Radiofrequency ablation of liver tumors - A systematic review

Objectives: To systematically review radiofrequency ablation (RFA) for treating liver tumors. Data Sources: Databases were searched in July 2003. Study Selection: Studies comparing RFA with other therapies for hepatocellular carcinoma (HCC) and colorectal liver metastases (CLM) plus selected case series for CLM. Data Extraction: One researcher used standardized data extraction tables developed before the study, and these were checked by a second researcher. Data Synthesis: For HCC, 1.3 comparative studies were included, 4 of which were randomized, controlled trials. For CLM, 13 studies were included, 2 of which were nonrandomized comparative studies and 11 that were case series. There did not seem to be any distinct differences in the complication rates between RFA and any of the other procedures for treatment of HCC. The local recurrence rate at 2 years showed a statistically significant benefit for RFA over percutaneous ethanol injection for treatment of HCC (6% vs 26%, 1 randomized, controlled trial). Local recurrence was reported to be more common after RFA than after laser-induced thermotherapy, and a higher recurrence rate and a shorter time to recurrence were dassociated with RFA compared with surgical resection (1 nonrandomized study each). For CLM, the postoperative complication rate ranged from 0% to 33% (3 case series). Survival after diagnosis was shorter in the CLM group treated with RFA than in the surgical resection group (1 nonrandomized study). The CLM local recurrence rate after RFA ranged from 4% to 55% (6 case series). Conclusions: Radiofrequency ablation may be more effective than other treatments in terms of less recurrence of HCC and may be as sale, although the evidence is scant. There was not enough evidence to determine the safety or efficacy of RFA for treatment of CLM.

Recurrent ischemic colitis in a patient with leiden factor V mutation and systemic lupus erythematous with antiphospholipid syndrome

Ischemic colitis results from insufficient blood supply to the large intestine and is often associated with hypercoagulable states. The condition comprises a wide range presenting with mild to fulminant forms. Diagnosis remains difficult because these patients may present with non-specific abdominal symptoms. We report a 51- year-old female patient with known Leiden factor V mutation as well as systemic lupus erythematous along with antiphospholipid syndrome suffering from recurrent ischemic colitis. At admission, the patient complained about abdominal pain, diarrhea and rectal bleeding lasting for 24 hours. Laboratory tests showed an increased C-reactive protein (29.5 mg/dl), while the performed abdominal CT-scan revealed only a dilatation of the descending colon along with a thickening of the bowel wall. Laparotomy was performed showing an ischemic colon and massive peritonitis. Histological examination proved the suspected ischemic colitis. Consecutively, an anti-coagulation therapy with coumarin and aspirin 100 was initiated. Up to the time point of a follow up examination no further ischemic events had occurred. This case illustrates well the non-specific clinical presentation of ischemic colitis. A high index of suspicion, recognition of risk factors and a history of non-specific abdominal symptoms should alert the clinicians to the possibility of ischemic disease. Early diagnosis and initiation of anticoagulation therapy or surgical intervention in case of peritonitis are the major goals of therapy.

Comparison of denture microwave disinfection and conventional antifungal therapy in the treatment of denture stomatitis: a randomized clinical study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Pre-therapy inflammation and coagulation activation and long-term CD4 count responses to the initiation of antiretroviral therapy

OBJECTIVES Pre-antiretroviral therapy (ART) inflammation and coagulation activation predict clinical outcomes in HIV-positive individuals. We assessed whether pre-ART inflammatory marker levels predicted the CD4 count response to ART. METHODS Analyses were based on data from the Strategic Management of Antiretroviral Therapy (SMART) trial, an international trial evaluating continuous vs. interrupted ART, and the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, evaluating three first-line ART regimens with at least two drug classes. For this analysis, participants had to be ART-naïve or off ART at randomization and (re)starting ART and have C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer measured pre-ART. Using random effects linear models, we assessed the association between each of the biomarker levels, categorized as quartiles, and change in CD4 count from ART initiation to 24 months post-ART. Analyses adjusted for CD4 count at ART initiation (baseline), study arm, follow-up time and other known confounders. RESULTS Overall, 1084 individuals [659 from SMART (26% ART naïve) and 425 from FIRST] met the eligibility criteria, providing 8264 CD4 count measurements. Seventy-five per cent of individuals were male with the mean age of 42 years. The median (interquartile range) baseline CD4 counts were 416 (350-530) and 100 (22-300) cells/μL in SMART and FIRST, respectively. All of the biomarkers were inversely associated with baseline CD4 count in FIRST but not in SMART. In adjusted models, there was no clear relationship between changing biomarker levels and mean change in CD4 count post-ART (P for trend: CRP, P = 0.97; IL-6, P = 0.25; and D-dimer, P = 0.29). CONCLUSIONS Pre-ART inflammation and coagulation activation do not predict CD4 count response to ART and appear to influence the risk of clinical outcomes through other mechanisms than blunting long-term CD4 count gain.

Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level:: The Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study.

BACKGROUND Rivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk-benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. METHODS Prospective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow-up. RESULTS We enrolled 537 patients (73±11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2±1.3 and 2.4±1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naïve (VN-group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6±1.4 under VKA to 5.5±0.8 points (P<0.001), and overall physician satisfaction from 3.9±1.3 to 5.4±0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4±0.9) and physician's satisfaction (5.5±0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01-1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05-1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03-3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. CONCLUSION Initiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction.

Complications of perioperative warfarin therapy in total knee arthroplasty

Patients presenting for knee replacement on warfarin for medical reasons often require higher levels of anticoagulation peri-operatively than primary thromboprophylaxis and may require bridging therapy with heparin. We performed a retrospective case control study on 149 consecutive primary knee arthroplasty patients to investigate whether anti-coagulation affected short-term outcomes. Specific outcome measures indicated significant increases in prolonged wound drainage (26.8% of cases vs 7.3% of controls, p<0.001); superficial infection (16.8% vs 3.3%, p<0.001); deep infection (6.0% vs 0%, p<0.001); return-to-theatre for washout (4.7% vs 0.7%, p=0.004); and revision (4.7% vs 0.3%, p=0.001). Management of patients on long-term warfarin therapy following TKR is particularly challenging, as the surgeon must balance risk of thromboembolism against post-operative complications on an individual patient basis in order to optimise outcomes.

Postoperative Volume Therapy in Cardiac Surgery : Effects on Hemostatic and Circulatory Variables

Background: Patients may need massive volume-replacement therapy after cardiac surgery because of large fluid transfer perioperatively, and the use of cardiopulmonary bypass. Hemodynamic stability is better maintained with colloids than crystalloids but colloids have more adverse effects such as coagulation disturbances and impairment of renal function than do crystalloids. The present study examined the effects of modern hydroxyethyl starch (HES) and gelatin solutions on blood coagulation and hemodynamics. The mechanism by which colloids disturb blood coagulation was investigated by thromboelastometry (TEM) after cardiac surgery and in vitro by use of experimental hemodilution. Materials and methods: Ninety patients scheduled for elective primary cardiac surgery (Studies I, II, IV, V), and twelve healthy volunteers (Study III) were included in this study. After admission to the cardiac surgical intensive care unit (ICU), patients were randomized to receive different doses of HES 130/0.4, HES 200/0.5, or 4% albumin solutions. Ringer’s acetate or albumin solutions served as controls. Coagulation was assessed by TEM, and hemodynamic measurements were based on thermodilutionally measured cardiac index (CI). Results: HES and gelatin solutions impaired whole blood coagulation similarly as measured by TEM even at a small dose of 7 mL/kg. These solutions reduced clot strength and prolonged clot formation time. These effects were more pronounced with increasing doses of colloids. Neither albumin nor Ringer’s acetate solution disturbed blood coagulation significantly. Coagulation disturbances after infusion of HES or gelatin solutions were clinically slight, and postoperative blood loss was comparable with that of Ringer’s acetate or albumin solutions. Both single and multiple doses of all the colloids increased CI postoperatively, and this effect was dose-dependent. Ringer’s acetate had no effect on CI. At a small dose (7 mL/kg), the effect of gelatin on CI was comparable with that of Ringer’s acetate and significantly less than that of HES 130/0.4 (Study V). However, when the dose was increased to 14 and 21 mL/kg, the hemodynamic effect of gelatin rose and became comparable with that of HES 130/0.4. Conclusions: After cardiac surgery, HES and gelatin solutions impaired clot strength in a dose-dependent manner. The potential mechanisms were interaction with fibrinogen and fibrin formation, resulting in decreased clot strength, and hemodilution. Although the use of HES and gelatin inhibited coagulation, postoperative bleeding on the first postoperative morning in all the study groups was similar. A single dose of HES solutions improved CI postoperatively more than did gelatin, albumin, or Ringer’s acetate. However, when administered in a repeated fashion, (cumulative dose of 14 mL/kg or more), no differences were evident between HES 130/0.4 and gelatin.

