Direct peroral cholangioscopy with red dichromatic imaging 3 detected the perihilar margin of superficial papillary extension in a patient with intraductal papillary neoplasm of the bile duct.

Intraductal papillary neoplasms of the bile duct (IPNB) are a tumor derived from bile duct epithelium that tends to spread laterally and non-invasively. Surgery is the first-choice treatment for IPNB. It is extremely important to accurately diagnose the extent of lateral tumor extension. Although peroral cholangioscopy (POCS) is a potentially useful modality for detecting tumor range with direct observation, poor image quality is a limitation of POCS. Recently, a new-generation endoscopy system (EVIS X1) was equipped with functions such as red dichromatic imaging to improve image quality. A 75-year-old man with cholangitis was referred to our department. Various imaging studies showed a mass in the middle to lower bile duct and dilatation of the common bile duct and the intrahepatic bile duct. Endoscopic retrograde cholangiopancreatography was performed. A biopsy of the main tumor in the lower common bile duct revealed IPNB. It was difficult to determine the extent of superficial tumor extension with modalities such as contrast-enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography but the detailed evaluation was possible using POCS with red dichromatic imaging 3. The patient underwent hepatopancreatoduodenectomy. This case suggests the usefulness of direct observation using POCS with red dichromatic imaging 3 to determine the range of IPNB.

Tumor necrosis factor­related apoptosis­inducing ligand is a novel transcriptional target of runt­related transcription factor 1.

Runt­related transcription factor 1 (RUNX1), which is also known as acute myeloid leukemia 1 (AML1), has been frequently found with genomic aberrations in human leukemia. RUNX1 encodes a transcription factor that can regulate the expression of hematopoietic genes. In addition, tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) performs an important function for malignant tumors in immune surveillance. However, the regulatory mechanism of TRAIL expression remain to be fully elucidated. In the present study, tetradecanoylphorbol 13­acetate­treated megakaryocytic differentiated K562 cells was used to examine the effect of RUNX1 on TRAIL expression. Luciferase assay series of TRAIL promoters for the cells co­transfected with RUNX1 and core­binding factor ß (CBFß) expression vectors were performed to evaluate the nature of TRAIL transcriptional regulation. Electrophoresis mobility shift assay of the RUNX1 consensus sequence of the TRAIL promoter with recombinant RUNX1 and CBFß proteins was also performed. BloodSpot database analysis for TRAIL expression in patients with acute myeloid leukemia were performed. The expression of TRAIL, its receptor Death receptor 4 and 5 and RUNX1 in K562 cells transfected with the RUNX1 expression vector and RUNX1 siRNA were evaluated by reverse transcription­quantitative PCR (RT­qPCR). TRAIL and RUNX1­ETO expression was also measured in Kasumi­1 cells transfected with RUNX1­ETO siRNA and in KG­1 cells transfected with RUNX1­ETO expression plasmid, both by RT­qPCR. Cell counting, lactate dehydrogenase assay and cell cycle analysis by flow cytometry were performed on Kasumi­1, KG­1, SKNO­1 and K562 cells treated with TRAIL and HDAC inhibitors sodium butyrate or valproic acid. The present study demonstrated that RUNX1 is a transcriptional regulator of TRAIL. It was initially found that the induction of TRAIL expression following the megakaryocytic differentiation of human leukemia cells was RUNX1­dependent. Subsequently, overexpression of RUNX1 was found to increase TRAIL mRNA expression by activating its promoter activity. Additional analyses revealed that RUNX1 regulated the expression of TRAIL in an indirect manner, because RUNX1 retained its ability to activate this promoter following the mutation of all possible RUNX1 consensus sites. Furthermore, TRAIL expression was reduced in leukemia cells carrying the t(8;21) translocation, where the RUNX1­ETO chimeric protein interfere with normal RUNX1 function. Exogenous treatment of recombinant TRAIL proteins was found to induce leukemia cell death. To conclude, the present study provided a novel mechanism, whereby TRAIL is a target gene of RUNX1 and TRAIL expression was inhibited by RUNX1­ETO. These results suggest that TRAIL is a promising agent for the clinical treatment of t(8;21) AML.

C11orf21, a novel RUNX1 target gene, is down-regulated by RUNX1-ETO.

