Breakthrough Research Articles

Risk factors and outcome for breakthrough candidaemia in patients with cancer

While candidaemia that develops during systemic antifungal prophylaxis or therapy [breakthrough (BT) candidaemia] has been reported increasingly, the risk factors and outcome of BT candidaemia are not yet known definitely. We evaluated a consecutive series of cancer patients with candidaemia at Asan Medical Center during 6 years to identify risk factors and outcome in BT candidaemia comparing with non-BT candidaemia. Fifty-four episodes of candidaemia in cancer patients diagnosed during this period were reviewed retrospectively. There were 10 episodes (18.5%) of BT candidaemia in which the species distribution and frequency of catheter-related infection in the BT and non-BT groups were similar. BT candidaemia had a tendency to occur more frequently in patients with haematological than non-haematological diseases. Profound neutropenia and disseminated candidiasis were more common in the BT group; however, these differences were not statistically significant (P = 0.17 and 0.07 respectively). The duration of prior antibiotic therapy and duration of profound neutropenia (<100 mm(-3)) were identified as risk factors for BT candidaemia (P < 0.01 and 0.02 respectively) in univariate analysis and the latter was the only risk factor in multivariate analysis. The death rates due to candidaemia were 85.7% in the BT group and 42.9% in the non-BT group (P = 0.08); however, BT candidaemia alone did not increase mortality rate.

Analysis of HCV co-infection with occult hepatitis B virus in patients undergoing IFN therapy

Occult hepatitis B virus (HBV) infection is characterized by the presence of HBV DNA in the absence of hepatitis B surface antigen (HBsAg) in the patient serum. Although such infections have been identified in patients with chronic hepatitis C, the clinical significance of those co-infections is still not understood. Our aim was, therefore, to assess the prevalence and clinical consequences of occult HBV infection in chronic hepatitis C patients undergoing antiviral therapy. The study population consisted of 53 HBsAg-negative patients with chronic hepatitis C treated with IFN/ribavirin or IFN/ribavirin/amantadine. Nine patients experienced a viral breakthrough (BT), 30 were non-responders (NR) and 14 were responders (R). HBV-DNA detection by PCR was performed using primers specific for the S region of the HBV genome and HCV-RNA detection by PCR with primers localised in both the 5'NC and core region of HCV genome, before, during and after treatment. Viral genome sequences were also studied. Occult HBV genomes were found in the serum of four of 53 (7.5%) patients, unrelated to anti-HBc status. No significant differences in biochemical, virological, or histological markers, age, duration of infection, were observed in patients with or without HBV DNA. There was an inverse correlation in the evolution of HBV DNA and HCV RNA levels. Direct sequencing showed that S gene of occult HBV presented mutations in the "a" determinant while no specific mutation in the core region of HCV was observed. None of the four patients co-infected with HBV and HCV were responders to anti-HCV therapy. In our clinical setting, the prevalence of occult HBV co-infection among patients with chronic hepatitis C was low and independent of the presence of markers of previous HBV infection. Further studies in larger cohort of patients are warranted to determine if occult HBV co-infection may be involved in HCV resistance to combination therapy.

Comparison of the adsorption dynamics of air on zeolite 5A and carbon molecular sieve beds

Adsorption and desorption in zeolite 5A and CMS beds were compared by using a ternary mixture (N 2/ O2/Ar; 78 : 21 : 1 vol%). Because the breakthrough curves for both beds show a tail by temperature variance, a non- isothermal mathematical model was applied to the simulation of adsorption dynamics. The LDF model with a constant rate parameter was enough to predict the experimental brea kthrough and temperature curves of an equilibrium separa- tion bed, while the modified LDF model with a concentrati on-dependent parameter should be applied to a kinetic sep- aration bed. In the CMS bed initially saturated with He, Ar was the first breakthrough component with N 2 following after a short interval. Then, after a long interval, the breakthrough of O 2 occurred with a broad roll-up due to its fast diffusion rate and the relative ly slow diffusion rate of N 2. In the CMS bed initially saturated with O 2, the breakthrough curves of O2 and N2 showed a very broad shape because of the slow diffusion of N 2 into CMS. In the zeolite 5A bed, the breakthrough time sequence was Ar, O2, and N2 at very close time intervals. After the sharp roll-ups of O 2 and Ar, the variation of the breakthrough curves was negligible. The in flection of the temperature profile in the zeolite 5A bed was caused by the crossover of the O 2 and N2 MTZs, while in the CMS bed it was caused by the difference in the diffu- sion rates of O2 and N2.

