Diffusely infiltrative squamous cell carcinoma of the esophagus resembling scirrhous gastric cancer: a case report.

Diffusely infiltrative squamous cell carcinoma of the esophagus is rare and difficult to diagnose. Case presentation: The patient was a 75-year-old woman whose chief complaints were dysphagia and upper abdominal pain. Esophagogastroduodenoscopy and biopsy revealed squamous cell carcinoma at the abdominal esophagus. After neoadjuvant chemotherapy, esophagogastroduodenoscopy showed diffuse thickening and poor distensibility of the stomach wall. We suspected scirrhous gastric cancer and performed multiple biopsies, which revealed no evidence of malignancy. We then performed staging laparoscopy. There were no apparent changes in the serous membrane of the stomach, but peritoneal lavage cytology revealed squamous cell carcinoma. Thus, we made a diagnosis of squamous cell carcinoma of the esophagus with diffuse invasion of the stomach. Intraoperative pathological diagnosis revealed that there was greater diffuse submucosal invasion of the oral esophagus than we expected, and we had to resect the esophagus at the level of the middle thoracic esophagus. Despite multidisciplinary treatment (surgery, chemotherapy, and radiotherapy), the patient died 20 months after the initial diagnosis. Clinical discussion: In this case, although biopsy did not lead to a diagnosis, peritoneal lavage cytology led to the correct diagnosis. Moreover, it was impossible to preoperatively predict the exact extent of the expansion because of diffuse submucosal invasion. Conclusion: When diffusely infiltrative squamous cell carcinoma of the esophagus is suspected, peritoneal lavage cytology may be useful for confirming the diagnosis; however, it should be assumed that accurate preoperative evaluation of the range of diffusely infiltrative squamous cell carcinoma is difficult.

Emergency open drainage of massive hemoperitoneum and early stage left hepatectomy for abdominal compartment syndrome due to hepatocellular carcinoma rupture: a case report.

BACKGROUND: Spontaneous rupture is one of the most life-threatening complications of hepatocellular carcinoma (HCC). Transcatheter arterial embolization (TAE) effectively achieves hemostasis in patients with hemodynamic instability. However, there have been no reports of abdominal compartment syndrome (ACS) caused by massive intra-abdominal hematoma after TAE. We report emergency open drainage of a massive hematoma for abdominal decompression and early stage left hepatectomy at the same time. CASE PRESENTATION: A 75-year-old woman was transported to our emergency department with hypovolemic shock. Dynamic contrast-enhanced computed tomography revealed extravasation of contrast medium from a HCC lesion in the medial segment of the liver and a large amount of high-density ascites. TAE was immediately performed to achieve hemostasis. Three hours after the first TAE, we decided to perform a second TAE for recurrent bleeding. After the second TAE, the patient's intra-abdominal pressure increased to 35 mmHg, her blood pressure gradually decreased, and she had anuria. Thus, she was diagnosed with ACS due to spontaneous HCC rupture. Twenty-seven hours after her arrival to the hospital, we decided to perform open drainage of the massive hematoma and left hepatectomy for ACS relief, prevention of re-bleeding, tumor resection, and intraperitoneal lavage. The operative duration was 225 min, and the blood loss volume was 4626 g. Postoperative complications included pleural effusion and grade B liver failure. She was discharged on postoperative day 33. The patient survived for more than 3 years without functional deterioration. CONCLUSIONS: Even after hemostasis is achieved by TAE for hemorrhagic shock due to spontaneous rupture of HCC, massive hemoperitoneum may lead to ACS, particularly in cases of re-bleeding. Considering the subsequent possibility of ACS and the recurrence of bleeding, early stage hepatectomy and removal of intra-abdominal hematoma after hemodynamic stabilization could be a treatment option for HCC rupture.

Endovascular repair using a covered stent for a ruptured infected aneurysm of the superior mesenteric artery after pancreaticoduodenectomy: a case report.

BACKGROUND: Delayed arterial hemorrhage after pancreaticoduodenectomy is a life-threatening complication. There are no reports about infected aneurysms of the superior mesenteric artery after pancreaticoduodenectomy without clinically relevant pancreatic fistula. CASE PRESENTATION: A 78-year-old woman with borderline resectable pancreatic ductal adenocarcinoma involving the superior mesenteric arterial nerve plexus underwent pancreaticoduodenectomy with en bloc resection of the superior mesenteric vein and the superior mesenteric arterial nerve plexus after neoadjuvant chemotherapy. On postoperative day 14, she had bacteremia and sudden fever with chills. During the postoperative course, macroscopic abscesses or distinct infectious signs, including pancreatic fistula or bile fistula, were not present, but pylephlebitis was observed. After the antimicrobial treatment course, the patient was discharged. After 17 days, she was hospitalized for melena. Contrast-enhanced computed tomography showed a ruptured aneurysm of the superior mesenteric artery into the small intestine without a major intraabdominal abscess. E. coli was isolated from blood cultures. The patient was diagnosed with a ruptured infected aneurysm of the superior mesenteric artery. She was treated successfully with a covered stent by the cardiology team. There was no recurrence of bleeding at the 4-month follow-up, and the stent was patent in all subsequent computed tomography scans. CONCLUSIONS: Endovascular repair using a covered stent was effective in palliating acute bleeding from an infected aneurysm of the superior mesenteric artery.