The fusion protein RUNX1-ETO is an oncogenic transcription factor generated by t(8;21) chromosome translocation, which is found in FAB-M2-type acute myeloid leukemia (AML). RUNX1-ETO is known to dysregulate the normal RUNX1 transcriptional network, which should involve essential factors for the onset of AML with t(8;21). In this study, we screened for possible transcriptional targets of RUNX1 by reanalysis of public data in silico, and identified C11orf21 as a novel RUNX1 target gene because its expression was down-regulated in the presence of RUNX1-ETO. The expression level of C11orf21 was low in AML patient samples with t(8;21) and in Kasumi-1 cells, which carry RUNX1-ETO. Knockdown of RUNX1-ETO in Kasumi-1 cells restored C11orf21 expression, whereas overexpression of RUNX1 up-regulated C11orf21 expression. In addition, knockdown of RUNX1 in other human leukemia cells without RUNX-ETO, such as K562, led to a decrease in C11orf21 expression. Of note, the C11orf21 promoter sequence contains a consensus sequence for RUNX1 binding and it was activated by exogenously expressed RUNX1 based on our luciferase reporter assay. This luciferase signal was trans-dominantly suppressed by RUNX1-ETO and site-directed mutagenesis of the consensus site abrogated the reporter activity. This study demonstrated that C11orf21 is a novel transcriptional target of RUNX1 and RUNX1-ETO suppressed C11orf21 transcription in t(8;21) AML. Thus, through this in silico approach, we identified a novel transcriptional target of RUNX1, and the depletion of C11orf21, the target gene, may be associated with the onset of t(8;21) AML.

Biliary Schwannoma That Required Differentiation from Bile Duct Cancer.

Schwannomas are benign tumors originating from Schwann cells, which are the main component of the neural sheath. Biliary schwannomas are extremely rare. We report the case of a 78-year-old man who presented with no abdominal symptoms or jaundice. CT imaging showed a hyperdense mass extending along the extrahepatic bile duct, and the upstream bile ducts were dilated. We performed extrahepatic bile duct resection under a preoperative diagnosis of the extrahepatic bile duct cancer. A histopathological examination of the resected specimen revealed that the tumor consisted of spindle cells which exhibited a palisading arrangement. Immunohistochemical staining was positive for protein S-100 and vimentin. Based on these pathological findings, we diagnosed the patient with schwannoma of the extrahepatic bile duct. Our search of the relevant literature revealed 19 case studies of biliary schwannomas. In our case, the surgical findings showed that the tumor was noninvasive and mobile. During surgery, a fast frozen section analysis was performed, and no malignant findings were observed. These results enabled us to avoid extrahepatic bile duct resection with major hepatectomy. We experienced a case of biliary schwannoma that was difficult to distinguish from bile duct cancer.

A useful and safe method for retrieving a round metallic object from an airway.

The endoscopic net forceps with the support of a laryngeal mask airway are a dependable choice for retrieving a round metallic object from an airway.

[Laparoscopic Lymphadenectomy without Gastrectomy for Lymph Nodes Recurrence after Endoscopic Submucosal Dissection (ESD)].

A case oflaparoscopic lymphadenectomy in a patient with lymph node recurrence after endoscopic submucosal dissection (ESD)is presented. A 77-year-old man underwent ESD for gastric cancer. After 2 years, the patient was referred to our hospital with the diagnosis of lymph node recurrence. We offered radical surgery, including gastrectomy and lymphadenectomy; however, this suggestion was denied by the patient because ofstrong anxiety for gastrectomy. As an alternative therapy, laparoscopic lymphadenectomy for the limited area of high recurrence, without gastrectomy, was performed. Postoperative course was uneventful. The patient was discharged on the 10th postoperative day and remains cancer-free over 2 years after the operation. Laparoscopic lymphadenectomy for high risk area of recurrence may be considered in frail elderly patients to avoid the high burden ofgastrectomy.

[A Case of Curatively Resected Goblet Cell Carcinoid of the Appendix Diagnosed via Intraoperative Frozen Sectional Examination].

