Liver Function Studies Research Articles

Contemporary Experience with Cholecystectomy: Establishing ‘Benchmarks’ Two Decades after the Introduction of Laparoscopic Cholecystectomy

With quality and public reporting of increasing importance, benchmarks are anticipated to grow in relevance. We studied cholecystectomy in a practice in an urban tertiary care hospital. A total of 1083 cholecystectomies were performed in 2008 and 2009. Laparoscopic cholecystectomy was performed in 97.8 per cent of patients with a 2.2 per cent conversion rate. A planned open procedure was performed in only 2.2 per cent of patients. Approximately half of procedures were urgent and performed during an acute hospitalization. Most patients (74%) were female and most patients were overweight or obese (64.8%). Ages into the tenth decade of life were represented. Comorbidities included hypertension, 28.7 per cent; coronary disease, 15.6 per cent; diabetes mellitus, 13.4 per cent; gastroesophageal reflux disease, 10.7 per cent; and asthma, 5.5 per cent. Of female patients, 98 (12.2%) were postpartum and five (0.6%) were pregnant. Of 137 patients without gallstones, 59.1 per cent had biliary dyskinesia and 27 per cent had acalculous cholecystitis. Preoperative magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography (ERCP) were performed in most patients with suspected choledocholithiasis. Intraoperative cholangiograms were performed in 6.9 per cent of patients, 3.3 per cent for abnormal liver function studies. Postoperative ERCP was used in most patients with positive intraoperative cholangiograms. All-cause mortality was 0.8 per cent and attributable mortality was 0.2 per cent. Complications occurred in 7.5 per cent of patients, including retained common bile duct stones in 1.1 per cent, bile duct leak in 0.3 per cent, and common bile duct injury in 0.1 per cent.

Efficacy and Safety Of Pegelated Interferon alpha2a once Monthly Compared To Once Weekly Dose In Patients With Essential thrombocythemia

Essential thrombocythemia(ET) is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis, bone marrow megakaryocytic hyperplasia and an increased risk of thrombosis and hemorrhage. The goal of treatment is to prevent the development of vascular complications without increasing the risk of transformation. Patients aged>60 years or a history of thrombosis have a high risk of thrombosis while those with a platelet count>1,500x109/l have a higher risk of hemorrhage.Patients with low-risk ET can be managed with low-dose of acetylsalicylic acid or even observation only, while patients with a high-risk disease are candidates to cytoreductive treatment, hydroxyurea being the first choice therapy. Anagrelide is the most suitable option for patients with resistance or intolerance to hydroxyurea. All patients must be submitted to a rigorous control of cardiovascular risk factors. Interferon alfa2a (pegasis) is a nonleukemogenic drug that can induce cytogenetic remissions or reversion from monoclonal to polyclonal patterns of hematopoiesis in some cases, this study addressing the safety efficacy and toxicity of pegasis( once weekly versus once monthly ) in ET MethodsInclusion criteria were: Patients with ET diagnosed as per WHO classification 2008, age 18 to 45 years, and either no previous treatment or Hydroxyurea or anagralide for less than 1 years. ET diagnosis workup included ferritin, exclusion of secondary causes like infections and not meeting WHO criteria for PV, MDS and CML Pretreatment evaluation also included patient history, physical examination, complete blood count (CBC) and serum chemistries (UE), including liver and renal function studies, thyroid function tests (TFT), and molecular study for JAK2V617F mutation.Exclusion criteria included (significant hepatic and renal dysfunction, history of psychiatric disorder, in particular depression, autoimmune hepatitis, severe cardiac dysfunction, known hypersensitivity to IFN. The primary end point was hematological response to pegasis at 12 months. Complete hematological response (CR) as per ELN guidelines' and Molecular response (MR) was defined as “complete” when JAK2V617F became undetectable with the technique used (ie, %V617F< 1%), “partial” when > 50% decrease of baseline %V617F was obtained, and “minor” when %V617F decrease was between 20% and 49%. Follow-up evaluations included adverse event (AE) assessment monthly for 3 months, then every third month until the 12th month with CBC, UE weekly during the first month and monthly thereafter. TFT, CBC, JAK2 mutation studies were taken every 6 months. After inclusion, HU was stopped 2 weeks before Pegasis initiation. Pegasis was started subcutaneously at 50 microgram weekly for 4 weeks then 135 mcg/wk from week 5.all patients achieved complete hematological remission from week 10 were randomized into two arms arm(A)135 mcg/wk and arm(B) 135 mcg/monthBaseline characteristics of the patients are. Median age was 31.5 year vs 30 year, and 20 patients in each arm 18 patients were males 22 were females three patients had a history of major thrombotic events. Treatment before inclusion included HU in 18 patients, and no treatment in the remaining 22 patients,JAK2 mutation was found in all patients All the patients responded to Pegasis at the 12-month evaluation including 40 hematological CRs (100%)No patient experienced signs or symptoms of thrombosis or hemorrhage during the whole study period. Median relative decrease of %V617F during the first year was 52% decreased in arm A versus 50 % in arm B,.Hematological response was achieved in all of the patients within 2 months and were sustained beyond the first year. Most common toxicities during the first month included musculoskeletal pain in 6 patients versus 2, skin toxicity in 4 versus 0, and GI symptoms in 2 versus 0 , none of the toxicity exceeds WHO Grade 2 with no stsatistical differences between the two groups. Conclusion135 mcg Pegasis once monthly is as effective as once weekly dose with reduced toxicity Reducing the vascular risk and preventing evolution to MF, MDS, Percentage of V617F appears to be a good tool to monitor minimal residual disease and to evaluate treatment efficacy however further studies are needed to confirm these results and to look for the efficacy of more reduced doses. Disclosures:Yassin:qatar national research fund: Patents & Royalties, Research Funding. Al-Dewik:qatar national research fund: Patents & Royalties, Research Funding. Cassinat:qatar national research fund: Patents & Royalties, Research Funding.

