Hideto Ito

Upregulation of BNIP3 by 5-aza-2′-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death

BackgroundPancreatic cancer cells often show resistance to hypoxia-mediated apoptosis, but the molecular mechanism underlying that resistance remains unknown. The purpose of the present study, therefore, was to examine the role of epigenetic gene alteration in the resistance to hypoxia-mediated apoptosis among pancreatic cancer cells.MethodsReverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of five genes associated with hypoxia-mediated apoptosis (PUMA, Caspase-8 [CASP8], APAF-1, BNIP3, and BNIP3L) in a panel of pancreatic cancer cell lines. Protein expression was examined by Western blot analysis, using lysates from cells incubated under normoxic or hypoxic conditions. The methylation status of the genes was determined using bisulfite-PCR and sequencing. The percentages of cells that were apoptotic were determined using flow cytometry.ResultsUnder normoxic conditions, the expression of the BNIP3 gene varied among the 12 pancreatic cancer cell lines tested, with 50% of them showing no BNIP3 expression at all, whereas expression of the other four genes was readily detected in all 12 cell lines. DNA methylation of BNIP3’s CpG island in the region around the transcription start site of the gene was closely associated with its silencing. The expression of BNIP3 was restored by the methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC), as was the hypoxia-mediated pancreatic cancer cell death.ConclusionsBNIP3 expression is silenced in some pancreatic cancer cells by the methylation of its CpG island. Demethylation of BNIP3, using a methyltransferase inhibitor, restores the gene’s expression and induces hypoxia-mediated cell death. BNIP3 may thus be a useful target for new therapies aimed at treating pancreatic cancer.

Mucin Expression Profile Is Related to Biological and Clinical Characteristics of Intraductal Papillary-mucinous Tumors of the Pancreas

Objectives: Biologic and clinical characteristics of intraductal papillary-mucinous tumors of the pancreas (IPMTs) were studied in reference to immunohistochemical mucin (MUC1, MUC2, and MUC5AC) expression. Methods: Histologic grade, immunohistochemical ki-67 and p53 expression, and findings in imaging tests of 21 IPMTs (9 carcinomas, 6 borderline tumors, and 6 adenomas) were examined according to the mucin expression profile. Results: IPMTs were divided into groups: M1 group (MUC1+, n = 4), M2 group (MUC2 + MUC1−, n = 12), and M5 group (MUC5AC + MUC1−MUC2−, n = 5). The M2 group was subdivided into M2s (strongly positive) and M2w (weakly positive) groups. The rates of carcinoma in the M1, M2s, M2w, and M5 groups were 100%, 40%, 0%, and 0%, respectively. The Ki-67 labeling indexes were significantly higher in the M1 and M2s groups. p53 staining was positive in 50% and 40% of the IPMTs in the M1 and M2s groups, respectively, but in none of the IPMT in the M2w and M5 groups. Morphologic changes in imaging tests during the observation periods were most remarkable in the M1 group. Conclusions: Our results suggest that MUC1 is related to malignant character but MUC5AC alone is related to benign character in IPMTs and that malignant potential of IPMTs expressing MUC2 depends on the degree of MUC2 expression.

A 25-year clinical history of portopulmonary hypertension associated with latent myeloproliferative disorder

Pulmonary hypertension associated with increased pulmonary vascular resistance occurring in the setting of portal hypertension, referred to as “portopulmonary hypertension”, is a complication of chronic liver disease, and occurs in 2% to 3% of patients with portal hypertension. Portal hypertension is a relatively common finding in patients with chronic myeloproliferative disorder (CMPD). Pulmonary hypertension is also an occasional finding in CMPD patients. Latent myeloproliferative disorder, on the other hand does not fulfill the diagnostic criteria of classical CMPD and is characterized by younger age of onset, slow disease progression, a high risk of thrombosis, platelet dysfunction, and normal or increased platelet count in spite of the presence of splenomegaly. We report findings in a 50-year-old woman with portal hypertension for which there were three major etiological findings—increased splenic blood flow, infiltration of hematopoietic cells in the liver, and thrombosis in the portal or hepatic vein—over a 25-year clinical course, during which there was also reversible stenosis of the portal vein. Twenty-three years after her first admission, her condition was diagnosed as latent myeloproliferative disorder, and she developed pulmonary hypertension. Her clinical history and data indicated that the portopulmonary hypertension was due to the latent myeloproliferative disorder.