A 52-year-old patient presented with epigastric pain.An enhanced CT scan showed a strongly enhanced appendix with abscess formation.Appendectomy was performed under the diagnosis of acute appendicitis with perityphlitic abscess.The stump of the appendix was white and hard, suggesting malignant transformation.Intraoperative frozen sectional examination indicated goblet cell carcinoid(GCC)of the appendix.Thereafter, we performed ileocecal resection with lymphadenectomy (D3).The final pathological diagnosis was GCC, pSS, pN1, Stage III a by the Japanese classification of colorectal carcinoma. Immunohistochemical examination was consistent with GCC including synaptophysin(+), chromogranin A(+), somatostatin receptor(SSTR)2(±), SSTR5(+), and cytokeratin 20(+).The patient received adjuvant chemotherapy and remains cancer-free over 5 years after the operation.

[Simultaneous Laparoscopic Resection of Gastric Cancer and Hepatocellular Carcinoma].

A report of simultaneous laparoscopic resection for a patient with synchronous gastric cancer and hepatocellular carcinoma (HCC)is presented.A 76-year-old man was referred to our hospital for gastric cancer located in the antrum.In the preoperative examination, enhanced CT and MRI revealed a liver tumor located at S2 that had high contrast enhancement in the arterial phase but that was not washed out in the delayed phase.An early HCC was suspected, and simultaneous laparoscopic distal gastrectomy and partial resection of the liver was performed.The postoperative course was uneventful, and the patient was discharged on the 14th postoperative day.Simultaneous laparoscopic resection of gastric cancer and HCC is possible with special attention to surgical procedures and port settings.

[A Case of Advanced Gastric Cancer with Extensive Lymph Node Metastases Treated by Capecitabine plus Cisplatin plus Trastuzumab Chemotherapy,Followed by Conversion Surgery].

An 82-year-old woman underwent upper gastrointestinal endoscopy to evaluate upper abdominal pain.A type 2 tumor (adenocarcinoma, por, HER2+)was found in the lesser curvature of the gastric antrum.Abdominal CT showed bulky lymph node metastases and pancreatic invasion of lymph node No.6 , resulting in a diagnosis of cT3N3M0, Stage III B.Radical resection was not possible by gastrectomy, and chemotherapy(capecitabine plus cisplatin plus trastuzumab)was administered. The primary lesion and lymph node showed significant regression on CT after the administration of 8 courses of chemotherapy, which also clarified the border between the lymph node and pancreas.At this stage, it was determined that radical resection was feasible; distal gastrectomy(Roux-en-Y reconstruction)and D2 dissection and cholecystectomy were performed.No cancer cells were found in the primary lesion on histopathology.The therapeutic effect of preoperative chemotherapy was assessed as Grade 3, pCR, and retained tumor was only found in lymph node No.5 . On follow-up observation, the patient is alive 11 months after surgery, with no evidence of recurrence without neoadjuvant chemotherapy.

[Synchronous Triple Malignant Tumors (Hilar Cholangiocarcinoma, Ascending Colon Cancer, Liposarcoma) Resected in a Two-Stage Procedure--A Case Report].

A 70-year-old man with a history of myocardial infarction (MI) and taking 2 antiplatelet drugs was diagnosed with anemia his 6-month post-MI checkup. A lower gastrointestinal endoscopy detected ascending colon cancer, and contrast-enhanced a computed tomography scan revealed hilar cholangiocarcinoma as well as lesions suspicious for gastrointestinal stromal tumors of the small intestine. The patient was given a preoperative diagnosis of synchronous triple malignant tumors. The decision to perform a two-stage procedure was made for the following reasons: the impossibility of discontinuing antiplatelet drugs 6 months after drug-eluting stent placement, continuous bleeding due to colon cancer and the possibility of suffering severe stress from surgery while at high risk for diseases such as hepatic failure. In the initial procedure, a right hemicolectomy and surgical resection of the mesenteric tumor (later diagnosed as a liposarcoma) were performed after portal vein embolization. Confirmation of an enlarged residual liver was confirmed 2 months after the initial procedure. The patient underwent right hepatectomy and resection of the extrahepatic bile duct and the biliary tract was surgically reconstructed. Safe resection of tumors was successfully performed by choosing a two-stage procedure for triple malignancy, including hilar cholangiocarcinoma, ascending colon cancer, and liposarcoma, in a single patient.

[A Case of Advanced Gastric Cancer for Which Curative Resection Was Performed, Despite CEA Elevation].