Educating Patients About Hypoglycemia Prevention and Self-Management

Mrs. B was a 68-year-old, Asian-American woman with a 15-year history of type 2 diabetes. Her coexisting medical conditions included unilateral intraductal carcinoma of the breast, which was treated with a modified radical mastectomy 6 years ago and showed no evidence of recurrence. Although there was no history of alcohol use, her liver function studies had been elevated to two times the upper limit of normal for several years. A liver biopsy revealed the presence of nonalcoholic steatohepatitis (NASH). She was admitted to the hospital on one occasion within the past year for bleeding esophageal varices. Mrs. B had no history of macrovascular disease, chronic kidney disease, retinopathy, or neuropathy. For the past 10 years, she had taken 10 mg glyburide daily. Her primary care provider (PCP) was concerned that her A1C had increased from 7.4 to 7.9% in the past 6 months. Her family members stated that they rarely spoke about diabetes, self-monitoring of blood glucose (SMBG), or diabetes-related complications. In fact, the patient's 72-year-old husband also has type 2 diabetes and is undergoing dialysis. In the past year, Mr. B has had at least two episodes of severe hypoglycemia that required hospitalization. He blames his end-stage renal disease on medication he is taking to control his blood glucose levels. Because of concerns about Mrs. B's increasing A1C, her PCP asked her to consult with a local endocrinologist who added basal insulin to her diabetes treatment regimen. She was not provided with any specific instructions about how to inject the basal insulin or when to perform SMBG. Her son noted that she tended to get “confused,” but he did not attribute this to her blood glucose level because he never saw her checking her glucose. Her handwritten glucose log showed several readings in the low 50 to 60 mg/dl …

Sudden Purpuriform Rash in an Infant

A 10-month-old boy presents with erythematous swelling of bothears and right eyelid and erythematous perioral macules following a respiratory tract infection 12 days before presentation (Figure, A). Within 4 days the lesions increased in size, becoming large erythematous plaques on the face (Figure, B). Targetoid, purpuric lesions developed on the limbs (Figure, C), along with hand edema. There were no trunk lesions and no involvement of the mucous membranes. The child is otherwise in good general health. On examination he is afebrile, has normal vital signs, and there is no lymphadenopathy or organomegaly. Findings from urinalysis, complete blood cell count, coagulation studies, and liver and kidney function studies are unremarkable.

Evaluation of fatty liver by using in-phase and opposed-phase MR images and in-vivo proton MR spectroscopy

The purpose of this study was to evaluate the necessity of in-phase and opposed-phase MR images and their correlations with weight, the aspartate aminotransferase/alanine aminotransferase (AST/ALT) value, and age. Magnetic resonance spectroscopy (MRS) was used as a reference in this study. We selected 68 people as subjects, among which 14 were volunteers with normal AST/ALT values (<40/35 U/L) on a liver function study and 54 were non-alcoholic fatty liver patients for whom ultrasonic images had been obtained within 3 months of the study. In this study, the liver was more enhanced than the spleen or kidney. When the Eq. (3) formula was applied to normal volunteers, the difference between the in-phase and the opposed-phase images was −3.54 ± 12.56. The MRS study result showed a high sensitivity of 96.6% and a specificity of 100% (p = 0.000) when the cutoff value was 20%. Furthermore, this result showed a high sensitivity of 94% and a specificity of 80% with a similar cutoff when the Eq. (2) formula was applied to non-alcoholic fatty liver patients (p = 0.000). The MRS study revealed a strong correlation between normal volunteers and non-alcoholic fatty liver patients (r = 0.59, p = 0.04). The correlations between AST/ALT and Eq. (3) (r = 0.45, p = 0.004), age and Eq. (3) (r = 0.73, p = 0.03), and weight and Eq. (3) (r = 0.77, p = 0.000) values were all statistically significant. In the case of non-alcoholic liver disease, MRS was found to be significantly correlated with Eq. (1) (r = 0.39, p = 0.002), Eq. (2) (r = 0.68, p = 0.04), Eq. (3) (r = 0.67, p = 0.04), and AST/ALT (r = 0.77, p = 0.000). In conclusion, in-phase and opposed-phase images can help to distinguish a normal liver from a fatty liver in order to identify non-alcoholic fatty liver patients. The intensity difference between the in-phase and opposed-phase MR signals showed valuable correlations with respect to weight, AST/ALT value, and age, with all values being above the mild lipid value (r = 0.3).

