The Warburg effect and tumour immune microenvironment in extramammary Paget's disease: overexpression of lactate dehydrogenase A correlates with immune resistance.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant skin cancer. One of the hallmarks of cancers, including EMPD, is an enhancement of aerobic glycolysis, which is also known as the Warburg effect. In the last step of glycolysis, the enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactic acid, the accumulation of which contributes to the creation of an acidic tumour microenvironment. This in turn results in immunosuppression in various types of cancers. However, the contribution of these pathways has not been well-studied in EMPD. OBJECTIVE: To investigate the significance of the Warburg effect and its contribution to the tumour immune microenvironment in EMPD. METHODS: The mRNA expression levels of molecules involved in glycolysis and immune-related cytokines were examined by ddPCR. The number of immune cells was assessed by immunohistochemistry (IHC). RESULTS: The levels of two glycolytic enzymes, HK2 and LDHA, in tumour tissues were significantly increased compared to those in paired-normal tissues. IHC analyses revealed increased numbers of PD-L1+ , PD-1+ , CD163+ M2 macrophages, Iba1+ macrophages and Foxp3+ Tregs that were associated with high LDHA levels in EMPD. ddPCR demonstrated that multiple cytokines including IL-4, IL-6, IL-10, TGF-ß and CCL-2 were upregulated and associated with high LDHA levels in EMPD. Statistical analyses showed that IL-6 mRNA expression correlated with the number of CD163+ , Iba-1+ and Foxp3+ cells. CONCLUSION: The Warburg effect contributes to immunomodulation in the tumour microenvironment and further elucidation may lead to better understanding of the pathogenesis of EMPD.

Circulating fibrocytes correlate with the asthma control test score.

BACKGROUND: Bronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting ß2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. METHODS: There were 20 patients with asthma and seven healthy controls. The number of CD45(+)Collagen I(+) circulating fibrocytes was assessed in the peripheral blood by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short-acting ß2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. CONCLUSION: The results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma.

Living-Donor Liver Transplantation for Hepatic Metastasis From Meningeal Hemangiopericytoma: A Case Report.

We report the case of a 58-year-old man referred to our hospital for liver tumor treatment. The patient had a history of neurosurgery for a meningeal hemangiopericytoma 16 years previously. Pre-operative imaging revealed a hypervascular tumor extending from Couinaud segment 4 to segment 8 of the liver, measuring 95 mm in diameter, indicating an atypical hepatocellular carcinoma. Because right trisectionectomy of the liver was considered to be high risk, living-donor liver transplantation (LDLT) was indicated. After transcatheter arterial embolization, LDLT was performed with the use of a left-lobe liver graft from the patient's son. Post-operative histological findings of the liver tumor were identical to those for meningeal hemangiopericytoma, therefore the patient was diagnosed with meningeal hemangiopericytoma that had metastasized to the liver. After LDLT, the patient had a healthy, active life for 2 years; then, a subcutaneous relapse was discovered in the left chest. The patient did not undergo any systemic chemotherapy in response to the relapse. After thoracic and orthopedic surgeries and radiotherapy for multiple metastases, the patient died 5 years and 5 months after LDLT. LDLT could be an effective treatment for localized metastatic hemangiopericytoma in the liver, but it should be indicated only for carefully selected patients.

Temporary auxiliary partial orthotopic liver transplantation using a small graft for familial amyloid polyneuropathy.

Donor shortage is a major issue in liver transplantation. We have successfully performed temporary auxiliary partial orthotopic liver transplantation (APOLT) using a small volume graft procured from a living donor for recipients with familial amyloid polyneuropathy (FAP). The aim of this study was to evaluate this procedure by comparing it with standard living donor liver transplantation (LDLT). We compared 13 recipients undergoing this procedure with 23 recipients undergoing a standard LDLT for the treatment of FAP. The estimated donor graft volume and the graft volume/recipient's standard liver volume ratio were significantly smaller in the temporary APOLT group than in the standard LDLT group. Postoperative complications were comparable, although the hospital stay was longer in the temporary APOLT group. All the patients safely underwent a remnant native liver resection about 2 months after their first operation in the temporary APOLT group. No symptoms related to FAP developed before the remnant liver resection, and no significant differences in graft and patient survival were observed between the two groups. We successfully performed temporary APOLT using a small volume liver graft without postoperative liver failure for FAP. Temporary APOLT for FAP might be a useful alternative procedure for expanding the donor pool for LDLT.

