Hepatoprotective effects of baicalein against liver ischemia-reperfusion injury and partial hepatectomy in a rat model.

BACKGROUND: Baicalein is the main active flavonoid in Scutellariae Radix and is included in shosaikoto, a Kampo formula used for treating hepatitis and jaundice. However, little is known about its hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI), a severe clinical condition directly caused by interventional procedures. We aimed to investigate the hepatoprotective effects of baicalein against HIRI and partial hepatectomy (HIRI + PH) and its potential underlying mechanisms. METHODS AND RESULTS: Male Sprague-Dawley rats received either baicalein (5 mg/kg) or saline intraperitoneally and underwent a 70% hepatectomy 15 min after hepatic ischemia. After reperfusion, liver and blood samples were collected. Survival was monitored 30 min after hepatic ischemia and hepatectomy. In interleukin 1ß (IL-1ß)-treated primary cultured rat hepatocytes, the influence of baicalein on inflammatory mediator production and the associated signaling pathway was analyzed. Baicalein suppressed apoptosis and neutrophil infiltration, which are the features of HIRI + PH treatment-induced histological injury. Baicalein also reduced the mRNA expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). In addition, HIRI + PH treatment induced liver enzyme deviations in the serum and hypertrophy of the remnant liver, which were suppressed by baicalein. In the lethal HIRI + PH treatment group, baicalein significantly reduced mortality. In IL-1ß-treated rat hepatocytes, baicalein suppressed TNF-α and chemokine mRNA expression as well as the activation of nuclear factor-kappa B (NF-κB) and Akt. CONCLUSIONS: Baicalein treatment attenuates HIRI + PH-induced liver injury and may promote survival. This potential hepatoprotection may be partly related to suppressing inflammatory gene induction through the inhibition of NF-κB activity and Akt signaling in hepatocytes.

Sulforaphane Is Protective against Warm Ischemia/Reperfusion Injury and Partial Hepatectomy in Rats.

Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1ß (IL-1ß)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1ß-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes.

[A Case of Adenocarcinoma of Duct of Luschka].

A 75-year-old man was transferred to our hospital with a diagnosis of acute cholecystitis. On next day, a laparoscopic cholecystectomy was performed. Histologic examination confirmed an adenocarcinoma arising from duct of Luschka. Patient underwent additional resection of the liver bed. No residual adenocarcinoma was seen in the surgical specimen. Adenocarcinoma of duct of Luschka is rare, but it is important during cholecystectomy to consider the presence of duct of Luschka, possibility of malignant disease and careful dissection of the gallbladder from its fossa staying close to the gallbladder wall.

[Repeat Hepatectomy for Primary Hepatic Neuroendocrine Carcinoma in the Remnant Liver Nine Years after the First Resection].

The patient was a 55-year-old man who had undergone extended right lobectomy of the liver with a diagnosis of primary hepatic carcinoid tumor. Nine years after the operation, enhanced abdominalCT revealed a tumor measuring 2.2 cm in the remnant liver. He was diagnosed with recurrence of primary hepatic neuroendocrine carcinoma and underwent partial hepatectomy. Pathologically, the tumor cells had round nuclei and formed trabecular patterns. Immunohistologically, the cells were positive for CD56, synaptophysin, and chromogranin A. The Ki-67 index was 6%, which was equivalent to Grade 2 in the WHO classification revised in 2010. Since there were no other lesions suspected to be the primary site other than in the liver, it was diagnosed as recurrence of the primary hepatic neuroendocrine carcinoma. Two years after the operation, he was diagnosed with recurrence of primary hepatic neuroendocrine carcinoma and underwent partialhepatectomy again.

[A Case of Abdominal Compartment Syndrome after Laparotomy for Peritonitis Caused by Colon Perforation Due to Gallbladder Carcinoma].