Pegylated Interferon-Alfa-2a Induces Complete Hematologic and Molecular Responses with Low Toxicity in Essential Thrombocythemia

AbstractAbstract 1743Essential thrombocythemia (ET) is a myeloproliferative Neoplasm (MPNs) marked by a risk of thrombotic and hemorrhagic complications, and by a long-term risk of evolution to myelofibrosis (MF), myelodys-plastic syndrome (MDS), and acute leukemia (AL). In addition to its role in pathophysiology and diagnosis, the constitutively active JAK2V617F mutation may be a prognostic marker because the percentage of circulating mutated alleles (%V617F) appears to be significantly higher in patients who develop vascular complications.Interferon alfa2a (pegasis) is a nonleukemogenic drug that can induce cytogenetic remissions or reversion from monoclonal to polyclonal patterns of hematopoiesis in some cases, this is the first study addressing the effects of pegasis in ET. Methods.Inclusion criteria were: Patients with ET diagnosed as per WHO classification 2008, age 18 to 45 years, and either no previous treatment or Hydroxyurea or anagralide for less than 1 years. ET diagnosis workup included ferritin, exclusion of secondary causes like infections and not meeting WHO criteria for PV, MDS and CML Pretreatment evaluation also included patient history, physical examination, complete blood count (CBC) and serum chemistries (UE), including liver and renal function studies, thyroid function tests (TFT), and molecular study for JAK2V617F mutation.Exclusion criteria included (significant hepatic and renal dysfunction, history of psychiatric disorder, in particular depression, autoimmune hepatitis, severe cardiac dysfunction, known hypersensitivity to IFN. The primary end point was hematologic response to pegasis at 12 months. Complete hematologic response (CR) as per ELN guidelines’ and Molecular response (MR) was defined as “complete” when JAK2V617F became undetectable with the technique used (ie, %V617F < 1%), “partial” when > 50% decrease of baseline %V617F was obtained, and “minor” when %V617F decrease was between 20% and 49%. Follow-up evaluations included adverse event (AE) assessment monthly for 3 months, then every third month until the 12th month with CBC, UE weekly during the first month and monthly thereafter. TFT, CBC, JAK2 mutation studies were taken every 6 months. After inclusion, HU was stopped 2 weeks before Pegasis initiation. Pegasis was started subcutaneously at 50 microgram weekly for 4 weeks then 135 microgramg/wk from week 5.Baseline characteristics of the patients are. Median age was 31.5 years (19–44) years), and 16 patients were males 24 were femals Five patients had a history of major thrombotic events. Treatment before inclusion included HU in 15 patients, and no treatment in the remaining 25 patients, all recently diagnosed.JAK2 mutation was found in all patientsAll the patients responded to Pegasis at the 12-month evaluation including 35 hematologic CRs (94.6%), and 5 PRs (5.4%). Cumulative incidences of hematologic CRs and PRs showing that 100% of responses were achieved within 12 months.No patient experienced signs or symptoms of thrombosis or hemorrhage during the whole study period. Median relative decrease of %V617F during the first year was 50% (33%-60%). %V617F decreased in all patients,After the first year, %V617F continued to decrease without evidence for a plateau, the proportion of mutant JAK2 being always similar or lower in the last sample compared with the previous one and none of the responding patient experienced an increase of %V617F during follow-up. Median %V617F was, 58% at 12 months, (P<.001). Complete or partial MR was observed in all patients.Hematologic response was achieved in all of the patients within 2 months and were sustained beyond the first year. Most common toxicities during the first month included musculoskeletal pain in 6 patients, skin toxicity in 4, and GI symptoms in 2, none of the toxicity exceeds WHO Grade 2. Conclusion.Pegylated Interferon alfa2a is effective and promising treatment for ET Reducing the vascular risk and preventing evolution to MF, MDS, and AL.with low toxicity profiles and good Hematological and Molecular response, Percentage of V617F appears to be a good tool to monitor minimal residual disease and to evaluate treatment efficacy however further studies are needed to confirm these results. Disclosures:Yassin:Qatar National Research Fund: Patents & Royalties, Research Funding. Off Label Use: use of pegelated interferon alfa 2a in treatment of patients with ET. Al-Dewik:Qatar National Research Fund: Patents & Royalties, Research Funding. Rafii El-Ayoubi:Qatar National Research Fund: Patents & Royalties, Research Funding.

