E2F target score is associated with cell proliferation and survival of patients with hepatocellular carcinoma.

BACKGROUND: E2F target genes are essential for the cell cycle. A score that quantifies its activity is expected to reflect the aggressiveness and prognosis of hepatocellular carcinoma. METHODS: Cohorts of hepatocellular carcinoma patients (total n = 655) from The Cancer Genome Atlas, GSE89377, GSE76427, and GSE6764 were analyzed. The cohorts were divided into high versus low by the median. RESULTS: All the Hallmark cell proliferation-related gene sets were consistently enriched in hepatocellular carcinoma with high E2F targets score, and E2F score was associated with grade, tumor size, American Joint Committee on Cancer staging, proliferation score, and MKI67 expression, as well as with less abundance of hepatocytes and stromal cells. E2F targets enriched DNA repair, mTORC1 signaling, glycolysis, and unfolded protein response gene sets and were significantly associated with the higher intratumoral genomic heterogeneity, homologous recombination deficiency, and progression of hepatocellular carcinoma. On the other hand, there was no relationship between E2F targets and mutation rates or neoantigens. High E2F hepatocellular carcinoma did not enrich any of the immune-response-related gene sets but was associated with high infiltration of Th1, Th2 cells, and M2 macrophage; however, there was no difference in cytolytic activity. In both early (I and II) and late (III and IV) stages of hepatocellular carcinoma, a high E2F score was associated with worse survival and was an independent prognostic factor for overall and disease-specific survival in patients with hepatocellular carcinoma. CONCLUSION: The E2F target score, associated with cancer aggressiveness and worse survival, could be used as a prognostic biomarker in patients with hepatocellular carcinoma.

[A Case of Laparoscopic Hartmann's Procedure for Rectal Cancer with Inferior Mesenteric Vein-Left Ovarian Vein Shunt].

A 77-year-old woman presented with a chief complaint of bloody stools. Detailed examination revealed a semi-circumferential type 2 tumor in the lower rectum, and a diagnosis of Group 5, tub1-2, cT3N2aM0, cStage Ⅲb rectal cancer was made. Preoperative abdominal CT scans revealed a shunt in the inferior mesenteric vein and left ovarian vein. Laparoscopic Hartmann's procedure was performed, and when the sigmoid mesentery was moved from the inner side, a shunt flowing from the left ovarian vein to the inferior mesenteric vein in the sigmoid mesentery was found, which was then dissected. The operating time was 253 min, and blood loss was approximately 140 g. There was no postoperative liver dysfunction, and the patient was transferred to another hospital on postoperative day 36. Causes of portal-systemic shunts are portal hypertension occurring due to liver cirrhosis or congenital causes and organ adhesion from abdominal surgery. In this case, there was no liver cirrhosis, and the blockage of the left renal vein perfusion by the superior mesenteric artery may have resulted in congestion and varicose of the left ovarian vein. Furthermore, the shunt with the inferior mesenteric vein may have been formed due to the adhesion of the left ovarian vein after ovariectomy. If preoperative tests reveal varices, a surgical treatment is recommended while keeping in mind the possibility of shunt formation as in this case.

[A Case of Pancreatotomy of the Pancreatic Tail with a Preserved Residual Stomach Using ICG Fluorescence Method for Pancreatic Cancer after Gastrectomy of the Pyloric Side].

A 53-year-old male had a history of gastrectomy of the pyloric side for gastric cancer and Billroth Ⅰ reconstruction done 20 years ago. The patient visited the gastrointestinal internal medical department of our hospital with abdominal pain as the chief complaint. Pancreatic cancer was diagnosed with the help of an abdominal CT, and he was then referred to our department. The preoperative disease stage was cT3, N0, M0, Stage ⅡA. As it was over 20 years since the previous surgery and the preoperative CT showed cardiac branches of the left inferior phrenic artery, we inferred that the residual stomach can be preserved. The blood flow was confirmed by the intraoperative ICG fluorescence method, and we then performed pancreatotomy of the pancreatic tail, preserving the stomach and a splenectomy. The pathologic findings were invasive ductal carcinoma, pT3, N1a, M0, Stage ⅡB, and R0. S-1 was administered orally as postoperative adjunctive chemotherapy. The postoperative course has been favorable without recurrence for 2 years. In case a pancreatotomy of the pancreatic tail is performed for cancer of the pancreatic body after gastrectomy of the pyloric side, it was considered that the intraoperative ICG fluorescence method was useful to confirm the blood flow of the residual stomach.