A70 -year-old man with a diagnosis of panperitonitis caused by colon perforation due to invasion of gallbladder cancer was transferred to our hospital. The next day, an emergency operation was performed. During laparotomy, the ascending colon was perforated; therefore, ileocecal resection was performed. Six hours after the operation, the stoma became ischemic with marked abdominal distention. The intra-abdominal pressure increased to 28 mmHg, and the patient was diagnosed as having abdominal compartment syndrome(ACS). He immediately underwent decompressive laparotomy at bedside. Multiple organ failure was avoided and he recovered, but he died of advanced gallbladder cancer 4 months after the surgery. This case suggests that immediate surgical decompressive laparotomy for ACS can prevent multiple organ failure.

[A Case of Port Site Recurrence of Gallbladder Carcinoma after Laparoscopic Cholecystectomy].

The patient was a 76-year-old man who underwent laparoscopic cholecystectomy with a diagnosis of cholecystolithiasis. Since the definite diagnosis of gallbladder carcinoma was made after the operation, he underwent additional resection. Four years later, he revisited the hospital complaining of painful swelling of the port site of his epigastrium. Magnetic resonance imaging of the abdomen revealed a mass 3.4 cm in diameter at the epigastrium. Thus, port site recurrence of gallbladder carcinoma was the suspected diagnosis. We resected the peritoneum, rectus abdominis muscle, and skin, as well as the tumor, and the abdominal wall was reconstructed using synthetic composite mesh. Histological examinations revealed recurrence of gallbladder carcinoma. Port site recurrence of gallbladder carcinoma is known to have a poor prognosis, but long survival can be expected in patients after complete resection of the metastatic lesion, if the recurrence develops more than a year after the initial operation.

[A Case of Pancreatic Neuroendocrine Tumor with Necrolytic Migratory Erythema].

A 45-year-old man was admitted because of necrolytic migratory erythema. A computed tomographic scan of the abdomen revealed a 4.5cm mass in the tail of the pancreas. We performed distal pancreatectomy and splenectomy, and a definitive diagnosis of pancreatic neuroendocrine tumor(WHO class grade 2)was made histopathologically.

[Changes in Endocrine Function in Patients after Pancreatic Surgery].

We investigated glucose metabolism in patients who underwent pancreatoduodenectomy(PD), distal pancreatectomy (DP), and partial resection(PR). Fifteen patients(36%)were diabetic(HbA1c≥6.5%)before PD, 16(38%)were diabetic after PD, and 6(60%)were diabetic both before and after DP. The level of HbA1c was not significantly different preoperatively( PD: 7.5±2.7%, DP: 7.5±1.3%)vs postoperatively(PD: 6.7±1.1%, DP: 6.3±0.7%). These results suggest that pancreatic endocrine function was fairly preserved in patients who underwent pancreatic surgery.

[A Case Report of Difficult Esophagojejunal Anastomosis for Multiple Primary Cancer of Malignant Lymphoma and Gastric Cancer].

A 54-year-old man presented with cervical lymph node swelling and exhibited high levels of sIL-2R. Enhanced cervical, chest, and abdominal CT scanning demonstrated swelling of the cervical, hilar, axilla, and abdominal lymph nodes. The patient was diagnosed with malignant, non-Hodgkin's lymphoma, B-cell, follicular lymphoma using biopsy of the cervical lymph nodes. Gastrointestinal endoscopy revealed II c like advanced tumor in the upper gastric body and post-wall area. He was diagnosed with primary multiple cancer comprising malignant lymphoma and gastric cancer. It was difficult to elevate the jejunum for esophagojejunal anastomosis due to the giant abdominal lymph node swelling. The patient received 5 courses of combination R-CHOP chemotherapy for malignant lymphoma. The swollen lymph nodes considerably reduced in size after chemotherapy. Totalgastrectomy with reconstruction using the Roux-en-Y method was performed for gastric cancer. Histopathological findings revealed pT3(SS), pN0, pH0, pP0, pStage I B. The patient achieved complete remission following another course of chemotherapy and involved field radiation therapy. At present, he shows no signs of recurrence of primary multiple cancer.

[The Efficiency of Postoperative Endoscopy for Anastomotic Leakage after Total Gastrectomy].

