth muscle, and hyperplastic glands with cystic dilatation. The three colon polyps were finally diagnosed both clinically and histologically as IMGP. Endoscopists should bear in mind that a polyp featuring endoscopic findings of pedunculation or semipedunculation; a red, smooth, spherical, and hyperemic surface; and patchy mucosa exudation and erosion is likely to be an IMGP.

[Comparison of the efficacies of silver-containing dressing materials for treating a full-thickness rodent wound infected by methicillin-resistant Staphylococcus aureus].

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) may cause infections during wound dressing. We aimed to compare the antibacterial activities and wound-healing effects of commercially available silver-coated or silver-impregnated wound dressings on MRSA-infected wounds. METHODS: Full-thickness skin defects were made on the back of rats (N=108) and were infected with MRSA. The rats were divided into the following 6 groups according to the dressing used for the wounds: nanocrystalline silver (Acticoat), silver carboxymethylcellulose (Aquacel-Ag), silver sulfadiazine (Medifoam silver), nanocrystalline silver (PolyMem silver), silver sulfadiazine (Ilvadon), and 10% povidone iodide (Betadine). We analyzed the wound sizes, histological findings, and bacterial colony counts for the groups. We also inoculated the silver materials on Mueller-Hinton agar plates containing MRSA and compared the inhibition zones in the agar plates. RESULTS: The order of the rate of wound-size decrease was Acticoat>Aquacel-Ag>PolyMem silver>Medifoam silver>Ilvadon>Betadine. The histological findings revealed that the Acticoat showed more reepithelialization and granulation tissue formation and less inflammatory cell infiltration than the other materials. The order of the time required for wound healing was Acticoat>Aquacel -Ag>PolyMem silver>Ilvadon>Medifoam silver>Betadine. The bacterial colony counts reduced in all the groups, except in the Medifoam silver group. The order of the size of the inhibition zone was Acticoat>Aquacel-Ag>Ilvadon>PolyMem silver>Betadine>Medifoam silver. CONCLUSIONS: Silver-coated or silver-impregnated wound dressings can be used for treating MRSAinfected wounds. Considering its superior efficacy in comparison to the efficacies of other silver-coated or silver-impregnated wound dressings, Acticoat should be preferentially used for the treatment of MRSA-infected skin wounds.

Asymptomatic lymphangioma involving the spleen and retroperitoneum in adults.

Lymphangioma, a benign neoplasm of the lymphatic system, is common in children but rare in adults. Its clinical manifestations include abdominal pain, nausea, vomiting and a palpable mass. However, abdominal sonography or abdominal computed tomography (CT) scan can also incidentally reveal lymphangioma. A larger or symptomatic lymphangioma is treated with total resection to prevent recurrence, infection, torsion and enlargement. Although lymphangioma rarely becomes malignant, its prognosis is generally good. We report a cystic lymphangioma of the spleen and retroperitoneum, which was incidentally found in a 56-year-old man who was hospitalized due to a colon mass. Physical examination showed no specific findings. Abdominal CT revealed a 5.7 cm, non-enhanced multilobulated cystic mass with multiple septa in the spleen and a 10 cm lobulated cystic mass in the paraaortic area. Splenectomy and retroperitoneal resection of the cystic mass were conducted. The endothelium of splenic and retroperitoneal cyst was immunohistochemically stained with D2-40 antibody. The patient was finally diagnosed with splenic cystic and retroperitoneal cavernous lymphangioma.

[A case of a Korean adult affected by type B Niemann-Pick disease: secondary sea-blue histiocytosis and molecular characterization].