[Metachronous Gastric Intramural Metastasis following Esophageal Cancer ESD-A Case Study].

We report a case of metachronous gastric intramural metastasis following esophageal cancer endoscopic submucosal dissection( ESD). The patient was an 80s man who was referred to the department of gastroenterology of our hospital for earlystage esophageal cancer by a local physician. ESD was performed for a lesion(Lt, 0-Ⅱa+Ⅱc, cT1N0M0, StageⅠ)located 35- 38 cm from the incisors. Pathologic diagnosis revealed that the lesion was a 2.5×2.0 cm-sized, pSM2, 506 mm, well-differentiated squamous cell carcinoma, ly+, v-, pHM0, pVM0. The patient was indicated for additional treatment, but because the patient requested not to undergo operative treatment, radiation therapy, or chemotherapy, strict follow-upwas performed. Upper endoscopy performed 1 year after ESD revealed the presence of a submucosal tumor(diameter of 5 cm)accompanied by ulceration in the gastric cardia, and biopsy findings led to the diagnosis of squamous cell carcinoma. The patient was referred to our department for operative treatment, and considering the possibility of primary squamous cell carcinoma of the stomach, we performed total gastrectomy(D2 dissection, Roux-en-Y)and cholecystectomy. The pathologic diagnosis was well-differentiated squamous cell carcinoma, ly1, v0, SE, N1. Because esophageal cancer and the tissue type were consistent and the primary locus of the tumor was the submucosal layer, the patient was diagnosed with esophageal cancer with gastric intramural metastasis. We report a rare case of metachronous gastric intramural metastasis of esophageal cancer along with a review of the literature.

[Papillary Carcinoma Arising in Thyroglossal Duct Cyst in the Right Lateral Neck].

A 47-year-old woman was admitted to our institution with the chief complaint of a right cervical mass. Imaging examination findings showed a cystic mass of 25mm with a nodular lesion in the right cervical region. Therefore, we performed extirpation of the right cervical cystic mass to allow diagnosis of the lesion. The histopathological findings showed a partial thyroid tissue on the cyst wall covered with glandular epithelium or metaplastic squamous epithelium, and tumor cells proliferating in the papillary form. Considering the histopathological evidence of the characteristic epithelium of the thyroglossal duct cyst, the potential carcinogenesis from the remnant thyroid tissues, and the absence of primary tumor in the thyroid gland, the patient was diagnosed with thyroid papillary carcinoma arising from the thyroglossal duct cyst in the right lateral cervical region. We found recurrence of the right cervical lymph node at 1 year and 5 months after the initial operation. Thus, we performed dissection of the right cervical lymph nodes. Two years and 10 months after the operation, neither recurrence nor metastasis have been observed. It was suggested that, thyroid papillary carcinoma arising from the thyroglossal duct cyst should be taken into consideration when a lateral cervical mass lesion is found.

Biliary hemorrhage after removal of an expandable metallic stent during liver transplantation.

The self-expandable metallic stent (SEMS) has become a common device for palliative treatment of malignant biliary obstructions or benign strictures. Despite the ease of placement of SEMSs, their removal has been reported to be very difficult. Here, we report a case with primary sclerosing cholangitis who developed massive hemorrhage after intraoperative removal of a SEMS. Possible living donor liver transplantation (LT) was considered for a 49-year-old female with primary sclerosing cholangitis. However, her general condition did not meet the criteria for LT; therefore, she was referred back to her primary physician. Two years later, she developed jaundice, and her primary physician placed multiple SEMSs, 1 of which was placed across the papilla of Vater. She was evaluated rapidly, and underwent living donor LT. During the operation, the common bile duct was examined and an incision was made. A stent was found firmly embedded in the bile duct. Each wire of the SEMS was pinched and then successfully pulled out 1 by 1. Finally, all parts of the SEMS were removed. Before creating the Roux-en-Y limb, hemorrhage from the remnant bile duct was confirmed by examination of the duodenum and bile duct stump. The bile duct was sewn internally with monofilament stitches and compressed for 10 minutes. Finally, hemostasis was brought about and transplantation was completed successfully. Despite some reports regarding successful endoscopic removal of SEMSs, its removal in patients with portal hypertension coagulopathy is risky. SEMSs should not be placed in patients who are candidates for LT.