An 81-year-old man underwent total gastrectomy with Roux-en-Y reconstruction for cardiac cancer in our department. He developed high fever on postoperative day 3, and pathological examination showed WBC and CRP level of 12,000/mL and 29.983mg/dL, respectively. A diagnosis of anastomotic leakage was confirmed using enhanced abdominal CT scanning that demonstrated free air around the esophagojejunalanastomosis after totalgastrectomy. The drainage tube was replaced by a 12 Fr sump tube because of leakage on postoperative day 10. Nasal endoscopy performed on postoperative day 13 revealed anastomotic leakage from the sump tube in the abdominal cavity. Endoscopy performed on postoperative day 20 confirmed the anastomotic leakage as a fistula that allowed air to leak into the abdominal cavity. On postoperative day 28, the sump tube was removed and oralintake was started. In conclusion, postoperative endoscopy might be usefulfor the assessment and drainage of anastomotic leakage.

[A Case of Gallbladder Carcinoma and Breast Cancer Associated with Pancreaticobiliary Maljunction].

We report a case of gallbladder cancer and right breast cancer associated with pancreaticobiliary maljunction.The patient was a 74-year-old woman who presented with abdominal pain due to cholecystitis.Abdominal CT detected a gallbladder tumor and right breast tumor.Enhanced CT and MRCP examination revealed gallbladder cancer and right breast cancer associated with pancreaticobiliary maljunction.We performed a gallbladder bed resection, bile duct resection, and right total mastectomy.The histopathological diagnosis of the gallbladder was moderately tubular adenocarcinoma and that of the breast tumor was scirrhous carcinoma.The patient remains recurrence-free 8 months after surgery.

[A Case of Adenosquamous Carcinoma of the Ascending Colon].

We report a case of adenosquamous carcinoma of the colon. A 70-year-old woman underwent a colonoscopic examination because of a positive fecal occult blood test. Colonoscopy demonstrated a type 2 tumor of the ascending colon, and a biopsy specimen showed poorly-moderately differentiated tubular adenocarcinoma. We performed a right hemicolectomy with D2 lymphadenectomy. The histopathology of the tumor demonstrated adenosquamous adenocarcinoma. Primary adenosquamous carcinoma of the colon is relatively rare and has a poor prognosis. Therefore, adenosquamous carcinoma of the colon may require strict follow-up.

[Difficulty in Preoperative Diagnosis of Residual Gastric Cancer after Distal Gastrectomy for Duodenal Ulcer].

A 67-year-old man underwent distal gastrectomy via the Billroth Ⅱ method (B-Ⅱ) for a duodenal ulcer. He presented with appetite loss and nausea in May 2014. Gastrointestinal endoscopy revealed wall thickness around gastrojejunostomy and the gastric mucosal fold. Biopsy and re-biopsy revealed a group 2 tumor. Laparotomy for diagnosis was performed because of stenosis and tumor progression. Intraoperative frozen section examination revealed adenocarcinoma in the lymph nodes of the jejunum. Residual gastrectomy with reconstruction using the Roux-en-Y method was performed for residual gastric cancer. Histopathological findings revealed pT4a, pN0, pM1 for the tumor in the lymph nodes of the jejunum, pStage Ⅳ. A distorted gastrojejunostomy site and the presence of anastomotic strictures are important for the rapid diagnosis of residual gastric cancer.

[Two Cases of Small Bowel Obstruction Due to Postoperative Adhesions Treated with Laparoscopic Adhesiolysis].

We occasionally require surgical treatment for postoperative adhesion ileus. One patient had adhesion ileus 14 times in 14 years after distal gastrectomy and Billroth-Ⅰreconstruction for gastric cancer. He underwent laparoscopic adhesiolysis for a small bowel obstruction that adhered to the entire surface. Another patient experienced adhesion ileus 7 times in 1.5 years after distal gastrectomy and Billroth-Ⅰreconstruction for gastric cancer. He underwent laparoscopic adhesiolysis for a small bowel obstruction adhering to the scar and the retroperitoneum. After laparoscopic treatment, he underwent an open operation for ischemic colitis but no small bowel obstruction was found. Laparoscopic adhesiolysis was found to be useful in both cases.