Arterial reconstruction in a case of subintimal dissection of celiac arterial tributaries in living donor liver transplantation: a case report.

BACKGROUND: Hepatic arterial reconstruction is one of the critical issues in living donor liver transplantation (LDLT). Herein we have reported an LDLT case whose celiac arterial trunk tributaries were insufficient as host arteries because of extensive subintimal dissection proceeding to all tributaries of the celiac arterial trunk. PATIENTS AND METHODS: A 45-year-old woman with fulminant hepatic failure underwent LDLT. After reperfusion of the hepatic and portal veins, subintimal dissection of the recipient right and left hepatic arteries was found to extend to all tributaries of the celiac arterial trunk, preventing an anastomosis using the more proximal part of these arteries. Therefore, a jejunal arterial arcade of Roux-en-Y limb mobilized for biliary reconstruction was anastomosed to the donor left hepatic artery in end-to-end fashion. RESULTS: Arterial blood flow to the grafted liver was established successfully, and the patient's postoperative recovery was excellent. Postoperative computed tomography demonstrated sufficient hepatic arterial blood flow. The patient is doing well 4 years after transplantation. CONCLUSION: The method of hepatic graft arterialization described herein is an important option for LDLT recipients when tributaries of the celiac arterial trunk are insufficient as host arteries.

Domino liver transplantation in living donors.

Domino liver transplantation (DLT) has been developed as a method to expand the donor pool. In living donors DLT, the prime concern is to avoid any disadvantage to the donor and the first recipient. Seven DLTs were performed among 211 patients who underwent living donor liver transplantation. The domino recipients included six with hepatocellular carcinoma and one with citrullinemia. The domino grafts were obtained from patients with familial amyloid polyneuropathy (FAP) including the left liver in three cases and the right liver in four. Among the seven domino recipients, a 64-year-old woman with advanced hepatocellular carcinoma died of lung metastasis. The other six domino recipients are alive without FAP symptoms. In living donor liver transplantation, because the vessels of the graft from the first donor are not long enough for anastomosis, the hepatic vessels must be left as long as possible when removing the liver from the FAP patients in order to ensure sufficient safety for vascular reconstruction. With careful decision making during the procedure, such as where to divide the vessels in the FAP patients, DLT may help address the shortage of liver grafts.

[Liver transplantation for liver metastases of colorectal cancer].

Because of the critical shortage of donor organs, liver transplantation for metastatic tumors should be reserved for patients in whom long-term survival is possible. Transplantation in patients with metastatic tumors from colorectal cancer has resulted only in short disease-free intervals, and palliation was achieved in only a few patients. In patients with symptomatic neuroendocrine tumors unresponsive to conventional therapy, on the other hand, reasonably good disease-free intervals and prolonged survival may justify liver transplantation.

[Liver transplantation].

In western countries, liver transplantation in patients with hepatocellular carcinoma (HCC) has been performed with the use of grafts from brain dead donors, while in Japan this has begun being performed using partial liver grafts from living donors. This report describes our current results after liver transplantation for HCC and domino liver transplantation, which was introduced to resolve the organ shortage.

Role of Kupffer cells in the survival after rat liver transplantation with long portal vein clamping times.