A novel adeno-associated virus serotype (AAV)-8 capsid mutant improves human coagulation factor IX expression in vivo

Recombinant AAV-8 vectors have shown significant promise for hepatic gene therapy of hemophilia B. However, the theme of AAV vector dose dependent immunotoxicity seen with AAV2 vectors earlier seem to re-emerge with AAV8 vectors as well. It is therefore important to develop novel AAV8 vectors that provide enhanced gene expression at significantly less vector doses. We hypothesized that AAV8 during its intracellular trafficking, are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal degradation machinery and modification of specific serine/threonine kinase or ubiquitination targets on AAV8 capsid (Fig.1A) may improve its transduction efficiency. To test this, point mutations at specific serine (S)/threonine (T) > alanine (A) or lysine (K)>arginine (R) residues were generated on AAV8 capsid. scAAV8-EGFP vectors containing the wild-type (WT) and each one of the 5 S/T/K-mutant(S276A, S501A, S671A, T251A and K137R) capsids were evaluated for their liver transduction efficiency at a dose of 5 X 1010 vgs/ animal in C57BL/6 mice in vivo. The best performing mutant was found to be the K137R vector in terms of either the gene expression (46-fold) or the vector copy numbers in the hepatocytes (22-fold) compared to WT-AAV8 (Fig.1B). The K137R-AAV8 vector that showed significantly decreased ubiquitination of the viral capsid had reduced activation of markers of innate immune response [IL-6, IL-12, tumor necrosis factor α, Kupffer cells and TLR-9]. In addition, animals injected with the K137R mutant also demonstrated decreased (2-fold) levels of cross-neutralizing antibodies when compared to animals that received the WT-AAV8 vector. To study further the utility of the novel AAV8-K137R mutant in a therapeutic setting, we delivered human coagulation factor IX (h.FIX) under the control of liver specific promoters (LP1 or hAAT) at two different doses (2.5x10^10 and 1x10^11 vgs per mouse) in 8-12 weeks old male C57BL/6 mice. As can be seen in Fig.1C/D, the circulating levels of h.FIX were higher in all the K137R-AAV8 treated groups as compared to the WT-AAV8 treated groups either at 2 weeks (62% vs 37% for hAAT constructs and 47% vs 21% for LP1 constructs) or 4 weeks (78% vs 56% for hAAT constructs and 64% vs 30% for LP1 constructs) post hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel vector for potential gene therapy of hemophilia B.

Mesenchymal stem cell therapy for the treatment of myocardial infarction

Mesenchymal stem cells (MSCs) are currently under investigation as repair agents in the preservation of cardiac function following myocardial infarction (MI). However concerns have emerged regarding the safety of acute intracoronary (IC) MSC delivery specifically related to mortality, micro-infarction and microvascular flow restriction post cell therapy in animal models. This thesis aimed to firstly identify an optimal dose of MSC that could be tolerated when delivered via the coronary artery in a porcine model of acute MI (AMI). Initial dosing studies identified 25x106 MSC to be a safe MSC cell dose, however, angiographic observations from these studies recognised that on delivery of MSC there was a significant adverse decrease in distal blood flow within the artery. This observation along with additional supportive data in the literature (published during the course of this thesis) suggested MSC may be contributing to such adverse events through the propagation of thrombosis. Therefore further studies aimed to investigate the innate prothrombotic activity of MSC. Expression of the initiator of the coagulation cascade initiator tissue factor (TF) on MSC was detected in high levels on the surface of these cells. MSC-derived TF antigen was catalytically active, capable of supporting thrombin generation in vitro and enhancing platelet-driven thrombus deposition on collagen under flow. Infusion of MSC via IC route was associated with a decreased coronary flow reserve when delivered but not when coadministered with an antithrombin agent heparin. Heparin also reduced MSC-associated in situ thrombosis incorporating platelets and VWF in the microvasculature. Heparin-assisted MSC delivery reduced acute apoptosis and significantly improved infarct size, left ventricular ejection fraction, LV volumes, wall motion and scar formation at 6 weeks post AMI. In addition, this thesis investigated the paracrine factors secreted by MSC, in particular focusing on the effect on cardiac repair of a novel MSC-paracrine factor SPARCL1. In summary this work provides new insight into the mechanism by which MSC may be deleterious when delivered by an IC route and a means of abrogating this effect. Moreover we present new data on the MSC secretome with elucidation of the challenges encountered using a single paracrine factor cardiac repair strategy.