Acinar cell carcinoma of the pancreas with intraductal growth: Report of a case

Acinar cell carcinomas (ACCs) of the pancreas are rare neoplasms, accounting for approximately 1% of all exocrine pancreatic tumors. This type of tumor is known to be aggressive, although the survival rates are somewhat better than they are for ductal carcinoma. The tumor tends to present nonspecific symptoms. It occurs in older patients, and jaundice is infrequent. This report presents a case of ACC of the pancreas with intraductal papillary growth and lymph node metastasis.

Use of a Fibrinogen/Thrombin-Based Collagen Fleece (TachoComb, TachoSil) With a Stapled Closure to Prevent Pancreatic Fistula Formation Following Distal Pancreatectomy.

Background/Purpose. Postoperative pancreatic fistula formation remains a source of significant morbidity following distal pancreatectomy. The aim of this study was to evaluate the rate of clinically significant fistulas (International Study Group on Pancreatic Fistula grade B and grade C) after distal pancreatectomy using a fibrinogen/thrombin-based collagen fleece (TachoComb, TachoSil) with a stapled closure. Methods. Seventy-five patients underwent distal pancreatectomy at our institution between January 2005 and March 2014. A fibrinogen/thrombin-based collagen fleece was applied to the staple line of the pancreas before stapling. Results. Twenty-six patients (34.7%) developed a pancreatic fistula, 8 patients (10.7%) developed a grade B fistula, and no patients developed a grade C fistula. The duration of the drain was significantly different in patients with or without a pancreatic fistula (8.0 ± 4.5 vs 5.4 ± 1.3 days, P = .0003). Histological analysis showed that there was a tight covering with the fibrinogen/thrombin-based collagen fleece. Conclusion. The fibrinogen/thrombin-based collagen fleece (TachoComb, TachoSil) with a stapled closure has low rates of fistula formation and provides a safe alternative to the conventional stapled technique in distal pancreatectomy.

Treatment of Chilaiditi syndrome using laparoscopic surgery

Chilaiditi syndrome is defined as the interposition of the bowel between the liver and right diaphragm. It is a rare disease and may be difficult to diagnose and manage. Treatment for asymptomatic patients with Chilaiditi is usually conservative and does not require surgical intervention, but surgery may be necessary if conservative treatment fails. This report describes a rare case of Chilaiditi syndrome causing small bowel obstruction and corrected using laparoscopic surgery.

Postpancreatectomy Hemorrhage After Pancreatic Surgery in Patients Receiving Anticoagulation or Antiplatelet Agents

Background. Postpancreatectomy hemorrhage (PPH) is a serious complication after pancreatic surgery. In this study, we evaluated PPH and thromboembolic complications after pancreatic surgery in patients with perioperative antithrombotic treatment. Methods. Medical records of patients undergoing pancreatic surgery were reviewed retrospectively. Patients receiving thromboprophylaxis were given either bridging therapy with unfractionated heparin or continued on aspirin as perioperative antithrombotic treatment according to clinical indications and published recommendations. The International Study Group of Pancreatic Surgery definition of PPH was used. Risk factors associated with PPH were assessed by multivariate analysis. Results. Thirty-four of 158 patients received perioperative antithrombotic treatment; this group had a significantly higher PPH rate (29.4% vs 6.5%, P = .001) and mortality (11.8% vs 2.4%, P = .039) than patients not receiving thromboprophylaxis. Multivariate analysis revealed that perioperative antithrombotic treatment was the only independent risk factor for PPH after pancreatic surgery (odds ratio 4.77; 95% CI 1.61-14.15; P = .005). Conclusions. Perioperative antithrombotic treatment is an independent risk factor for PPH in patients undergoing pancreatic surgery, although this treatment effectively prevents postoperative thromboembolic events.