A 32-year-old man was admitted to our hospital with the complaint of epigastric pain. Gastrointestinal endoscopy revealed a type 5 advanced gastric cancer at the posterior wall of the antrum. Contrast-enhanced computed tomography (CT) and endoscopic ultrasonography showed a fluid collection, indicating peritoneal metastasis. CEA levels were elevated, at 16.5 ng/mL. A diagnosis was made of cStage Ⅳ (T4aN3H0P1M1), and he underwent first-line chemotherapy using CDDP and S-1. However, this immediately failed with the severe adverse effect of vomiting.Docetaxel and S-1 were adopted as second-line chemotherapy. Since progression of the disease was confirmed after 8 cycles of second-line chemotherapy, nab-paclitaxel was administered as third-line chemotherapy. Despite a trend of increasing CEA after 4 cycles of third-line chemotherapy, CT revealed a tumor volume reduction as well as the disappearance of the fluid collection, after which staging laparoscopy was performed. Based on the finding that non-curative factors such as fluid collection and peritoneal nodules were not observed, distal gastrectomy was performed. Histopathological examination showed a ypStage ⅠA (T1bN0H0P0M0)tumor with a grade 3 therapeutic response to chemotherapy.The patient is currently doing well with no recurrence 11 months after the operation.

[A Case of Pathological Complete Response after Primary Tumor Resection Followed by Hepatectomy-A Sigmoid Colon Cancer with Synchronous Liver Metastases].

The case is of a 62-year-old man with no medical history and no family history.A type 2 tumor was found in the entire circumference of the sigmoid colon by colonoscopy after a positive result on a fecal occult blood test, and 5 liver metastases were recognized in both lobes of the liver by using contrast-enhanced CT.He was first treated by primary tumor resection. Subsequently, 5-fluorouracil/l-leucovorin/oxaliplatin (mFOLFOX6) plus bevacizumab (BV) was started 1 month after the surgery and a total of 8 cycles of mFOLFOX6 plus BV were administered without any adverse events.On CT assessment after the chemotherapy, the patient was diagnosed with stable disease according to RECIST guidelines since the size of the tumor only showed a slight reduction.However, it was considered to be an optimal response based on the morphologic criteria. Thereafter, a medial segmentectomy and partial resection of the liver was performed.A mucus reservoir was found in the tumor site, and no viable tumor cells were detected pathologically, which confirmed the pathological complete response with mFOLFOX6 plus BV.

Risk factors for acute pancreatitis in patients with severe motor and intellectual disabilities.

BACKGROUND: Acute pancreatitis in patients with severe motor and intellectual disability (SMID) is a rare but life-threatening condition. Possible causes of acute pancreatitis in these patients including valproic acid therapy, hypothermia and nasoduodenal tube feeding, have not yet been investigated in detail. The aim of this study was therefore to investigate the risk factors for acute pancreatitis in patients with SMID. METHODS: Five SMID patients with acute pancreatitis and 15 SMID patients without acute pancreatitis were reviewed. Age; serum total cholesterol, triglyceride, total protein, and albumin; height; bodyweight; body surface area; body mass index; daily calorie intake; daily calorie intake per unit of body mass surface area; daily calorie intake per kilogram bodyweight; and valproic acid usage were examined. RESULTS: A statistically significant difference was observed in serum albumin level between the two groups (P = 0.026). CONCLUSION: The mechanism of acute pancreatitis in these patients was considered as pancreatic morphological change, acinar damage, and elevated serum trypsinogen level caused by malnutrition. It is likely that acute pancreatitis in patients with SMID occurs due to the same mechanism as in anorexia nervosa and malnourished patients. To prevent acute pancreatitis in these patients, it is important to maintain adequate nutritional status.

Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.

OBJECTIVE: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. METHODS: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. RESULTS: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. INTERPRETATION: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions.

[Three pediatric cases of group A coxsackievirus-associated encephalitis/encephalopathy].

We report three pediatric cases of group A coxsackievirus-associated encephalitis/encephalopathy. A 4-year-old girl with coxsackievirus A6 infection presented with an exanthem on her upper body on the fourth day of fever. The following day, she developed an episode of convulsions, and subsequently experienced sudden cardiopulmonary arrest. A head computed tomography scan revealed severe brain edema. Two patients with neurological sequelae had initially presented with status epilepticus that required intravenous barbiturate treatment. Both cases had high-signal-intensity lesions on their diffusion-weighted brain magnetic resonance images. A 5-year-old girl with subcortical white matter lesions was diagnosed with acute encephalopathy with febrile convulsive status epilepticus, and a 2-year-old boy with bilateral hippocampal lesions was diagnosed with parainfectious limbic encephalitis. These findings indicate that group A coxsackievirus is a causative agent of pediatric encephalitis/encephalopathy; moreover, the prognosis may be poor in some cases.