Prospective study of disc repair with allogeneic chondrocytes Presented at the 2012 Joint Spine Section Meeting

The purpose of the study was to evaluate the safety and initial efficacy of NuQu allogeneic juvenile chondrocytes delivered percutaneously for the treatment of lumbar spondylosis with mechanical low-back pain (LBP). NuQu is a cell-based biological therapy for disc repair. The authors report the results at 12 months of the NuQu Phase I investigational new drug (IND) single-arm, prospective feasibility study for the treatment of LBP for single-level degenerative disc disease (Pfirrman Grades III-IV) at L3-S1. Fifteen patients (6 women and 9 men) were enrolled at 2 sites. Institutional review board approval was obtained, and all patients signed a study-specific informed consent. All patients have completed a minimum of 1 year of follow-up. Patients were evaluated pretreatment and at 1, 3, 6, and 12 months posttreatment. Evaluations included routine neurological examinations, serum liver and renal function studies, MRI, the Oswestry Disability Index (ODI), the Numerical Rating Scale (NRS), and the 36-Item Short Form Health Survey (SF-36). Fifteen patients were treated with a single percutaneous delivery of NuQu juvenile chondrocytes. The mean patient age was 40 years (19-47 years). Each treatment consisted of 1-2 ml (mean injection 1.3 ml) of juvenile chondrocytes (approximately 10(7) chondrocyte cells/ml) with fibrin carrier. The mean peak pressure during treatment was 87.6 psi. The treatment time ranged from 5 to 33 seconds. The mean ODI (baseline 53.3, 12-month 20.3; p < 0.0001), NRS (baseline 5.7, 12-month 3.1; p = 0.0025), and SF-36 physical component summary (baseline 35.3, 12-month 46.9; p = 0.0002) scores all improved significantly from baseline. At the 6-month follow-up, 13 patients underwent MRI (one patient underwent CT imaging and another refused imaging). Ten (77%) of these 13 patients exhibited improvements on MRI. Three of these patients showed improvement in disc contour or height. High-intensity zones (HIZs), consistent with posterior anular tears, were present at baseline in 9 patients. Of these, the HIZ was either absent or improved in 8 patients (89%) by 6 months. The HIZ was improved in the ninth patient at 3 months, with no further MRI follow-up. Of the 10 patients who exhibited radiological improvement at 6 months, findings continued to improve or were sustained in 8 patients at the 12-month follow-up. No patient experienced neurological deterioration. There were no disc infections, and there were no serious or unexpected adverse events. Three patients (20%) underwent total disc replacement by the 12-month follow-up due to persistent, but not worse than baseline, LBP. This is a 12-month report of the clinical and radiographic results from a US IND study of cell-based therapy (juvenile chondrocytes) in the treatment of lumbar spondylosis with mechanical LBP. The results of this prospective cohort are promising and warrant further investigation with a prospective, randomized, double-blinded, placebo-controlled study design. Clinical trial registration no.: BB-IND 13985.

Studies of Lipid Profile, Liver Function and Kidney Function Parameters of Rat Plasma after Chronic Administration of “Sulavajrini Vatika”

The successful use of Ayurvedic medicines is for many years but there is no guideline for studying the toxicity of these preparations through preclinical or clinical investigations. The present study was conducted to evaluate the effect of conventionally prepared Sulavajrini Vatika (SBB), an Ayurvedic formulation on various biochemical parameters of experimental animals after chronic administration. The animal used was albino rats (Rattus norvegicus: Sprague-Dawley strain) and SBB was administered orally at a single dose of 100 mg kg(-1) b.wt. day(-1), up to 62 days. During the study, forty rats, equally of both sexes, were randomly grouped into four where one male and one female group were used as control and other groups were used as test. Among the lipid components, Triglyceride (TG) was decreased very high significantly in both sexes of animal. The decrease of Total Cholesterol (TC), Very Low Density Lipoprotein (VLDL) and high-density lipoprotein (HDL) were also highly significant. Low Density Lipoprotein (LDL) decreased in all SBB treated group. In the liver function parameters, the total protein and albumin content were increased very high significantly in both sexes of rat. But the bilirubin was decreased insignificantly in male and female rats. Serum Glutamic Pyruvic Transaminase (GPT), Glutamic Oxaloacetic Transaminase (GOT) and Alkaline Phosphatase (ALP) were decreased in all treated animals and it was very high significant. In case of kidney function parameters, creatinine was increased very high significantly but the urea was decreased very high significantly in both sexes of rat. The decrease in uric acid was not significant in none of the sexes of rat. The present study confirms that SBB can be contributory for the complications in diabetics with hyperlipidemia and nephropathy as it lowers most of the lipids components and improves liver function and kidney function parameters.