[Two Patients with Recurrence of Hepatocellular Carcinoma after Liver Resection Who Achieved Long-Term Stable Disease with Small Doses of Sorafenib Therapy].

Case 1: A6 4-year-old man with hepatocellular carcinoma (HCC) had received local therapy repeatedly for 20 years. In 2012, he underwent hepatic right lobectomy for recurrence of HCC. Multiple recurrences were found in the hepatic remnant, and transcatheter arterial chemoembolization (TACE) was performed. Considering his condition, a small dose of sorafenib (200 mg per day) was administered. He complained of general fatigue, so we prolonged the administration interval (200 mg every other day). Thereafter, compliance improved and long-term stable disease (long SD), for more than 6 months, long SD was achieved. Case 2: A7 5-year-old man with HCC was treated by TACE repeatedly for multiple recurrences after liver resection (segment 6). In 2008, metastases to the thoracic vertebra and left rib were treated by radiation therapy and radiofrequency ablation, respectively. Subsequently, sorafenib (400 mg per day) was administered. We reduced the dose of sorafenib to less than 400 mg per day because of diarrhea, hypertension, and general fatigue. Thereafter, long SD was achieved despite the small dose of sorafenib. We report here 2 cases of HCC where we achieved long SD in spite of treating with a small dose of sorafenib.

[A case report of residual gastric cancer 15 years after pancreatoduodenectomy with modified child's reconstruction].

A 75-year-old man underwent pancreatoduodenectomy for pancreatic cancer. He had presented with epigastralgia in June 2008. Gastrointestinal endoscopy revealed type 2 gastric cancer in the cardiac area. Enhanced abdominal CT scanning confirmed an enhanced mass in the cardiac area. Gastrectomy with Roux-en-Y reconstruction was performed for residual gastric cancer. Histopathological findings revealed, pT3(SS), pN0, pH0, pP0, pStageIIA. Single-agent TS-1 therapy was chosen as adjuvant chemotherapy but was changed to TS-1+CDDP because of CT-detected recurrence 3 months after the second operation. After a 6 month course of chemotherapy, complete reduction of the tumor was obtained.

Giant hemorrhagic pancreatic pseudocyst with suspected cystic pancreatic tumor: a case report.

Pancreatic pseudocysts are surrounded by a non-epithelialized wall confined to the pancreas and localized to the pancreatic tissue or adjacent pancreatic cavity. In contrast, pancreatic cystic tumors occur less frequently than solid lesions and are often detected incidentally on imaging. Regarding the qualitative diagnosis of pancreatic pseudocysts, it is important to differentiate them from neoplastic cysts. We report the case of a 74-year-old woman with a giant hemorrhagic pancreatic pseudocyst and a suspected cystic pancreatic tumor, wherein distal pancreatectomy and splenectomy with lymph node dissection were performed. The patient was discharged 11 days postsurgery, with a good postoperative course. There are no reports of giant pancreatic pseudocysts larger than 10 cm with hematoma contents. The presumptive diagnosis of pseudocysts based on imaging alone may be difficult. Surgical resection is considered when it is difficult to distinguish a giant pancreatic pseudocyst from a cystic neoplasm.

Hepatoprotection of a Standardized Extract of Cultured Lentinula edodes Mycelia against Liver Injury Induced by Ischemia-Reperfusion and Partial Hepatectomy.