Applying the orthotopic rat liver transplantation (ORLT) model, postoperative survival has been shown to be mainly dependent on the portal vein clamping time (PVCT). It was hypothesized that prolonged intestinal congestion was responsible for the activation of Kupffer cells (KC) with overproduction of TNF, secondary to splanchnic endotoxin accumulation and release on reperfusion. The role of KCs was directly investigated in the context of long PVCTs by eliminating them (using liposome-encapsulated dichloromethylene diphosphonate), by preventing their activation (using a calcium channel blocker, nisoldipine) and by inhibiting TNF production (using thalidomide). Livers from different groups of rats were transplanted following 24-h cold preservation in the UW solution with long PVCTs (from 18-21 min). KCs depletion, preservation with nisoldipine and pretreatment with thalidomide significantly improved survival in conditions using long PVCTs. KC depletion and nisoldipine preservation had no effect on liver enzymes or pathological findings while lung injury was significantly improved. The present data confirm that, in the context of ORLT with long PVCTs, KCs are directly responsible for the systemic endotoxin-like shock syndrome and their effect is mediated through overproduction of TNF.

[Effect of vasodilators on femoral-to-radial arterial pressure gradient after cardiopulmonary bypass].

In 57 adult patients undergoing valve replacement surgery or valve plastic surgery, pressure gradient between the femoral and radial artery was evaluated after cardiopulmonary bypass (CPB). During CPB, the rectal temperature was kept at mild or moderate hypothermia. Nitrates and prostaglandin E1 were administered in all patients during operation. Patients were divided into two groups; Group A of 31 patients who had history of hypertension and received some vasodilators up to the operation, and Group B of 27 patients who had no history of such medication. There was no difference in patient's characteristics, anesthetic time, CPB time and aortic cross clamping time between the two groups. There was a significant difference between the pre-CPB and post-CPB in hematocrit data. Systemic vascular resistance (SVR) decreased significantly from the pre-CPB level to the post-CPB level. There was no significant difference between Group A and Group B in SVR, but a higher femoral-to-radial artery pressure gradient was observed in Group A until the end of operation. Hypertension and the use of vasodilator change the tone of peripheral blood vessels and intensify femoral-to-radial artery pressure gradient after CPB.

Effects of portal vein clamping time on rat liver microcirculation following extended cold preservation and transplantation.

Orthotopic rat liver transplantation (ORLT) following extended cold preservation in University of Wisconsin (UW) solution has been shown to induce alterations of the hepatic microcirculation, mainly characterized by areas of no-reflow. The present study was performed to determine whether these alterations were related to the portal vein clamping time (PVCT), shown to be the main determinant of survival after ORLT. The hepatic microcirculation was evaluated using the multiple-indicator dilution curve (MIDC) technique after ORLT following 24-hour cold ischemia in UW solution. Two groups of rats were studied: one with PVCTs of less than 14 min (survival conditions) and one with PVCTs of more than 18 min (nonsurvival conditions). Four hours after ORLT, only long PVCTs were associated with small, but significant, nonperfused areas, about 10% of the liver not being perfused by water; however, in both survival and nonsurvival conditions, the sinusoidal sieving function was well-maintained in perfused areas. In addition, liver viability parameters and hepatocyte function were similarly and minimally altered. The hepatic microcirculation is minimally altered 4 h after ORLT following extended cold preservation in UW solution, whatever the survival condition. Although only found after long PVCTs, the low magnitude of areas of no-reflow should not be associated with lethal injury of the transplanted liver, a finding further supporting the concept that survival after ORLT following 24-hour cold preservation in UW solution is mainly influenced by extrahepatic factors.

Decreased survival in rat liver transplantation with extended cold preservation: role of portal vein clamping time.

Primary liver graft dysfunction is currently related to cold ischemia-reperfusion injury, although a wide survival range has been reported using 24-hour preservation in cold University of Wisconsin (UW) solution. We hypothesized that the portal vein clamping time (PVCT) played a more important role than cold preservation injury in the postoperative outcome. Rat liver transplantation was performed using different clamping times after 24-hour cold ischemia in the UW solution. Survival rates, plasma tumor necrosis factor (TNF), and nitrate/nitrite levels were examined. Subsequently, the effect of clamping time was evaluated on hepatocyte and sinusoidal endothelial cell (SEC) function using isolated perfused livers. Survival rate was directly related to clamping time length. Marked increases in TNF and nitrate/nitrite levels were found after surgery, particularly after long clamping times. In perfusion studies, the SEC function was already markedly altered after preservation alone and was not further modified by transplantation. By contrast, the hepatocyte function was moderately altered after transplantation, irrespective of clamping times, even when rats operated with long clamping times were in terminal conditions. In rats, 24-hour preservation in cold UW solution is not a severely compromising condition leading to primary liver nonfunction. Long PVCTs are associated with an endotoxemia-like syndrome more related to a warm intestinal ischemia than to cold ischemia injury of the liver.

A case of primary non-Hodgkin's lymphoma of the uterine cervix treated by combination chemotherapy (THP-COP).

We present a case of primary non-Hodgkin's lymphoma of the uterine cervix, Ann Arbor stage IE. This 64-year-old multiparous Japanese woman showed markedly elevated serum levels of lactate dehydrogenase (LDH) and of soluble interleukin-2 receptor (sIL-2R) at the time of diagnosis. Combination chemotherapy was administered and consisted of pirarubicin, cyclophosphamide, vincristine sulfate, and prednisolone (THP-COP). After 3 courses of such therapy, the serum levels of LDH and of sIL-2R decreased within normal limits, and the patient achieved a complete remission.

Effect of calcium antagonists on rat liver during extended cold preservation-reperfusion.

BACKGROUND: Nisoldipine, a calcium antagonist, has been reported to improve the quality of grafted rat livers. We thus assessed the protective effect of two calcium antagonists, nisoldipine and nickel, during extended cold ischemia-reperfusion. METHODS: Rat livers were isolated and perfused before or after 24 hr of cold ischemia in University of Wisconsin solution (4 degrees C) with or without nisoldipine or nickel. Sinusoidal endothelial cell and hepatocyte functions were measured by hyaluronic acid and taurocholate elimination, respectively. RESULTS: Similar alterations in hepatocyte and sinusoidal cell functions were found in all groups after cold ischemia with or without calcium antagonists. In a second set of experiments, liver transplantation was performed in two groups of rats with livers stored under identical conditions with or without nisoldipine. Seven of 12 animals (62.5%) in both groups survived for over 10 days after 24-hr preservation in University of Wisconsin solution. Survival rates were similar in both groups. CONCLUSIONS: Calcium antagonists do not appear to have a direct protective effect on sinusoidal endothelial cell and hepatocyte functions, nor on the overall liver preservation after extended cold preservation-reperfusion.

Laparoscopic closure for perforation of the sigmoid colon by endoscopic linear stapler.

Immediate open surgery has been recommended for the management of perforation during colonoscopic examination. Laparoscopic closure for perforation of the sigmoid colon caused by diagnostic colonoscopy is described. The perforation site was identified in the antimesenteric border of the sigmoid colon by laparoscopic survey, and four ports were inserted in the lower abdomen. The margin of the perforation was lifted by two graspers, and the defect was completely closed using an endoscopic linear stapler. The patient recovered quickly without any associated complications. Postoperative barium enema showed no stenosis or leakage. This method is less invasive and allows earlier recovery of patients with colonic perforation.

Radiofrequency hyperthermia for malignant liver tumors: the clinical results of seven patients.

BACKGROUND/AIMS: Since 1991, we have performed radiofrequency hyperthermia combined with chemotherapy preliminarily for malignant liver tumors. MATERIALS AND METHODS: We were using the BSD-1000 Annular phased array system and monitored intratumoral, skin superficial and intrarectal temperature. The subjects consisted of five patients with hepatocellular carcinoma and two with metastatic liver cancer. All seven patients received therapy from once to five times, with a mean frequency of 3.3 +/- 1.3 (S.D) times. RESULTS: The maximum intratumoral temperature was 42.2 +/- 1.0 (S.D.) degrees of centigrade, the length that intratumoral temperature reached 41 degrees of centigrade was 17.1 +/- 6.9 (S.D.) minutes and the length that intratumoral temperature kept above 41 degrees of centigrade was 30.8 +/- 7.5 (S.D.) minutes. The skin superficial and intrarectal temperature were 39.3 +/- 1.1 (S.D.) degrees of centigrade, 40.3 +/- 1.8 (S.D.) degrees of centigrade, respectively. The most common complaints were nausea (28%) and dyspnea (14%). CONCLUSIONS: No severe side effects were observed, although one case experienced an abdominal skin burn. We thus found that it was possible to heat deepseated liver tumors safely.

Isolated hepatic caudate lobectomy.

BACKGROUND: Isolated caudate lobectomy is a challenging surgical procedure for which safe and reliable techniques have yet to be developed. METHODS: Isolated caudate lobectomy was performed by initial inflow control of the caudate lobe, full mobilization of the liver from the inferior vena cava by dividing all short hepatic veins, and parenchymal division dorsal to the major hepatic veins with a clockwise rotation of the liver while the liver was selectively devascularized by Pringle's maneuver and occlusion of the confluence of the major hepatic veins flush with the inferior vena cava. RESULTS: Two patients with cirrhosis underwent this procedure successfully without intraoperative hemodynamic instability or postoperative liver dysfunction. CONCLUSIONS: This technique allows safe and truly selective excision of the caudate lobe without the need for occlusion of the inferior vena cava or venovenous bypass.

Lipiodolization for unresectable hepatocellular carcinoma: an analysis of 205 patients using univariate and multivariate analysis.

Since 1982 we have developed and successfully performed lipiodolization on 205 patients with unresectable hepatocellular carcinoma. The 1-, 2-, 3-, 4-, and 5-year survival rates were 55.6%, 31.7%, 16.3%, 8.7%, and 2.9%, respectively, while the median survival was 413 days, and 20 patients survived longer than 3 years after the first lipiodolization. Our study demonstrated that the factors for a comparatively good prognosis were as follows: patient older than 50 years, nodular type hepatocellular carcinoma < 5 cm in diameter, negative tumor invasion of portal vein, < 10 intrahepatic metastases, serum alpha-fetoprotein level < 400 ng/ml, and Okuda stage I. Lipiodolization did not cure hepatocellular carcinoma. It did, however, in this study, achieve a prolongation of the patient's survival.

Clinical correlation between necrosis of hepatocellular carcinoma nodule and early recurrence after hepatic resection.

Here we report on the case of a 51-year-old man who presented with a high-grade fever six weeks prior to hepatic resection. The resected specimen of the liver showed a well encapsulated and completely necrotic mass and some intrahepatic metastatic disease. Widespread multinodular recurrence in the liver remnant and metastatic foci in the bones were detected approximately one year after surgery. This case suggests that transcatheter arterial embolization--which aims to bring about necrosis of the tumor--followed by hepatic resection might increase the risk of early recurrence of hepatocellular carcinoma, due to the fact that tumor necrosis can facilitate the release of cancer cells from the primary tumor.

Influence of hepatectomy on cell infiltration in the resected liver parenchyma compared with the biopsy specimen--a preliminary study.

We undertook a preliminary investigation to determine whether or not preoperative hepatitis activity can be evaluated by the finding of cell infiltration into the parenchyma of the resected specimen. In 28 patients who underwent hepatic resection, liver biopsies were obtained just after the laparotomy in order to make a histological comparison with the resected liver specimen. Histological changes were observed in 11 out of 28 patients. However, these were limited to minimal changes of neutrophil infiltration in the portal and subserosal area with no derangement of chronic cell infiltration. In addition, the preoperative liver function and operative findings did not differ between patients with and those without histological changes. The activity of hepatitis was therefore seen not to be histologically influenced by the surgical procedure. Thus, an accurate evaluation of chronic inflammatory cell infiltration activity in the resected liver specimen is a reliable indicator in chronic liver disease patients.