Study of Liver and Kidney functions in non-pregnant, pregnant and preeclamptic women

Three groups of subjects have been divided (25/group): healthy normotensive non-pregnant women (Group A), normal normotensive pregnant women (Group B), and women with preeclampsia (Group C).The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin , creatinine , blood urea nitrogen, triglyceride , total cholesterol and glucose have been estimated in all subjects. All measured parameters were determined by spectrophotometric analysis. The results showed a significant(P

Study of Liver and Kidney functions in non-pregnant, pregnant and preeclamptic women

Three groups of subjects have been divided (25/group): healthy normotensive non-pregnant women (Group A), normal normotensive pregnant women (Group B), and women with preeclampsia (Group C).The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin , creatinine , blood urea nitrogen, triglyceride , total cholesterol and glucose have been estimated in all subjects. All measured parameters were determined by spectrophotometric analysis. The results showed a significant(P

Study of perioperative liver function by dynamic monitoring of ICG-clearance.

To investigate the impact of liver resection on the perioperative hepatic function by evaluation of ICG-clearance. Twenty-five patients underwent major hepatic resection (Group A) and 36 underwent minor hepatic resection (Group B). Thirteen patients who received no liver surgery, acted as control group (Group C). ICG-clearance measured by a non-invasive technique was expressed in terms of plasma disappearance rate (PDR-ICG-%/min) and retention rate of ICG 15 min (ICG-R15-%) after administration ICG (0.5mg/kg) before anesthesia induction (T0), immediately after the surgery (T1) and 24h after (T2). There was statistically significant differences between the three groups: ICG-PDR (p<0.004) and ICG-R15 (p<0.040). These differences were observed between groups A and C at T1, between A and B, or A and C, at T2 for ICG-PDR and between groups A and B at T2 for ICG-R15. There were no differences between groups for hemoglobin, platelets, PT, creatinine, albumin, total protein, bilirubin and ALP. ICG clearance is a safe non-invasive dynamic tool to quantify the liver function in patients following hepatic surgery. It also can be used to evaluate the liver surgery impact on hepatic function which can help to diagnose early hepatic dysfunction and guide the therapeutic decision making process.

Nutmeg liver and ascites resulting from a membranous web obstruction at the hepatic origin of the inferior vena cava

A 30-year-old female presented to the hospital for an evaluation of anemia and intermittent abdominal distention. Laboratory studies revealed a profound iron-deficiency anemia with a hemoglobin level of 6.8, mean cell volume of 62, and a ferritin value of 3. BCS, Budd-Chiari syndrome; CAT, computerized axial tomography; IR, interventional radiology; IVC, inferior vena cava; PH, portal hypertension; US, ultrasound. On physical exam, her temperature was 97.9°F, pulse was 82, respiratory rate was 17, and blood pressure was 94/70. She was found to have hepatomegaly and moderate ascites on abdominal exam and was heme negative on rectal exam. An esophagogastroduodenoscopy and colonoscopy were unremarkable for a source of blood loss, and small bowel biopsies were not consistent with celiac sprue. A right upper quadrant ultrasound (US) revealed moderate ascites and hepatosplenomegaly. The liver had a lobular contour to it with increased echogenicity. A subsequent computerized axial tomography (CAT) scan illustrated a “nutmeg liver” and ascites (Fig. 1). A repeat US with Doppler showed patent hepatic and portal veins with normal direction of flow. Her liver function studies were all within normal limits, along with hepatitis serologies, antinuclear antibody, and Epstein-Barr virus titers. The ascites was sampled, revealing a serum ascites albumin gradient of >1.1 and a protein level of <2.5, consistent with portal hypertension (PH). Hepatic venous pressures were attempted by interventional radiology (IR). The pressure in the intrahepatic portion of the inferior vena cava (IVC) was elevated to 14 mmHg, and the right heart pressure was normal at 4 mmHg, yielding a 10-mmHg venous pressure gradient between the supra- and intrahepatic portion of the IVC. Attempts were made to cannulate the hepatic veins to obtain free hepatic pressures; however, these were unsuccessful because of a narrowing in the intrahepatic portion of the IVC. This prompted a third US in IR, demonstrating a web and turbulent flow at the origin of the hepatic vein from the IVC. IR performed a transhepatic venogram, and the web was found at the confluence of the middle hepatic vein and the IVC. The initial pressure gradient between the middle hepatic vein and the right atrium was significantly elevated at 20 mmHg. IR executed a successful angioplasty of the web with a 12 mm × 4 cm balloon, and the pressure gradient dropped to 4 mmHg (Fig. 2). The patient recovered nicely, with resolution of her ascites and symptoms. A 1-month follow-up US illustrated no residual stenosis (Fig. 3). A CAT scan 5 months later showed a dramatic improvement in the appearance of her liver (Fig. 4). As for her anemia, it was believed to be secondary to her menses and corrected nicely with iron supplementation. Budd-Chiari syndrome (BCS) occurs as a result of PH from hepatic venous outflow obstruction, usually from a hepatic vein thrombosis. Membranous webs can also rarely form in the hepatic venous system, eliciting the same organic response. Venous thrombosis can require pharmacologic thrombolysis and even liver transplantation. However, BCS resulting from membranous web obstruction can be successfully treated with angioplasty and, sometimes, with stenting.