Niemann-Pick disease (NPD) is an inherited metabolic disorder caused by a deficiency of the enzyme acid sphingomyelinase coded by SMPD1 gene. In contrast with type A NPD, a severe neurodegenerative disease of infancy, type B NPD patients have little or no neurodegeneration, and frequently survive into adulthood. Although over 100 mutations have been found within the SMPD1 gene causing NPD, there was only one report about SMPD1 mutation status of a Korean NPD patient. We report a case of a 32-yr-old female, who presented with thrombocytopenia without any neurologic involvement. Hepatosplenomegaly was detected by both physical examination and imaging studies, and a thoracic radiograph examination showed a pattern of interstitial lung disease. Biochemical tests revealed increased liver enzymes, cholesterol, triglyceride, and LDL-cholesterol, and decreased HDL-cholesterol. Sea-blue or foamy vacuolated histiocytes occurred in bone marrow and liver. Sequencing analysis of SMPD1 using genomic DNA from peripheral leukocytes identified a compound heterozygote of two mutations at exon 2: p.E246K and p.A357V. The former is a known mutation in an Italian patient, and the latter has not been reported yet. She has received oral rosuvastatin to treat hyperlipidemia at a dose of 10 mg per day for 4 months. This is the second report in which the mutation of SMPD1 gene was detected in a Korean NPD patient. The active genetic analysis of SMPD1 gene in patients with typical findings of type B NPD would enable us to facilitate diagnosis as well as to accumulate data on molecular characteristics of Korean NPD patients.

[Sigmoid colon diverticular bleeding in a 75-year-old woman].

Most common cause of brisk hematochezia is diverticular bleeding in Western countries. It occurs in 15% of patients with diverticulosis and one-third of them appear to be massive. Most of diverticulosis in Western countries occur in the left colon but the right colon is more common in Korea. Especially, the reports of diverticular bleeding on left colon are rare in Korea. We report a case presenting with multiple diverticuli complicated by recurrent massive bleeding restricted to the left colon. 75-year-old female was admitted due to hematochezia and dizziness. On past history, two years and two weeks ago respectively, she was treated of diverticular bleeding with and without diverticulitis. Hemoglobin level was 9.8 g/dL. On Colonoscopy, numerous diverticuli were seen at sigmoid colon upto splenic flexure which showed fresh blood clots in the lumen. We diagnosed her as recurrent massive diverticular bleeding on the sigmoid colon. She received elective laparoscopic left hemicolectomy.

[A case of mucinous noncystic carcinoma of the pancreas].

Mucinous (colloid) carcinoma is defined as pools of stromal extracellular mucin containing scanty, floating carcinoma cells. It is a well-defined entity in breast or large bowel. However, mucinous noncystic carcinoma of the pancreas (MNCC) is uncommon, comprising between 1% and 3% of all carcinomas of the pancreas. In the past, MNCC generally had been categorized together with ordinary ductal adenocarcinoma or misdiagnosed as mucinous cystadenocarcinoma or signet-ring cell carcinoma. The new WHO classification lists MNCC as a variant of ductal adenocarcinoma. Herein, we report a 32-year-old woman with incidentally found pancreatic body mass who underwent subtotal pancreatectomy. She was diagnosed as MNCC histologically.

Giant hyperplasia of the caudate lobe in a patient with liver cirrhosis: case report and literature review.

The caudate lobe often exhibits enlargement and nodularity in cases of cirrhosis, which makes differentiation of hepatocellular carcinoma from other mass-like lesions of the caudate lobe difficult in cirrhotic patients. A 12x6 cm mass-like enlargement of the caudate lobe was incidentally found by computed tomography in a 38-year-old man suffering from alcoholic liver cirrhosis. Magnetic resonance imaging, liver colloidal scan, and sonoguided liver biopsy were used for the differential diagnosis. A literature review revealed two case reports, all of which (like ours) presented with an enlarged caudate lobe supplied with blood via a branch of the portal vein. Therefore, in cases of giant hyperplasia of the caudate lobe, confirmation of the caudate lobe blood supply and the enhancement pattern might be important for the differentiation.

Myoepitheliomas of the soft palate: helical CT findings in two patients.

We describe the enhancement patterns of myoepithelioma in two patients with a soft palate mass. In the first case, helical CT revealed a faintly enhancing mass. Histologically, the tumor was composed of plasmacytoid cells in a background of rich myxoid stroma. Immunostaining for CD34 showed scanty blood vessels. In the second case, helical CT revealed an intensely enhancing mass. Histologically, the mass was a cellular tumor with fibrous stroma. Immunostaining for CD34 also showed frequent blood vessels.