Crows cross-modally recognize group members but not non-group members.

Recognizing other individuals by integrating different sensory modalities is a crucial ability of social animals, including humans. Although cross-modal individual recognition has been demonstrated in mammals, the extent of its use by birds remains unknown. Herein, we report the first evidence of cross-modal recognition of group members by a highly social bird, the large-billed crow (Corvus macrorhynchos). A cross-modal expectancy violation paradigm was used to test whether crows were sensitive to identity congruence between visual presentation of a group member and the subsequent playback of a contact call. Crows looked more rapidly and for a longer duration when the visual and auditory stimuli were incongruent than when congruent. Moreover, these responses were not observed with non-group member stimuli. These results indicate that crows spontaneously associate visual and auditory information of group members but not of non-group members, which is a demonstration of cross-modal audiovisual recognition of group members in birds.

Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene.

BACKGROUND: We isolated the human liver-specific organic anion transporter gene, LST-2 (OATP8/SLCO1B3), which is exclusively expressed in the basolateral membrane of the hepatocytes. In this study, we analyzed the transcriptional regulation of the LST-2 gene in hepatocyte-derived cells and the effect of bile acid. METHODS: Transcriptional activity of the LST-2 gene was measured using a human LST-2 promoter-luciferase reporter plasmid under various concentrations of bile acids. Electrophoresis mobility shift assays of farnesoid X receptor (FXR), hepatocyte nuclear factor (HNF) 1alpha, and HNF3beta were performed. RESULTS: Luciferase analysis showed that the 5'-flanking region from -180 to -20 bp is responsible for LST-2 transcriptional activity. By site-directed mutation analysis, it was revealed that the consensus binding sites for FXR, HNF1alpha, and HNF3beta play important roles in the transcriptional activity of the LST-2 gene. By electrophoresis mobility shift assay, we observed specific protein-DNA complexes of FXR, HNF1alpha, and HNF-3beta. Luciferase activity was increased fivefold when chenodeoxycholate or deoxycholate were added. Northern blot analyses revealed that the expression of LST-2 was increased by addition of chenodeoxycholate or deoxycholate in a dose-dependent manner. CONCLUSIONS: This study demonstrated that the transcription of the LST-2 gene is regulated by three transcription factors, FXR, HNF1alpha, and HNF3beta. HNF1alpha and HNF3beta might contribute to its liver-specific expression, and FXR might play a role in its transcriptional activation by bile acids.

Osmoregulation of vasopressin release and gene transcription under acute and chronic hypovolemia in rats.

Although acute decreases in plasma volume are known to enhance the osmotically induced arginine vasopressin (AVP) release, it is unclear whether there is also such interaction at the level of gene transcription. It also remains to be established how sustained changes in plasma volume affect the osmoregulation. In this study, we examined how acute and chronic decreases in blood volume affected the osmoregulation of AVP release and gene transcription in rats. Acute hypovolemia was induced by intraperitoneal injection of polyethylene glycol (PEG), and chronic hypovolemia was induced by 3 days of water deprivation (WD) or 12 days of salt loading (SL). Rats were injected with isotonic or hypertonic saline, and plasma AVP levels and AVP heteronuclear (hn)RNA expression in the supraoptic and paraventricular nuclei, an indicator of gene transcription, were examined in relation to plasma osmolality in each group. Plasma AVP levels were correlated with plasma Na levels in all groups. Whereas the regression lines relating plasma AVP to Na were almost identical among control, WD, and SL groups, the thresholds of plasma Na for AVP release were significantly decreased only in the PEG group. AVP hnRNA levels were also correlated with plasma Na levels in control and PEG groups, and the thresholds were significantly decreased in the PEG group. In contrast, there was no significant correlation of AVP hnRNA and plasma Na levels in WD and SL groups. Thus it was demonstrated that acute and chronic reduction in plasma volume affected the osmoregulation of AVP release and gene transcription in different ways.