Abstract 1935: Potent anti-tumor effects of TIC10 require Foxo3a and TRAIL gene upregulation

Abstract TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that induces tumor-selective apoptosis and is currently being tested in clinical trials as an anti-tumor agent. Despite promising preclinical activity, recombinant human TRAIL suffers from efficacy-limiting properties such as short serum half-life, stability, cost, and limitations in delivery, e.g. to the central nervous system. We hypothesized that induction of the human TRAIL gene by small molecules may overcome these limitations of TRAIL-based protein therapy. A cell-based luciferase reporter screen using the human TRAIL promoter identified TIC10 as a p53-independent small molecule inducer of the TRAIL gene. TIC10 induces TRAIL on the surface of normal and tumor cells, in sera of non-tumor-bearing mice, and throughout the tumor microenvironment. Co-culture experiments suggest that TRAIL upregulation by normal cells can contribute to the anti-tumor response of TIC10 through a TRAIL-mediated bystander effect. TIC10-induced TRAIL causes tumor-specific and TRAIL-mediated cell death as indicated by inhibition of cytotoxic effects following TRAIL gene knockdown in vitro and in vivo. Expression profiling of TIC10-induced transcriptional changes revealed altered expression levels of Foxo3a target genes, including DR5. We found that TIC10 causes the nuclear translocation of Foxo3a, but not Foxo1, to upregulate TRAIL gene transcription as determined by chromatin-immunoprecipitation assays. Western blot analysis indicated that TIC10 potently inhibits the phosphorylation of Foxo3a at Ser253 and Ser294 that normally docks the transcription factor to 14-3-3 proteins in the cytosol. Dual inhibition of Akt and ERK by TIC10, by other individual small molecule kinase inhibitors in combination or targeted siRNA inhibited the phosphorylation of these critical serine residues and synergistically induced Foxo3a-dependent TRAIL and TRAIL-mediated cell death. TIC10 is a promising first-in-class anti-tumor agent with a broad range of anti-tumor effects in preclinical animal models including othrotopic GBM, immunocompetent lymphoma, xenografted colon, lung, or breast cancers, and exhibits synergy with taxanes as well as bevacizumab among other agents. TIC10 appears to have no measurable toxic effects in mice including evaluation of serum chemistries, liver function studies, LDH, tissue histology, weight of the animals or behavioral changes. We are pursuing the clinical translation of these important findings that indicate a favorable and wide therapeutic index for a novel anti-tumor agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1935. doi:1538-7445.AM2012-1935

Nutmeg Liver and Ascites Resulting from a Membranous Web Obstruction at the Hepatic Origin of the Inferior Vena Cava

Purpose: A 30 year old female presented to the hospital for evaluation of anemia found on outpatient blood work along with complaints of intermittent abdominal distention. Laboratory studies revealed a profound iron deficiency anemia with a hemoglobin of 6.8, MCV of 62, and a ferritin of 3. On physical exam, she was found to have hepatomegaly and moderate ascites. She was heme negative on rectal exam. An EGD and colonoscopy were unremarkable for a source of blood loss, and small bowel biopsies were not consistent with celiac sprue. To further evaluate her liver, an ultrasound was performed, revealing moderate ascites and hepatosplenomegaly. The liver had a lobular contour to it with increased echogenicity. A subsequent CAT scan of the abdomen and pelvis illustrated a “nutmeg liver” and a large amount of ascites.(Fig 1) A repeat ultrasound with Doppler showed patent hepatic and portal veins with normal direction of flow. Her liver function studies were all within normal limits and hepatitis serologies, ANA, and EBV titers were all negative. The ascitic fluid was sampled with a diagnostic paracentesis. The fluid revealed a SAAG of >1.1 and a protein of <2.5, consistent with portal hypertension. Hepatic venous pressures were performed by interventional radiology (IR) to help determine the etiology of the patient's liver disease. The intrahepatic pressure was elevated to 14 mmHg and the right heart pressure was normal at 4 mmHg; yielding a 10 mmHg venous pressure gradient between the infra- and intrahepatic portion of the inferior vena cava (IVC). This prompted a third ultrasound in IR, demonstrating a web and turbulent flow at the origin of the hepatic veins from the IVC. A few days later, IR executed a successful angioplasty of the web with a 12 mm x 4 cm balloon. (Fig 2) The pressure gradient dropped to 4 mmHg following the breaking of the web. The patient recovered nicely, with resolution of her ascites and symptomatic improvement. She underwent a follow up ultrasound 1 month after her procedure that illustrated no significant residual stenosis and a decrease in hepatomegaly.Figure 1Figure 2