Empirical Antifungal Therapy (Rx) with Caspofungin (CAS) vs Liposomal Amphotericin B (L-AmB) for Persistently Febrile Neutropenic Patients (Pts) with Acute Myeloid Leukemia (AML).

Background: In a double-blind randomized trial of empirical antifungal Rx for persistently febrile neutropenic pts, CAS was as effective as and better tolerated than L-AmB. We now examine the results of this study in the subgroup of pts with AML.Methods: Randomization to CAS (70 mg x 1, then 50 mg/d) or L-AmB (3 mg/kg/d) was stratified by risk category [high risk = allogeneic hematopoietic stem cell transplant or relapsed acute leukemia] and use of antifungal prophylaxis. The primary efficacy endpoint was % of treated pts with documented fever and neutropenia who had a successful outcome defined by all the following: successful Rx of baseline (BL) invasive fungal infection (IFI) (if any), no breakthrough (BT) IFI to 7 d post-Rx, survival @7d post-Rx, no premature discontinuation (DC) due to lack of efficacy or study drug toxicity, and fever resolution x 48 hr during neutropenia.Results: 703/1095 (64%) of the treated pts had AML, including 364/556 (65%) and 339/539 (63%) in the CAS and L-AmB groups, respectively. Demographic characteristics were similar in AML pts in both Rx groups. 27% of CAS and 22% of L-AmB pts with AML were high risk. Median days of Rx were: CAS, 12; L-AmB, 11. The table shows % AML pts with a successful outcome by Rx group.% AML pts with a successful outcome by Rx groupCAS (N=364)L-AmB (N=339)Difference (CAS - L-AmB)95% CI for difference between treatment groupsSuccess Rx of BL IFI †503119(−16, 53)No BT IFI9395−2(−5, 2)Suvival @ 7d post-Rx92884(0, 8)No premature DC87862(−3, 7)Fever resolution48462(−5, 9)All of the above40382(−5, 10)† 7/14 CAS and 5/16 L-AmB pts had successful Rx of BL IFI.The composite success rates for the high risk AML pts were 46/99 (46%) for CAS and 31/76 (41%) for L-AmB.Conclusions: In this post hoc subgroup analysis, CAS provided an effective and generally well-tolerated option for the empirical Rx of persistently febrile neutropenic pts with AML.

Does cardiac pacing reproduce the mechanism of focal impulse initiation?

Stimulation of myocardium by either a native pacemaker or an artificial stimulus requires the initiation of a self-propagating wave of depolarization originating from the site of initial activation. In the present study we perform artificial stimulation at a site of focal discharge with the aim to compare the two mechanisms of impulse formation. High resolution epicardial mapping in senescent rat hearts provided examples of focal discharge during sinus rhythm at a single epicardial breakthrough (BKT) point emerging from an isolated Purkinje-ventricular muscle junction (PMJ) site. Stimulation was also performed at the same BKT point and potential distributions recorded during spontaneous and artificial stimulation were compared. During excitation latency, the negative potential pattern was elongated perpendicularly to fiber direction at both pacing and BKT point, in agreement with virtual cathode membrane polarization predicted by the bidomain model during point stimulation. During impulse initiation, activation wave fronts were initially circular around pacing site or BKT point and then elongated along local fiber direction. The similarity between impulse initiation during focal discharge and point stimulation in cardiac muscle suggests that high resolution pace mapping studies can help to elucidate the mechanism of abnormal impulse formation.

Ion exchange and chromatographic separation of cesium, strontium and europium from acidic streams using uranium antimonate

Summary Ion exchange properties of cesium, strontium and europium on uranium antimonate (USb) from nitric acid medium was studied. The distribution coefficient (K d) of 1046 mL/g for cesium, 2464 mL/g for strontium and ∼105 mL/g for europium were obtained for sorption from 0.01 M nitric acid and K d decreased with increase in the concentration of nitric acid. Rapid sorption of metal ions in the initial stages of equilibration followed by the establishment of equilibrium after 24 hours. Cesium sorption on USb follows ideal ion exchange while strontium and europium do not. From Langmuir adsorption model for the sorption of these ions on USb, the apparent sorption capacity was found to be of 6.9 mg/g for cesium, 19.1 mg/g for strontium and 37.2 mg/g for europium at 300 K. The enthalpy change (ΔH°) accompanied by the sorption was determined by the temperature variation method. The performance of the sorbent under dynamic conditions was assessed by following a breakthrough (BT) curve up to C/C 0=1. Extraction chromatography of individual ions from the mixture using USb was also reported in this paper.

Ion Exchange Studies of Cerium (III) on Uranium Antimonate

Ion exchange of cerium on uranium antimonate (USb) from nitric acid medium was studied. The distribution coefficient of ~19,000 mL/g was obtained for ion exchange of cerium in 0.1 M nitric acid and it decreased with increase in the concentration of nitric acid. Rapid ion exchange of cerium in the initial stages of equilibration followed by the establishment of equilibrium occurs after one hour. Ion exchange data were fitted into both Langmuir and Freundlich adsorption models using non-linear regression. The enthalpy change accompanied by ion exchange of cerium was determined by the temperature variation method. The performance of the ion exchanger under dynamic condition was assessed by following a breakthrough (BT) curve and the BT curve was fitted using Thomas equation.

The impact of hydrochemical boundary conditions on the evolution of limestone karst aquifers

The early evolution of karst aquifers depends on a manifold of initial and boundary conditions such as geological setting, hydrologic properties of the initial aquifer, and petrologic properties of the rock. When all water entering at various inputs into the aquifer has equal chemical composition with respect to the system H 2O–CO 2–CaCO 3 early evolution under conditions of constant head exhibits breakthrough (BT) behaviour. If the chemical compositions of the input waters are different, deep in the aquifer where the saturated solutions mix renewed aggressiveness occurs, and additional dissolutional widening of fractures by mixing corrosion (MC) changes the hydrologic properties of the aquifer. To study the impact of MC on the evolution of karst we have modelled a simple karst aquifer consisting of a confined limestone bed, with two symmetrically located inputs at constant head and open flow conditions along the entire width at base level. To calculate dissolutional widening of the fractures the well-known dissolution kinetics of limestone was used, which is linear up to 90% of saturation with respect to calcite and then switches to a nonlinear fourth order rate law. First, two extremes are modelled: (a) Both inputs receive aggressive water of equal chemical composition with [Ca 2+]=0.75[Ca 2+] eq. In this case two channels migrate downstream with that from one input more competitive and reaching base level first, causing BT. (b) Water at both inputs is saturated with respect to calcite, but in equilibrium with different partial pressures of CO 2. Therefore, dissolution widening can occur only where these waters mix. A central channel starts to grow extending down-head until base level is reached. Flow rates through the aquifer first rise and become constant after the channel has reached base level. In the following runs these two extreme modes of karstification are combined. The waters entering have different chemical compositions and therefore different equilibrium concentrations [Ca 2+] eq. This allows MC to be active. They are also undersaturated with the inflowing solutions at concentration [Ca 2+] in= f[Ca 2+] eq where f is the ratio of saturation. In comparison to the extreme limit (a) the action of MC now creates permeability where the solutions mix and diverts the evolution of conduits into this region. Finally one conduit reaches base level and causes BT. This behaviour is found for f=0.7, 0.9, and 0.96. For solutions more close to equilibrium with respect to calcite ( f=0.99, 0.9925, and 0.995) BT behaviour is replaced by a steady increase in flow rates. In the early state as in the case of MC controlled evolution (case b) a central channel not connected to the input is created by MC and reaches base level. After this event, further increase in flow rates is caused by slow dissolutional widening by the slightly undersaturated input solutions flowing towards the central channel. Comparison of the various model aquifers at termination of the computer runs reveals significant differences in their properties caused solely by changes of the hydrochemical boundary conditions.