A standardized extract of cultured Lentinula edodes mycelia (ECLM, AHCC®) has been shown to have beneficial effects on organ metabolism. ECLM has been indicated to have liver protective properties by suppressing inflammatory responses. The pathogenesis of hepatic ischemia-reperfusion injury is thought to involve the induction of inflammatory mediators. However, whether ECLM affects inflammatory mediators caused by warm hepatic ischemia-reperfusion injury and partial hepatectomy (HIRI+PH) has not been clarified. In this study, we evaluated the protective effects of ECLM against liver damage caused by HIRI+PH. Rats were fed a normal diet (HIRI+PH) or a normal diet with 2% ECLM (HIRI+PH and ECLM) for ten days, then the liver and duodenal ligament were clamped and subjected to 15 min of hepatic ischemia. After 70% hepatectomy, the inflow occlusion was released, and liver and blood samples were collected at 3, 6, and 24 h. The effect of ECLM on mortality induced by 30 min of ischemia and hepatectomy was evaluated. The results showed that ECLM attenuated pathological liver damage, including apoptosis, in the rats treated with HIRI+PH, and decreased serum aminotransferase activity; ECLM decreased mRNA levels of the inflammation-related genes inducible nitric oxide synthase and C-X-C motif chemokine ligand 1, and increased mRNA levels of interleukin 10, an anti-inflammatory cytokine; ECLM increased hepatocyte growth factor mRNA levels and Ki-67 labeled nuclei in the liver at 24 h; ECLM significantly reduced HIRI+PH-induced mortality. In conclusion, ECLM may prevent HIRI+PH-induced liver injury in part by suppressing various inflammatory responses and promoting liver regeneration.

COMBINATION THERAPY WITH A SENSE OLIGONUCLEOTIDE TO INDUCIBLE NITRIC OXIDE SYNTHASE MRNA AND HUMAN SOLUBLE THROMBOMODULIN IMPROVES SURVIVAL OF SEPSIS MODEL RATS AFTER PARTIAL HEPATECTOMY.

ABSTRACT: Sepsis after a major hepatectomy is a critical problem. In septic shock, the inflammatory mediator, nitric oxide (NO), is overproduced in hepatocytes and macrophages. The natural antisense (AS) transcripts, non-coding RNAs, are transcribed from a gene that encodes inducible nitric oxide synthase (iNOS). iNOS AS transcripts interact with and stabilize iNOS mRNAs. A single-stranded "sense oligonucleotide" (designated as SO1) corresponding to the iNOS mRNA sequence inhibits mRNA-AS transcript interactions and reduces iNOS mRNA levels in rat hepatocytes. In contrast, recombinant human soluble thrombomodulin (rTM) treats disseminated intravascular coagulopathy by suppressing coagulation, inflammation, and apoptosis. In this study, the combination therapy of SO1 and a low dose of rTM was evaluated for hepatoprotection in a rat septic shock model after partial hepatectomy. Rats underwent 70% hepatectomy, followed by intravenous (i.v.) injection of lipopolysaccharide (LPS) after 48 h. SO1 was injected (i.v.) simultaneously with LPS, whereas rTM was injected (i.v.) 1 h before LPS injection. Similarly to our previous report, SO1 increased survival after LPS injection. When rTM, which has different mechanisms of action, was combined with SO1, it did not interfere with the effect of SO1 and showed a significant increase in survival compared with LPS alone treatment. In serum, the combined treatment decreased NO levels. In the liver, the combined treatment inhibited iNOS mRNA and protein expression. A decreased iNOS AS transcript expression by the combined treatment was also observed. The combined treatment decreased mRNA expression of the inflammatory and pro-apoptotic genes while increasing that of the anti-apoptotic gene. Furthermore, the combined treatment reduced the number of myeloperoxidase-positive cells. These results suggested that the combination of SO1 and rTM has therapeutic potential for sepsis.

[A case of unresectable multiple hepatic metastases from ascending colon cancer successfully treated with panitumumab and FOLFIRI(5-FU/LV/irinotecan)therapy].

A 68-year-old man had undergone right hemicolectomy of ascending colon cancer with multiple liver metastases. This case of k-ras status on the cancer tissue also showed wild type. Chemotherapy with panitumumab and 5-FU/LV/irinotecan (FOLFIRI)regimen was performed after the resection of the ascending colon cancer. After seven curses of treatment, metastatic liver tumors were reduced considerably(PR). Liver resection(left hepatic lobectomy and partial resection of S4 and S5)and radiofrequency ablation therapy were performed. Recently, chemotherapy has improved overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. Combination chemotherapy using panitumumab, and FOLFIRI plus operation is a candidate as a standard treatment strategy for multiple liver metastases of colon cancer.