A bioartificial liver that combines plasma dialysis and whole liver perfusion.

BACKGROUND/AIMS: The development of a bioartificial liver with xenogeneic hepatocytes requires sufficient hepatocyte mass for metabolic support, decreased immunogenicity, and prevention of viral transmission. Therefore, the authors developed a plasma dialysis system using a selective plasma filter, and combined this dialysis system with whole liver plasma perfusion (PDWLP). In this system, the patient's plasma was dialyzed with normal plasma recycled through the pig liver. METHODOLOGY: Female inbred Large White pigs were used for the hepatic failure model and for liver donation. Fulminant hepatic failure (FHF) was induced by the intraportal administration of alpha-amanitin and lipopolysaccharide. Nine hours after this injection, the FHF pigs were connected to the dialysis system for 6 h (n = 5). Control FHF pigs were not connected to the dialysis system (n = 10). RESULTS: Animal survival was lengthened, and cardiovascular stability was demonstrated in the PDWLP treated pigs. This system suppressed the production of substances that promote encephalopathy. The liver necrosis and neutrophil infiltration were significantly less in the experimental pigs. CONCLUSIONS: The experimental treatment attenuated the progression of FHF. Extracorporeal liver, perfused with oxygenated plasma, functioned for 6 h without hyperacute rejection. This type of hybrid bioartificial liver may be useful for treating FHF patients.

Resection of a locally advanced hilar tumor and the hepatic artery after stepwise hepatic arterial embolization: a case report.

We herein report a case of a hilar tumor with extensive invasion to the proper hepatic artery, which was successfully treated with a radical resection in a 57-year-old female patient after a stepwise hepatic arterial embolization. She underwent right colectomy and partial hepatectomy for advanced colon cancer two years ago and radiofrequency ablation therapy for a liver metastasis one year ago, respectively. A recurrent tumor was noted around the proper hepatic artery with invasion to the left hepatic duct and right hepatic artery 7 mo previously. We planned a radical resection for the patient 5 mo after the absence of tumor progression was confirmed while he was undergoing chemotherapy. To avoid surgery-related liver failure, we tried to promote the formation of collateral hepatic arteries after stepwise arterial embolization of the posterior and anterior hepatic arteries two weeks apart. Finally, the proper hepatic artery was occluded after formation of collateral flow from the inferior phrenic and superior mesenteric arteries was confirmed. One month later, a left hepatectomy with hepatic arterial resection was successfully performed without any major complications.

A case of invasive hemolymphangioma of the pancreas.

Hemolymphangioma of the pancreas is a very rare benign tumor. There were only five reports of this disease until March 2008. Herein, we report a case of hemolymphangioma of the pancreas with gastrointestinal bleeding due to duodenal invasion. A 53-year-old man had been admitted a referral hospital because of severe anemia due to gastrointestinal bleeding in December 2005. He was then transferred to our institute with a diagnosis of a tumor of the head of the pancreas with duodenal invasion in January 2006. No abnormalities were revealed except for anemia in laboratory data including CEA and CA19-9. Gastrointestinal endoscopy revealed bleeding at the duodenum. Computed tomography also demonstrated a heterogenous mass at the pancreatic head and suspected invasion to the duodenal wall. Ultrasonography showed a huge mass at the pancreatic head with a mixture of high and low echoic areas. Pylorous-preserving pancreatoduodenectomy was performed. The pancreatic tumor was soft and had invaded to the duodenum. The pathological diagnosis was a hemolymphangioma of the pancreas invaded to the duodenum. His postoperative course was uneventful and he was discharged on the 26th d after surgery. Hemolymphangioma of the pancreas is a very rare benign tumor. In a literature review until March 2008, we found five case reports. Major symptoms are abdominal pain and distension due to the enlarged tumor. However, we experienced a case of hemolymphangioma of the pancreas with gastrointestinal bleeding due to invasion to the duodenum. This disease is a very rare entity, but should be considered when patients have gastrointestinal bleeding.

Hemosuccus pancreaticus: problems and pitfalls in diagnosis and treatment.