Liver-directed lentiviral gene therapy in a dog model of hemophilia B

We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia.

Effects of isoflavones on the coagulation and fibrinolytic system of postmenopausal women

Objective: We evaluated the effects of soy isoflavone supplementation on hemostasis in healthy postmenopausal women. Methods: In this double-blinded, placebo-controlled study, 47 postmenopausal women 47-66 y of age received 40 mg of soy isoflavone (n = 25) or 40 mg of casein placebo (n = 22) once a day for 6 mo. Levels of factors VII and X. fibrinogen, thrombin-antithrombin complex, prothrombin fragments I plus 2, antithrombin, protein C, total and free protein S, plasminogen, plasminogen activator inhibitor-1, and D-dimers were measured at baseline and 6 mo. Urinary isoflavone concentrations (genistein and daidzein) were measured as a marker of compliance and absorption using high-performance liquid chromatography. Baseline characteristics were compared by unpaired Student`s t test. Within-group changes and comparison between the isoflavone and casein placebo groups were determined by a mixed effects model. Results: The levels of hemostatic variables did not change significantly throughout the study in the isoflavone group; however, the isoflavone group showed a statistically significant reduction in plasma concentration of prothrombin fragments I plus 2; both groups showed a statistically significant reduction in antithrombin, protein C, and free protein S levels. A significant increase in D-dimers was observed only in the isoflavone group. Plasminogen activator inhibitor-l levels increased significantly in the placebo group. However, these changes were not statistically different between groups. Conclusion: The results of the present study do not support a biologically significant estrogenic effect of soy isoflavone on coagulation and fibrinolysis in postmenopausal women. However, further research will be necessary to definitively assess the safety and efficacy of isoflavone. (D 2008 Elsevier Inc. All rights reserved.

Procoagulant state after raloxifene therapy in postmenopausal women

AZEVEDO, George Dantas de et al. Procoagulant state after raloxifene therapy in postmenopausal women. Fertility and Sterility, Estados Unidos, v.84, n.6, p.1680-1684, 2005

Effectiveness of microwave disinfection of complete dentures on the treatment of Candida-related denture stomatitis

The effectiveness of microwave disinfection of maxillary complete dentures on the treatment of Candida-related denture stomatitis was evaluated. Patients (n = 60) were randomly assigned to one of four treatment groups of 15 subjects each; Control group: patients performed the routine denture care; Mw group: patients had their upper denture microwaved (650 W per 6 min) three times per week for 30 days; group MwMz: patients received the treatment of Mw group in conjunction with topical application of miconazole three times per day for 30 days; group Mz: patients received the antifungal therapy of group MwMz. Cytological smears and mycological cultures were taken from the dentures and the palates of all patients before treatment at day 15 and 30 of treatment and at follow-up (days 60 and 90). The effectiveness of the treatments was evaluated by Kruskal-Wallis and Mann-Whitney tests. Microbial and clinical analysis of the control group demonstrated no significant decrease in the candidal infection over the clinical trial. Smears and cultures of palates and dentures of the groups Mw and MwMz exhibited absence of Candida at day 15 and 30 of treatment. on day 60 and 90, few mycelial forms were observed on 11 denture smears (36.6%) from groups Mw and MwMz, but not on the palatal smears. Miconazole (group Mz) neither caused significant reduction of palatal inflammation nor eradicated Candida from the dentures and palates. Microwaving dentures was effective for the treatment of denture stomatitis. The recurrence of Candida on microwaved dentures at follow-up was dramatically reduced.