Association between antithrombotic therapy and risk of postoperative complications among patients undergoing endovenous laser ablation

BACKGROUND The aim of the study was to evaluate the clinical results and postoperative complications, especially recanalization or bleeding complications, in patients with saphenous varicose veins undergoing endovenous laser ablation (EVLA) while receiving antithrombotic therapy (ATT). METHODS This retrospective cohort study included 1136 Japanese patients undergoing EVLA with a 980-nm diode laser between January 2012 and November 2015 at our institution. The patients were divided into two groups: ATT users (ATT group) and nonusers (control group). The ATT group was further divided into two subgroups according to whether the patients received antiplatelet or anticoagulant therapy. Clinical outcomes and postoperative complications among these patients were assessed. RESULTS Approximately 20% of the patients undergoing surgery for saphenous varicose veins at our institution received ATT. Of these, 141 (12.4%) received antiplatelet therapy and 95 (8.4%) received anticoagulant therapy. Successful occlusion of the full length of the treated vein was achieved in 99.9% of the patients; there were no severe perioperative complications. Endovenous heat-induced thrombosis occurred in 2.4% of patients, whereas postoperative complications developed in 1.2% of patients. One patient experienced recanalization (0.08%). There were no significant between-group differences in the incidence of recanalization and postoperative complications on univariate analysis. CONCLUSIONS The clinical outcomes and postoperative complications of EVLA in the ATT group were equivalent to those in the control group, indicating that EVLA can be safely performed in patients receiving ATT.

Immunoglobulin G4-related sclerosing cholecystitis presenting as gallbladder cancer: a case report.

Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic inflammatory syndrome, and an understanding of its characteristics is currently evolving. IgG4-related cholecystitis is a manifestation of IgG4-related sclerosing disease in the gallbladder. This case report describes the clinical, radiographic, and histopathological findings in a young male patient who presented with a synchronous mass in the gallbladder. Serum levels of IgG4 and the IgG4/IgG ratio were normal, and there was no associated autoimmune pancreatitis. Therefore, establishing a preoperative diagnosis of IgG4-related cholecystitis was very difficult, and a differential diagnosis of gallbladder cancer infiltrating the liver was suggested. Postoperative histopathological examination established a diagnosis of IgG4-related cholecystitis definitively. A preoperative diagnosis of IgG4-related cholecystitis, although possible, would have been highly challenging in this case. It is difficult to establish whether surgical intervention is necessary in IgG4-related cholecystitis. Because malignant tumors are frequently suspected with this clinical presentation, surgical intervention should be undertaken only after due deliberation.

Effect of Blood Transfusions on Survival after Curative Resection for Advanced Gastric Cancer.

手術前後の輸血が胃癌切除後の予後と関連するか否かを検討した.教室における初発進行胃癌治癒切除症例を入院中の輸血たついて非輸血群144例,輸血量1,000ml未満の少量輸血群72例,1,000ml以上の大量輸血群69例に分けて比較すると,大量輸血群の生存率は非輸血群に比べ有意に低かった.両群間に進行程度の差がみられたため因子別に検討すると,深達度漿膜下層(ss)以上の症例およびリンパ節転移がないか1群までの症例で大量輸血群の生存率が非輸血群に比べ低かった.ss以上の症例では両群間に深達度,リンパ節転移の差はなかった.さらにss以上の症例について生存率に関与しうる11の臨床病理学的因子を選びCoxの比例ハザードモデルによる解析を行うと,周術期の輸血はリンパ節転移,腫瘍最大径,静脈侵襲とならんで有意に予後と関連していた.以上より進行胃癌治癒切除例,特に深達度ss以上の症例では周術期における輸血が切除後の生存率を悪くする可能性が示唆された.