Hemosuccus pancreaticus is a rare cause of intermittent upper gastrointestinal bleeding. We report two cases of hemosuccus pancreaticus with multiple episodes of upper gastrointestinal bleeding. The causes of hemorrhage were rupture of pseudoaneurysm of the splenic artery and bleeding from the wall of pancreatic pseudocyst. Interventional radiology is the first modality for early diagnosis and possible treatment of hemosuccus pancreaticus. When angiography shows no abnormal findings or interventional radiological therapy can not be successful, surgery should be considered without delay. Our patients herein underwent surgery without recurrence or sequelae. Intraoperative ultrasonography and pancreatoscopy were helpful modalities for confirming the source of hemorrhage and determining the cutting line of the pancreas. When we encounter intermittent upper gastrointestinal bleeding with an obscure source, hemosuccus pancreaticus should be included in differential diagnoses especially in patients with chronic pancreatitis, which would lead to a prompt and proper treatment.

Intraoperative ultrasound as an educational guide for laparoscopic biliary surgery.

AIM: To analyze the efficacy of routine intraoperative ultrasound (IOUS) as a guide for understanding biliary tract anatomy, to avoid bile duct injury (BDI) after laparoscopic cholecystectomy (LC), as well as any burden during the learning period. METHODS: A retrospective analysis was performed using 644 consecutive patients who underwent LC from 1991 to 2006. An educational program with the use of IOUS as an operative guide has been used in 276 cases since 1998. RESULTS: IOUS was highly feasible even in patients with high-grade cholecystitis. No BDI was observed after the introduction of the educational program, despite 72% of operations being performed by inexperienced surgeons. Incidences of other morbidity, mortality, and late complications were comparable before and after the introduction of routine IOUS. However, the operation time was significantly extended after the educational program began (P < 0.001), and the grade of laparoscopic cholecystitis (P = 0.002), use of IOUS (P = 0.01), and the experience of the surgeons (P = 0.05) were significant factors for extending the length of operation. CONCLUSION: IOUS during LC was found to be a highly feasible modality, which provided accurate, real-time information about the biliary structures. The educational program using IOUS is expected to minimize the incidence of BDI following LC, especially when performed by less-skilled surgeons.

Des-gamma-carboxy prothrombin as an important prognostic indicator in patients with small hepatocellular carcinoma.

AIM: To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS: Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. oneor=400 mAU/mL (P=0.02) were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP>or=400 mAU/mL was found to be an independent prognostic factor for recurrence-free (P=0.02) and overall survival (P=0.0005). In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free (P=0.02) and overall survivals (P=0.01). In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically. CONCLUSION: For small hepatocellular carcinoma, a high preoperative DCP level appears indicative for tumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body.

An easier method for performing a pancreaticojejunostomy for the soft pancreas using a fast-absorbable suture.

AIM: To clarify the usefulness of a new method for performing a pancreaticojejunostomy by using a fast-absorbable suture material irradiated polyglactin 910, and a temporary stent tube for a narrow pancreatic duct with a soft pancreatic texture. METHODS: Among 63 consecutive patients with soft pancreas undergoing a pancreaticoduodenectomy from 2003 to 2006, 35 patients were treated with a new reconstructive method. Briefly, after the pancreatic transaction, a stent tube was inserted into the lumen of the pancreatic duct and ligated with it by a fast-absorbable suture. Another tip of the stent tube was introduced into the intestinal lumen at the jejunal limb, where a purse-string suture was made by another fast-absorbable suture to roughly fix the tube. The pancreaticojejunostomy was completed by ligating two fast-absorbable sutures to approximate the ductal end and the jejunal mucosa, and by adding a rough anastomosis between the pancreatic parenchyma and the seromuscular layer of the jejunum. The initial surgical results with this method were retrospectively compared with those of the 28 patients treated with conventional duct-to-mucosa anastomosis. RESULTS: The incidences of postoperative morbidity including pancreatic fistula were comparable between the two groups (new; 3%-17% vs conventional; 7%-14% according to the definitions). There was no mortality and re-admission. Late complications were also rarely seen. CONCLUSION: A pancreaticojejunostomy using an irradiated polyglactin 910 suture material and a temporary stent is easy to perform and is feasible even in cases with a narrow pancreatic duct and a normal soft pancreas.

Anaplastic carcinoma associated with a mucinous cystic neoplasm of the pancreas during pregnancy: report of a case and a review of the literature.