Ex Vivo Sleeve Lobectomy and Autotransplantation After Chemoradiation.

A 51-year-old man presented to us for potential salvage surgery for local recurrence of a squamous cell carcinoma originating in the left lower lobe after definitive chemoradiotherapy. Salvage sleeve lower lobectomy was initially planned; however, intraoperatively the interlobar pulmonary artery was difficult to separate from the bronchus. To safely spare the upper lobe, we performed ex vivo sleeve lower lobectomy, followed by autotransplantation of the upper lobe. No major postoperative complication was noted and the patient has returned to normal life without recurrence for 9 months.

Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus.

Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy.

Discovery and hit-to-lead optimization of novel allosteric glucokinase activators.

We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by introduction of a hydrogen bond acceptor as proposed by molecular docking. Replacement of the initial alkylene linkers with a rigid 1,2-phenylene motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR.

Decreased insulin secretion and accumulation of triglyceride in beta cells overexpressing a dominant-negative form of AMP-activated protein kinase.

Adenosine 5' -monophosphate-activated protein kinase (AMPK) has been implicated in the regulation of energy metabolism, although its role in the pancreatic beta cells remains unclear. In the present, we have overexpressed a dominant negative form of AMPKalpha1 subunit (Asp57Ala) tagged with c-myc epitope (AMPKalpha1-DN) in INS-1D cells with an adenoviral vector. After 48 h of adenoviral infection, overexpression of AMPKalpha1-DN in INS-1D cells was confirmed by Western blot analysis with anti-c-myc antibody. Phosphorylation of the Thr172 in AMPKalpha1/alpha2 subunit was progressively decreased in parallel with increasing number of adenoviral titers. Glucose-stimulated insulin secretion in response to 30 mmol/L glucose was decreased in INS-1D cells overexpressing AMPKalpha1-DN as compared to control cells infected with adeno- LacZ vector. Neither cellular insulin content nor insulin mRNA level was changed between the two groups. Phosphorylation of acetyl-CoA carboxylase (ACC), a down-stream substrate of AMPK, was decreased, indicating that ACC activity was increased, due to the decreased AMPK activity. In fact, intracellular triglyceride content was increased as compared to control cells. The beta-oxidation of palmitate was decreased at 30 mmol/L glucose. Insulin secretion in response to potassium chloride or glibenclamide was also decreased as compared to control cells. In conclusion, suppression of AMPK activity in beta-cells inhibited insulin secretion in response to glucose, potassium chloride or glibenclamide without altering insulin content. Accumulation of triglyceride subsequent to the activation of ACC by suppression of AMPK activity, was suggested to be, at least in part, responsible for the impaired insulin secretion through so-called lipotoxicity mechanism.

Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous peroxisome proliferator-activated receptor-gamma-deficient mice on a high-fat diet.

Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation.

Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c.

Triglyceride (TG) accumulation in pancreatic beta-cells is thought to be associated with impaired insulin secretory response to glucose (lipotoxicity). To better understand the mechanism of the impaired insulin secretory response to glucose in beta-cell lipotoxicity, we overexpressed a constitutively active form of the sterol regulatory element-binding protein- 1c (SREBP-1c), a master transcriptional factor of lipogenesis, in INS-1 cells with an adenoviral vector. This treatment was associated with strong activation of transcription of the genes involved in fatty acid biosynthesis, increased cellular TG content, severely blunted glucose-stimulated insulin secretion, and enhanced expression of the uncoupling protein-2 (UCP-2), which supposedly dissipates the mitochondrial electrochemical potential. To decrease the up-regulated UCP-2 expression, small interfering RNA for UCP-2 was used. Introduction of the small interfering RNA increased the ATP/ADP ratio and partially rescued the glucose-stimulated insulin secretion in the cells overexpressing SREBP-1c, but did not affect the cellular TG content. Next, the effect of the AMP-activated protein kinase (AMPK) agonist, 5-amino-4-imidazolecarboxamide riboside, was examined in the lipotoxicity model. Exposure of the cells with lipotoxicity to 5-amino-4-imidazolecarboxamide riboside increased free fatty acid oxidation, partially reversed the TG accumulation, phosphorylated AMPK and acetyl-coenzyme A carboxylase, and improved the impaired glucose-stimulated insulin secretion. These results suggest that UCP-2 down-regulation and AMPK activation could be candidate targets for releasing beta-cells from lipotoxicity.

Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic beta-cells.

We studied acute changes of secretory vesicle pH in pancreatic beta-cells with a fluorescent pH indicator, lysosensor green DND-189. Fluorescence was decreased by 0.66 +/- 0.10% at 149 +/- 16 s with 22.2 mM glucose stimulation, indicating that vesicular pH was alkalinized by approximately 0.016 unit. Glucose-responsive pH increase was observed when cytosolic Ca2+ influx was blocked but disappeared when an inhibitor of glycolysis or mitochondrial ATP synthase was present. Glutamate dimethyl ester (GME), a plasma membrane-permeable analog of glutamate, potentiated glucose-stimulated insulin secretion at 5 mM without changing cellular ATP content or cytosolic Ca2+ concentration ([Ca2+]). Application of GME at basal glucose concentration decreased DND-189 fluorescence by 0.83 +/- 0.19% at 38 +/- 2 s. These results indicated that the acutely alkalinizing effect of glucose on beta-cell secretory vesicle pH was dependent on glucose metabolism but independent of modulations of cytosolic [Ca2+]. Moreover, glutamate derived from glucose may be one of the mediators of this alkalinizing effect of glucose, which may have potential relevance to the alteration of secretory function by glutamate.

Genetic manipulations of fatty acid metabolism in beta-cells are associated with dysregulated insulin secretion.

Triacylglyceride (TG) accumulation in pancreatic beta-cells is associated with impaired insulin secretion, which is called lipotoxicity. To gain a better understanding of the pathophysiology of lipotoxicity, we generated three models of dysregulated fatty acid metabolism in beta-cells. The overexpression of sterol regulatory element binding protein-1c induced lipogenic genes and TG accumulation. Under these conditions, we observed a decrease in glucose oxidation and upregulation of uncoupling protein-2, which might be causally related to the decreased glucose-stimulated insulin secretion. The overexpression of AMP-activated protein kinase was accompanied by decreased lipogenesis, increased fatty acid oxidation, and decreased glucose oxidation; insulin secretions to glucose and depolarization stimuli were decreased, probably because of the decrease in glucose oxidation and cellular insulin content. It was notable that the secretory response to palmitate was blunted, which would suggest a role of the fatty acid synthesis pathway, but not its oxidative pathway in palmitate-stimulated insulin secretion. Finally, we studied islets of PPAR-gamma(+/-) mice that had increased insulin sensitivity and low TG content in white adipose tissue, skeletal muscle, and liver. On a high-fat diet, glucose-stimulated insulin secretion was decreased in association with increased TG content in the islets, which might be mediated through the elevated serum free fatty acid levels and their passive transport into beta-cells. These results revealed some aspects about the mechanisms by which alterations of fatty acid metabolism affect beta-cell functions.

Disruption of adiponectin causes insulin resistance and neointimal formation.

The adipocyte-derived hormone adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity, and it has been reported to exhibit putative antiatherogenic properties in vitro. In this study we generated adiponectin-deficient mice to directly investigate whether adiponectin has a physiological protective role against diabetes and atherosclerosis in vivo. Heterozygous adiponectin-deficient (adipo(+/-)) mice showed mild insulin resistance, while homozygous adiponectin-deficient (adipo(-/-)) mice showed moderate insulin resistance with glucose intolerance despite body weight gain similar to that of wild-type mice. Moreover, adipo(-/-) mice showed 2-fold more neointimal formation in response to external vascular cuff injury than wild-type mice (p = 0.01). This study provides the first direct evidence that adiponectin plays a protective role against insulin resistance and atherosclerosis in vivo.

Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals.

The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic beta-cell function was investigated. PI 3-kinase activity in p85 alpha regulatory subunit-deficient (p85 alpha(-/-)) islets was decreased to approximately 20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in beta-cells from p85 alpha(-/-) mice with increased insulin sensitivity. However, p85 alpha(-/-) beta-cells exhibited a marked increase in the insulin secretory response to higher concentrations of glucose. When PI 3-kinase in wild-type islets was suppressed by wortmannin or LY294002, the secretion was also substantially potentiated. Wortmannin's potentiating effect was not due to augmentation in glucose metabolism or cytosolic [Ca(2+)] elevation. Results of p85 alpha(-/-) islets and wortmannin-treated wild-type islets stimulated with diazoxide and KCl showed that inhibition of PI 3-kinase activity exerted its effect on secretion, at least in part, distal to a cytosolic [Ca(2+)] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion.