Metabolomic/lipidomic-based analysis of plasma to diagnose hepatocellular ballooning in patients with non-alcoholic fatty liver disease: A multicenter study.

AIM: Liver biopsy is still required for the diagnosis of hepatocellular ballooning and inflammation, which are important histological features of non-alcoholic steatohepatitis. We undertook this multicenter, cross-sectional study to identify novel blood markers for the diagnosis of hepatocellular ballooning. METHODS: We enrolled 176 patients, of whom 132 were proven by liver biopsy as having non-alcoholic fatty liver disease (NAFLD) and classified as non-ballooning (ballooning grade 0) (n = 83) or ballooning (ballooning grade 1 and 2) (n = 49) by a central pathology review. We carried out gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography tandem mass spectrometry, and lipidomics with plasma. RESULTS: As correlates of hepatocellular ballooning, among the clinical parameters, serum type IV collagen 7S correlated most significantly with the ballooning grade (correlation coefficient [CC] = 0.463; P < 0.001). Among the metabolic/lipidomic markers, phosphatidylcholine (PC) (aa-44:8) correlated most significantly with the ballooning grade (CC = 0.394; P < 0.001). The area under the receiver operating characteristic curve of type IV collagen 7S, choline, and lysophosphatidylethanolamine (LPE) (e-18:2), was 0.846 (95% confidence interval, 0.772-0.919). CONCLUSIONS: Plasma levels of PC were positively correlated, and those of lysophosphatidylcholine and LPE were negatively correlated with hepatocellular ballooning in NAFLD patients. These non-invasive metabolic/lipidomic-based plasma tests might be useful to distinguish between cases of NAFLD with and without hepatocellular ballooning.

Efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: a multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin.

BACKGROUND: Substance P contributes to the hypersensitivity reaction (HSR) to paclitaxel in a rat model. Aprepitant acts as an inhibitor of the binding of substance P to the neurokinin-1 receptor and, consequently, may reduce the frequency of paclitaxel-induced HSR. While aprepitant has a prophylactic effect against vomiting caused by high-dose cisplatin, the benefits of aprepitant have not been clearly demonstrated in patients receiving paclitaxel and carboplatin (TC) combination chemotherapy. METHODS: We conducted a multicenter, placebo-controlled, double-blind, randomized study in Japanese patients with gynecologic cancer who received TC combination chemotherapy. Patients received aprepitant or placebo together with both a 5-HT3 receptor antagonist and dexamethasone prior to chemotherapy. The primary endpoint was the proportion of patients with HSR, and the secondary endpoints were the proportion of patients with "no vomiting", "no significant nausea", and complete response, respectively. RESULTS: Of the 324 randomized patients, 297 (151 in the aprepitant group; 146 in the placebo group) were evaluated. The percentage of patients with HSR (9.2 vs. 7.5 %, respectively; P = 0.339) was not significantly different between the groups. The percentage of "no vomiting" patients (78.2 vs. 54.8 %; P < 0.0001), "no significant nausea" patients (85.4 vs. 74.7 %; P = 0.014), and patients showing complete response (61.6 vs. 47.3 %, P = 0.0073) was significantly higher in the aprepitant group than in the placebo group. CONCLUSION: The administration of aprepitant did not have a prophylactic effect on the HSR but was effective in reducing nausea and vomiting in gynecologic cancer patients receiving TC combination chemotherapy.

Increasing Incidence of Degenerative Spinal Diseases in Japan during 25 Years: The Registration System of Spinal Surgery in Tohoku University Spine Society.

Spinal disorders affect mainly older people and cause pain, paralysis and/or deformities of the trunk and/or extremities, which could eventually disturb locomotive functions. For ensuring safe and high-quality treatment of spinal disorders, in 1987, the Tohoku University Spine Society (TUSS) was established by orthopedic departments in Tohoku University School of Medicine and its affiliated hospitals in and around Miyagi Prefecture. All spine surgeries have been enrolled in the TUSS Spine Registry since 1988. Using the data from this registration system between 1988 and 2012, we demonstrate here the longitudinal changes in surgical trends for spinal disorders in Japan that has rushed into the most advanced "aging society" in the world. In total, data on 56,744 surgeries were retrieved. The number of spinal surgeries has annually increased approximately 4-fold. There was a particular increase among patients aged ≥ 70 years and those aged ≥ 80 years, with a 20- to 90-fold increase. Nearly 90% of the spinal operations were performed for degenerative disorders, with their number increasing approximately 5-fold from 705 to 3,448. The most common disease for surgery was lumbar spinal stenosis (LSS) (35.9%), followed by lumbar disc herniation (27.7%) and cervical myelopathy (19.8%). In 2012, approximately half of the patients with LSS and cervical myelopathy were ≥ 70 years of age. In conclusion, the number of spinal operations markedly increased during the 25-year period, particularly among older patients. As Japan has a notably aged population, the present study could provide a near-future model for countries with aging population.

Characterization of binding mode of action of a blocking anti-platelet-derived growth factor (PDGF)-B monoclonal antibody, MOR8457, reveals conformational flexibility and avidity needed for PDGF-BB to bind PDGF receptor-ß.

Platelet derived growth factor-BB (PDGF-BB) is an important mitogen and cell survival factor during development. PDGF-BB binds PDGF receptor-ß (PDGFRß) to trigger receptor dimerization and tyrosine kinase activation. We present the pharmacological and biophysical characterization of a blocking PDGF-BB monoclonal antibody, MOR8457, and contrast this to PDGFRß. MOR8457 binds to PDGF-BB with high affinity and selectivity, and prevents PDGF-BB induced cell proliferation competitively and with high potency. The structural characterization of the MOR8457-PDGF-BB complex indicates that MOR8457 binds with a 2:1 stoichiometry, but that binding of a single MOR8457 moiety is sufficient to prevent binding to PDGFRß. Comparison of the MOR8457-PDGF-BB structure with that of the PDGFRß-PDGF-BB complex suggested the potential reason for this was a substantial bending and twisting of PDGF-BB in the MOR8457 structure, relative to the structures of PDGF-BB alone, bound to a PDGF-BB aptamer or PDGFRß, which makes it nonpermissive for PDGFRß binding. These biochemical and structural data offer insights into the permissive structure of PDGF-BB needed for agonism as well as strategies for developing specific PDGF ligand antagonists.

Extrahepatic platelet-derived growth factor-ß, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice.

BACKGROUND & AIMS: Platelet-derived growth factor-ß (PDGFB) is a mitogen for hepatic stellate cells (HSCs). We studied the cellular sources of PDGFB and the effects of a high-affinity monoclonal antibody against PDGFB (MOR8457) in mouse models of biliary fibrosis. METHODS: Cellular sources of PDGFB were identified using quantitative reverse-transcription polymerase chain reaction, biochemical, and immunohistologic methods. Mice with advanced biliary fibrosis, MDR2(Abcb4)-null mice, and C57Bl/6 (control) mice were placed on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diets and were given weekly intraperitoneal injections of MOR8457. Platelets were depleted from MDR2-null mice by injection of an antibody against CD41, or inhibited with diets containing low-dose aspirin. Liver tissues were collected and analyzed by quantitative reverse-transcription PCR and histologic and biochemical analyses. RESULTS: Levels of PDGFB protein, but not messenger RNA, were increased in fibrotic livers of MDR2-null mice, compared with control mice. Platelet clusters were detected in the hepatic endothelium, in close proximity to HSCs, and were identified as a source of PDGFB protein in MDR2-null mice. Levels of the PDGFB were increased in serum samples from patients with early stages of liver fibrosis of various etiologies (F1-2, n = 16; P < .05), compared with nonfibrotic liver tissue (F0, n = 12). Depletion of platelets from MDR2-null mice normalized hepatic levels of PDGFB within 48 hours, reducing levels of a marker of HSC activation (α-smooth muscle actin) and expression of genes that promote fibrosis. Diets supplemented with low-dose aspirin reduced circulating serum and hepatic levels of PDGFB and significantly reduced progression of fibrosis in MDR2-null mice over 1 year. MOR8457 produced a dose-dependent decrease in liver fibrosis in MDR2-null mice, reducing collagen deposition by 45% and expression of fibrosis-associated genes by 50%, compared with mice given a control antibody. In vitro, platelets activated freshly isolated HSCs (induction of α-smooth muscle actin and fibrosis-associated genes) via a PDGFB-dependent mechanism. MOR8457 also reduced liver fibrosis in mice placed on DDC-supplemented diets. CONCLUSIONS: Platelets produce PDGFB to activate HSC and promote fibrosis in MDR2-null mice and mice on DDC-supplemented diets. Antiplatelet therapy or selective inhibition of PDGFB might reduce biliary fibrosis in patients with liver disease.

Primary uterine müllerian mucinous borderline tumor (MMBT) associated with adenomyosis: a case report.

Müllerian mucinous borderline tumors (MMBTs) usually arise from the ovary. The present report is the first case of primary uterine MMBTs associated with adenomyosis. A 51-year-old woman was referred to our hospital for a complex cystic and solid 4×3 cm right adnexal mass. She had a history of a left ovarian endometriotic cyst and had undergone a left oophorectomy 2 yr prior. A laparotomy was performed, and the tumor was found to be originating in the posterior wall of the uterus. She underwent a total abdominal hysterectomy, right salpingo-oophorectomy, and left salpingectomy. Microscopically, the solid portion of the tumor contained papillary proliferations of glands, which were covered by a mucinous epithelium with mild to moderate nuclear atypia, accompanied by stromal infiltration of inflammatory cells. Islands of adenomyosis were also observed around the cyst. These pathologic findings were similar to the features of ovarian MMBT. We diagnosed this tumor as a uterine MMBT, probably arising from adenomyosis.

[Quality use of commercial laboratory for clinical testing services - considering laboratory's role].

The number of commercial laboratories for clinical testing in Japan run privately has decreased to about 30 companies, and their business is getting tougher. Branch Lab. and FMS businesses have not expanded recently due to the new reimbursement system which adds an additional sample management fee, becoming effective in 2010. This presentation gives an outline of each role for hospital and commercial laboratories, and their pros & cons considering the current medical situation. Commercial laboratories have investigated how to utilize ICT systems for sharing test information between hospitals and our facilities. It would be very helpful to clarify issues for each hospital. We will develop and create new values for clinical laboratory testing services and forge mutually beneficial relationships with medical institutions. (Review).

[Excision of a left atrial myxoma through right minithoracotomy in a patient with multiple myeloma; report of a case].

We present a case of a 63-year-old female who underwent an excision of a left atrial myxoma. Previously, she had been diagnosed with multiple myelomas and received radiation therapy and chemotherapy. A left atrial myxoma was found at an annual medical check-up. The myxoma was removed via a right minithoracotomy with peripheral cannulation to minimize bleeding complications and surgical site infection. She was transferred to the referring hospital on postoperative day 7 due to recurrence of multiple myelomas. She was doing well 14 months after the operation. Right minithoracotomy is a useful approach to minimizing the risks of bleeding and infection in patients with multiple myelomas.

Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1.

SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a K(i) of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling.

[Can local administration of tranexamic acid reduce aspirin-induced bleeding in off-pump coronary artery bypass grafting( CABG) ?].

OBJECTIVES: We examined the effect of local administration of tranexamic acid( TA) on reducing aspirin-induced bleeding in off-pump coronary artery bypass grafting(CABG). METHODS: From July 2009 to January 2011, 88 cases with off-pump CABG were divided into 4 groups:group C including 19 cases without preoperative aspirin or local administration of TA, group A including 23 cases with preoperative aspirin alone, group T including 19 cases with local administration of TA alone, and group AT including 27 cases with both preoperative aspirin and local administration of TA. RESULTS: The bleeding volume after 24 hours in group A was significantly larger than that in group C(p=0.0085). The bleeding volume in group AT was significantly smaller than that in group A (p<0.0001), and the bleeding volume in group T was also significantly smaller than that in group C (p=0.0054). There was no significant difference between group T and AT. CONCLUSIONS: The use of local administration of tranexamic acid indicated the reduction of postoperative bleeding even in patients with preoperative aspirin use.

Propensity score analysis comparing off-pump versus on-pump coronary artery bypass grafting in older adults.

OBJECTIVE: This study aimed to compare the results of off-pump and on-pump coronary artery bypass grafting in older adults and to examine early and late outcomes. METHODS: This study included 226 patients aged ≥ 75 years who underwent isolated coronary artery bypass grafting. Of these, 141 and 85 patients were included in the off-pump and on-pump groups, respectively. Propensity scores were calculated for each case, matched, and compared between the two groups (68 cases in each group), along with mid-term outcomes of survival and major adverse cardiac events. RESULTS: Operative time, red blood cell transfusion volume, and postoperative hospital stay duration were significantly higher in the on-pump group (267 vs 370 min, P < 0.001; 4.3 vs 17.2 units, P < 0.001; and 20.8 vs 35.8 days, P = 0.012, respectively). Postoperative occurrence of new atrial fibrillation was significantly higher in the on-pump group (4.4% vs 27.9%, P < 0.001), and Kaplan-Meier survival analysis showed a significantly worse prognosis in the on-pump group than in the off-pump group (3-year survival rate 90.7% vs 71.5%, log rank P = 0.007). However, there was no statistically significant difference in cardiovascular-related deaths (log rank P = 0.07). CONCLUSIONS: On-pump coronary artery bypass grafting in an older adult population resulted in increased transfusion volume and postoperative occurrence of atrial fibrillation. The mid-term postoperative outcomes were also poorer with on-pump coronary artery bypass grafting. Off-pump coronary artery bypass grafting reduced future all-cause deaths in older adults.

Iridium-catalyzed alkylation of methylquinolines with alcohols.

Iridium-catalyzed alkylation of methylquinolines at the methyl substituent was achieved using alcohols as alkylating agents. The reaction proceeded through a transfer hydrogenation pathway from the alcohol to the Ir complex, affording an aldehyde and Ir-H species, followed by base-assisted aldol condensation and hydrogenation. This method provides an atom-economical and convenient route to alkylquinolines from easily accessible methylquinolines.

[Efforts to achieve anastomosis forms in coronary artery bypass grafting; cuff-like and skirt-like anastomoses].

As the type of anastomotic site is considered to be one of the decisive factors for graft-patency in coronary artery bypass grafting(CABG),our aim is to achieve anastomosis forms that potentially promote long-term graft-patency rates. When an arterial graft is used, side-to-side anastomosis is performed, with its incision length being longer than that of the coronary artery, to achieve a cuff-like anastomosis form. When a vein graft is used, on the other hand, it is incised shorter than the coronary artery to achieve a skirt-like anastomosis form instead of a purse-like one. It is thus expected that reliable anastomosis forms can be observed in postoperative angiography.

[A case of bone marrow carcinomatosis from breast cancer treated with weekly Paclitaxel].

We report a case of bone marrow carcinomatosis originating from breast cancer that was treated with weekly paclitaxel (PTX). A 42-year-old female patient underwent mastectomy with axillary lymph node dissection for breast cancer in 2001. Multiple bone metastases were diagnosed in 2008, but she remained stable with chemotherapy and hormonal therapy for about two years. In 2010, thrombocytopenia occurred, and she was diagnosed with bone marrow carcinomatosis after bone marrow biopsy. She was treated with weekly PTX(80 mg/m2), and recovered successfully after treatment. About one year has elapsed since initiation of therapy, and there has been no recurrence. Bone marrow carcinomatosis originating from breast cancer is very rare, and is regarded as a disease with a poor prognosis. However, weekly PTX could be a valid treatment for prolonging survival of bone marrow carcinomatosis originating from breast cancer.

Surgical outcomes of acute type A aortic dissection in septuagenarians and octogenarians.

BACKGROUND: We studied surgical outcomes of acute type A aortic dissection and compared early and late outcomes between septuagenarians and octogenarians. METHODS: From 2010 to 2019, we evaluated 254 consecutive patients with acute type A aortic dissection. We performed emergent operations within 48 h of symptom onset for 188 patients, including 59 septuagenarians and 32 octogenarians. RESULTS: The overall 30-day mortality rate was 8.5% in septuagenarians and 9.4% in octogenarians (p = 1.0). The hospital mortality rate was 10.2% in septuagenarians and 12.5% in octogenarians (p = 0.74). Multivariate analysis identified prolonged ventilation (≥ 72 h) as a significant risk factor for hospital mortality. Being an octogenarian was not significantly associated with hospital mortality. The actuarial survival rate at 5 years was 80.1% in septuagenarians and 58.5% in octogenarians (log-rank p = 0.09). The freedom from aortic event rate at 5 years was 91.0% in septuagenarians and 100% in octogenarians (log-rank p = 0.23). CONCLUSION: The two groups showed no significant differences in hospital mortality or morbidity. Our tear-oriented strategies might be appropriate for both septuagenarians and octogenarians. Prolonged ventilation (≥ 72 h) was a significant risk predictor for hospital mortality.

Gaucher disease carrier with gestational thrombocytopenia and anemia: a case report.

BACKGROUND: Gaucher disease is an autosomal recessive inborn error of metabolism that causes disorders of blood, bone, and central nervous system as well as hepatosplenomegaly. We present the case of a carrier of Gaucher disease with gestational thrombocytopenia and anemia that required blood transfusion therapy. CASE PRESENTATION: A 24-year-old Nepalese primipara was diagnosed with idiopathic thrombocytopenia at 12 weeks of gestation. Her platelet count had reduced to 30,000/µL at 21 weeks of gestation, and the hemoglobin content reduced to 7.6 g/dL at 27 weeks of gestation. As she did not respond to any medication, blood transfusion was performed. A female infant weighing 2677 g was delivered vaginally at 39 weeks of gestation. On the 78th day of puerperium, the platelet count of the mother recovered to 101,000/µL, and the hemoglobin content recovered to 12.5 g/dL. The infant had convulsions, respiratory depression, wheezing, systemic purpura, and exfoliation of the epidermis at birth. The infant was diagnosed with Gaucher disease at 37 days of age and passed away at 82 days of age. Subsequently, the parents were diagnosed as carriers of Gaucher disease. CONCLUSION: As carriers of this disease do not usually show symptoms, it is imperative to provide information regarding disease management for future pregnancies.

A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation.

Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.

Sentinel node detection with (99m)Tc phytate alone is satisfactory for cervical cancer patients undergoing radical hysterectomy and pelvic lymphadenectomy.

BACKGROUND: If the sentinel-lymph-node (SLN) concept is valid in cervical cancer, most patients could avoid pelvic lymphadenectomy when absence of metastasis is intraoperatively confirmed in the SLN. We assessed feasibility and accuracy of SLN detection using (99m)Tc phytate in patients with cervical cancer. METHODS: Eighty-two women with stage Ia-IIb cervical cancer enrolled in this study. All underwent hysterectomy or trachelectomy with accompanying total pelvic lymphadenectomy. On the day before surgery, we injected fluid containing (99m)Tc-labeled phytate subepithelially into four cervical quadrants outside the tumor. Intraoperatively, SLNs were identified as radioactive "hot nodes" by gamma probe. Systematic bilateral pelvic lymphadenectomy was performed after the hot node sampling to evaluate the predictive ability of hot nodes. RESULTS: A total of 157 lymph nodes were detected as SLNs in 72 of 82 patients. SLN detection rate was 88%. Detection rate was 95% for the subgroups of patients with stage Ia-Ib1 disease and smaller tumor size (

Bilateral internal thoracic artery grafting: propensity analysis of the left internal thoracic artery versus the right internal thoracic artery as a bypass graft to the left anterior descending artery.

OBJECTIVES: To compare different configurations of the bilateral internal thoracic arteries for the left coronary system and examine early and late outcomes, including mid-term graft patency. METHODS: We reviewed 877 patients who underwent primary isolated coronary artery bypass grafting using in situ bilateral internal thoracic arteries [in situ right internal thoracic artery (RITA)-to-left anterior descending artery (LAD) grafting, n = 683; in situ left internal thoracic artery (LITA)-to-LAD grafting, n = 194]. We compared mid-term patency between the grafts. Propensity score matching was performed to investigate early and long-term outcomes. RESULTS: The 2-year patency rate for RITA-to-LAD and LITA-to-LAD grafts were similar. Multivariate analysis revealed that RITA-to-non-LAD anastomosis (P = 0.029), postoperative length of stay (P = 0.003) and chronic obstructive pulmonary disease (P = 0.005) were associated with graft failure. After statistical adjustment, 176 propensity-matched pairs were available for comparison. RITA-to-LAD grafting enabled a more distal anastomosis. Kaplan-Meier analysis revealed that the incidences of death, repeat revascularization and myocardial infarction were significantly higher in the LITA-to-LAD group among both the unmatched and matched samples (P = 0.045 and 0.029, respectively). CONCLUSIONS: The mid-term patency and outcomes of RITA-to-LAD grafting are good and reduces future cardiac event, in contrast to LITA-to-LAD grafting.