Amebic Liver Abscess: Fourteen Years Later

Purpose: A 41 year old Mexican American male presented to the hospital with fevers, chills, and headaches for two days. He denied any history of GI or liver disease. He used occasional NSAIDs for pain. He immigrated to the United States from Mexico 14 years ago and has not traveled outside of the country since immigration. He denied recent or remote contact with anyone with GI or liver disorders. Physical exam revealed a febrile male, with icteric sclera and hepatomegaly. Pertinent initial lab tests include neutrophilic leukocytosis and abnormal liver function studies (Total Bili 4.4, Direct Bili 1.8, ALT 261, AST 286 and Alk phos 261). Abdominal Ultrasound showed a 4 x 5 cm heterogeneous hypoechoic mass within the right hepatic lobe. MRI of the liver confirmed the peripherally enhancing lesion with areas of low signal intensity, suspicious for abscess. He was started empirically on metronidazole and levofloxacin. Within 48 hours, he was afebrile, LFT had normalized and leukocytosis improved. CT-guided FNA and core needle biopsy were obtained. The aspirate was thick and maroon colored and showed necrotic debris and inflammatory cells with eosinophilic infiltrate consistent with an abscess or inflammatory process. H&E and trichrome stain revealed structures suspicious for vegetative forms of amoeba. Serum amebiasis antibody test was positive. CT scan, obtained 13 days after MRI, showed a mild decrease in size of the abscess. He was asymptomatic on follow-up, three weeks after discharge. We present an unusual case of amebic liver abscess in a Mexican American male, who has not resided in an endemic area in 14 years. Approximately 10 percent of the world's population has amebiasis. Although prevalent worldwide, amebiasis is rare in the U.S. Hepatic abscess is the most common extraintestinal manifestation associated with invasive amebiasis. Patients with an amebic liver abscess typically present with RUQ pain and fever. Aspiration should be performed if imaging and serological studies are inconclusive. The mainstay of therapy is metronidazole followed by a luminal agent to ensure eradication. Awareness that amebic infections can occur without recent travel to endemic areas may lead to early diagnosis and treatment thereby reducing morbidity and mortality associated with this condition.Figure: No Caption available.

Nuclear medicine hepatobiliary imaging (cholescintigraphy)

Nuclear medicine hepatobiliary imaging (cholescintigraphy)

Characterization of Kupffer cells in livers of developing mice

BackgroundKupffer cells are well known macrophages of the liver, however, the developmental characteristics of Kupffer cells in mice are not well understood. To clarify this matter, the characteristics of Kupffer macrophages in normal developing mouse liver were studied using light microscopy and immunocytochemistry.MethodsSections of liver tissue from early postnatal mice were prepared using immunocytochemical techniques. The Kupffer cells were identified by their immunoreactivity to the F4/80 antibody, whereas endothelial cells were labelled with the CD-34 antibody. In addition, Kupffer cells and endothelial cells were labelled by systemically injected fluorescently labelled latex microspheres. Tissue slices were examined by fluorescence microscopy.ResultsIntravenous or intraperitonal injections of microspheres yielded similar patterns of liver cell labelling. The F4/80 positive Kupffer cells were labelled with both large (0.2 μm) and small (0.02 μm) diameter microspheres, while endothelial cells were labelled only with the smaller diameter microspheres. Microsphere labelling of Kupffer cells appeared stable for at least 6 weeks. Cells immunoreactive for F4/80 were identified as early as postnatal day 0, and these cells also displayed uptake of microspheres. Numbers of F4/80 Kupffer cells, relative to numbers of albumin positive hepatocytes, did not show a significant trend over the first 2 postnatal weeks.ConclusionsKupffer cells of the developing mouse liver appear quite similar to those of other mammalian species, confirming that the mouse presents a useful animal model for studies of liver macrophage developmental structure and function.