Oncogenesis of anaplastic carcinoma of the pancreas is a subject of controversy, because it shows sarcomatous nature with extremely poor prognosis. We herein report an unusual case of anaplastic carcinoma occurring with a recurrent mucinous cystic neoplasm in a 38-year-old female. A 10-cm retroperitoneal cystic mass was pointed out in the first pregnancy and a probable diagnosis of mucinous cystic neoplasm was made in October 2000. She refused surgery first and delivered her baby uneventfully. During her second pregnancy in 2002, however, she presented hematemesis and underwent urgent distal pancreatectomy, splenectomy and partial resection of the gastric wall where the tumor perforated. A diagnosis of borderline-type mucinous cystic neoplasm with ovarian-like stroma was made. Nine months later, CT visualized a recurrent cystic tumor near the pancreatic stump, which was subsequently resected. Pathology revealed that the tumor was composed of two different components of borderline-type mucinous cystic neoplasm and anaplastic carcinoma. The latter was intensely positive for vimentin, CD68, p53 and focally for cytokeratin, suggesting both sarcomatous and carcinomatous differentiation. She survived four years after the second surgery without tumor recurrence. Although the origin of anaplastic carcinoma has not been determined yet, it should be remembered that anaplastic carcinoma can occur in association with mucinous cystic neoplasm of more benign histology.

Attenuation of graft injury in porcine liver transplantation from non-heart beating donor by FR167653.

BACKGROUND/AIMS: Orthotopic liver transplantation (OLTx) from non-heart beating donor (NHBD) often involves hepatic warm ischemia and reperfusion injury which is triggered by the inflammatory cytokines. This study was carried out to investigate whether a newly synthesized cytokine suppressive anti-inflammatory agent, FR167653, attenuates graft injury in OLTx from NHBD. METHODOLOGY: Porcine OLTx from NHBD was performed. No-heart beating time was scheduled to be 60 minutes. Animals were divided into two groups: no treatment control (CT) group (n=5), and FR167653 treated (FR) group (n=5), in which FR167653 was administered intravenously before the aortic cross clamp in the donor, and before and after the hepatic allograft reperfusion in the recipient continuously. RESULTS: Four out of five pigs died within 24 hours and one on postoperative day 1 from graft liver failure in the CT group, while two pigs died on day 3, and three survived more than 7 days in the FR group (p<0.05). Microcirculatory disturbance was attenuated, liver injury was lessened, and ATP resynthesis was enhanced in the FR group. Additionally, FR167653 inhibited neutrophils infiltration in the liver tissue, and suppressed release of inflammatory cytokines after OLTx from NHBD. CONCLUSIONS: The treatments with FR167653 successfully prevented graft injury after OLTx from NHBD by means of improvement of liver microcirculation, and attenuation of neutrophils activation. The inhibitory effect of FR167653 on the release of inflammatory cytokines played an important role in the liver graft protection.

Attenuation of microcirculatory disturbance after liver ischemia by newly synthesized inflammatory cytokine suppressor, FR167653.

BACKGROUND/AIMS: Inflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, which activate neutrophils, contribute to hepatic warm ischemia-reperfusion injury. However, the role of the cytokines in hepatic microcirculation immediately after reperfusion is still unclear. This study was carried out to investigate whether FR167653, a dual inhibitor of interleukin-1 beta and tumor necrosis factor-alpha, attenuates hepatic microcirculatory disturbance at the initial phase of reperfusion following liver ischemia. METHODOLOGY: Adult mongrel dogs were subjected to 90 minutes of liver ischemia by a Pringle's maneuver under portosystemic bypass. The animals were divided into two groups: a control group (n = 10), subjected to hepatic warm ischemia only, and a FR167653 administered group (n = 5), which received 1 mg/kg/h FR167653 for 4 hours since 30 minutes before the ischemia to 2 hours after the reperfusion continuously. Seven days animal survival, hepatic tissue blood flow, liver function test, hepatic venous blood concentration of endothelin-1 and plasminogen activator inhibitor-1, liver tissue biochemistry, and histopathology were analyzed. RESULTS: The treatment with FR167653 attenuated microcirculatory disturbance, lessened liver injury, enhanced adenine nucleotides resynthesis, and improved animal survival after liver ischemia. In addition, FR167653 significantly inhibited release of both endothelin-1 and plasminogen activator inhibitor-1 from the liver cells. CONCLUSIONS: These results suggest that the inflammatory cytokines induce microcirculatory disturbance in the initial phase of reperfusion following liver ischemia.