Acute spinal subarachnoid haematoma following spinal anaesthesia treated conservatively: case report

Acute spinal subarachnoid haematoma following spinal anaesthesia treated conservatively: case report

Prospective Study Evaluating Use of Traditional Chinese Medicine to Treat Refractory Cytopenia(s) In Chronic Hematological Disorders - Safety, Efficacy and Impact on Quality of Life

AbstractAbstract 4764 IntroductionThe use of Traditional Chinese Herbs (TCM) to treat disease or improve outlook is common among patients in Singapore particularly in situations where they have failed to respond favorably to Western medicines. As TCM and Western medicine practices are not integrated, patients seek such services separately. Being herbal in origin, TCM is generally considered safe and no monitoring of biochemical or hematological parameters is mandated. Current data suggest no significant drug-herb interactions except possibly for drugs which are highly protein bound or have narrow therapeutic range but studies in this area are lacking. We undertook a study to investigate the safety, efficacy and impact on quality of life (QoL) of TCM in patients with refractory cytopenia(s) due to primary hematological disorders. MethodsAll patients had chronic acquired hematological diseases and stable but significant cytopenia(s) that had failed standard therapies or where no effective therapies were available. The duration of study was 6 months and during this period they were supplied prebrewed sealed packs of 160ml liquid of TCM herbal concoctions twice daily, prepared at central facilities. Patients were categorized into 1 of 4 fixed TCM syndromes as assessed by TCM specialist on basis of TCM principles and published criteria. The herbal concoction comprised of a varying mixture of 12–18 herbs depending on the patient's syndrome and response. One week after starting TCM and subsequently monthly evaluation of blood counts, liver and renal function studies were performed. For MDS and myelofibrosis patients, QoL was assessed with EORTC QLQ-C30 at beginning and end of study. Response criteria were based on - International Working Group Criteria for MDS, European Myelofibrosis Network and as recommended by Camitta for severe aplastic anemia (SAA). ResultsThe only significant adverse effect noted was development of hyperkalemia in 2 patients. Of 7 patients on study who were on ACE inhibitors or Angiotensin II receptor blockers (ARB), 2 developed hyperkalemia in absence of deteriorating renal function. Both patients had diabetic nephropathy. Hyperkalemia resolved upon stopping TCM. DiscussionTo date, hyperkalemia has not been reported with TCM use either alone or as herb-drug interaction. Further studies with larger patient numbers would be useful to confirm and possibly to define the herb component giving rise to this effect which we postulate could be due to herb-drug interaction. We recommend serum potassium monitoring in patients with diabetic nephropathy on ACE inhibitors or ARB who are taking TCM. Based on pre and post study EORTC QLQ-C30 QoL assessments of 15 MDS and myelofibrosis patients who completed study, significant improvements (moderate and very much) were noted in functional scale in 66%, symptom scale in 40% and global health status in 46%. This was despite the fact that only 4/15 (26%) of patients experienced hematological responses. Our study suggests a potential role of TCM in patient care to enhance quality of life and also therapeutically. Disclosures:No relevant conflicts of interest to declare.

Effects of Varespladib Methyl on Biomarkers and Major Cardiovascular Events in Acute Coronary Syndrome Patients

The purpose of this study was to investigate the effects of varespladib on cardiovascular biomarkers in acute coronary syndrome patients. Secretory phospholipase A(2) (sPLA(2)) represents a family of proatherogenic enzymes that hydrolyze lipoprotein phospholipids, increasing their affinity for intimal proteoglycans; contribute to cholesterol loading of macrophages by nonscavenger receptor mediated pathways; and activate inflammatory pathways. In prospective studies, high sPLA(2)-IIA levels predicted major adverse cardiovascular events in acute coronary syndrome (ACS) and stable coronary heart disease patients. This randomized, double-blind, prospective controlled clinical trial (phase 2B) was designed to investigate the effects of sPLA(2) inhibition with varespladib 500 mg daily versus placebo as adjunctive therapy to atorvastatin 80 mg daily on biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP], and sPLA(2)-IIA levels), major adverse cardiovascular events (unstable angina, myocardial infarction, death), and safety. In all, 625 ACS subjects were randomized within 96 h of the index event and treated for a minimum of 6 months. After 8 weeks (primary efficacy end point), varespladib/atorvastatin reduced mean LDL-C levels from baseline by 49.6% compared with 43.4% with placebo/atorvastatin (p = 0.002). Respective 8-week median reductions in sPLA(2)-IIA levels were 82.4% and 15.6% (p < 0.0001), and hsCRP levels were lowered by 75.0% and 71.0% (p = 0.097). At 24 weeks, respective reductions with varespladib and placebo were as follows: LDL-C 43.5% versus 37.6% (p < 0.05), hsCRP 79.8% versus 77.0% (p = 0.02), and sPLA(2)-IIA 78.5% versus 6.4% (p < 0.0001). Major adverse cardiovascular events were not different from placebo 6 months post-randomization (7.3% varespladib vs. 7.7% placebo). No treatment differences in elevated liver function studies on >1 occasion were observed. Varespladib therapy effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional therapy including atorvastatin 80 mg daily. There were no treatment differences in clinical cardiovascular events. (FRANCIS [Fewer Recurrent Acute Coronary Events With Near-Term Cardiovascular Inflammation Suppression]-ACS Trial: A Study of the Safety and Efficacy of A 002 in Subjects With Acute Coronary Syndromes; NCT00743925).