Tenofovir and HBV mutants after liver transplantation

Aim:Resistant HBV strains develops in approximately 30% of post liver transplant (LTx) recipients treated with lamivudine(LAM) within 2 years trom nine of transplantatinn. Adetbvir(ADV) has recently been reported to be ettective against mutants, however its use may be limited by nephrotoxicity. We report our experience with tenotbvir(TNV), another nudeotide analogue reverse transcriptase inhibitor, in LTx recipients developing I.AM resistanceMethods:8 pts developed resistance to LAM 10 to 85 mos (median: 26) post-kTx. TNV (300 mg/ day, P.O.) was added 1 to 66 mos after breakthrough (BT), and continued for 2 to 12 mos (mefflan: 4). Prior to receiving TNV, these paUents had been excluded from recewing ADV due to: age> 80 yo. (5), HIV co-infection (1), enhstment in another drug study (1) and potential non-compliance (1). Criteria for BT included elevation of liver chemistries along with reappearance of HBs~g, HBeAg and/or HBVDNA. HBV genotype and ~NIDD variants were identified through DNA sequence analysis prior to and after TNV; sequential HBVDNA levels were measured by hybridization (pts 2,4,6,7&8) or PCR (pts 1,3&5).Results:No adverse reactinn was associated with TNV, The tables below summarize the data pertaining the study pts.Condusion:This preliminary experience indicates that TNV markedly decreases rephcation of L4M-resiatant HBV variants post-kTx These results demonstrate anottaer potential option tbr tfie treatment of HBV L~.lvl resistance

Removal of cesium and strontium from acid solution using a composite of zirconium molybdate and zirconium tungstate

A composite mixture of zirconium molybdate and zirconium tungstate was prepared and studied for the sorption of cesium and strontium as a function of nitric acid, metal ion concentration, time and temperature. The distribution coefficient (Kd) of 7000 ml/g (~90% sorption) and 70 ml/g (~20% sorption) was obtained for the sorption of cesium and strontium in 0.1M nitric acid, respectively. Experimental sorption capacity, b for cesium was found to be 50 mg/g from 0.1M HNO3 and 30 mg/g for strontium from 0.001M nitric acid. The sorption of strontium on the sorbent was accompanied by the absorption of heat but the sorption of Cs+ results in the liberation of heat. Column studies were conducted by following a breakthrough (BT) curve of cesium and strontium up to C/C0=1 and the results are reported.

Risk factors and predictors of outcome in patients with cancer and breakthrough candidemia.

Hematogenous candidiasis adds substantially to the morbidity and mortality rates of patients with cancer. Little is known about the risk factors and outcome in patients with breakthrough (BT) candidemia while on systemic antifungal therapy. All 479 episodes of candidemia in 474 consecutive patients with candidemia that was diagnosed at M. D. Anderson Cancer Center from 1988 through 1992 were studied retrospectively. A total of 49 patients had BT candidemia, defined as candidemia that developed after at least 5 days of systemic antifungal therapy. Risk factors for BT candidemia and predictors of mortality were investigated. Multivariate analysis revealed that intensive care unit stay, neutropenia, use of corticosteroids, and duration of neutropenia as significant risk factors for BT candidemia. Seventy-six percent of patients with BT candidemia died, compared with 50% of patients with non-BT infection. In multivariate analysis, intensive care unit stay, being and remaining neutropenic, APACHE III score, and disseminated disease were independent prognostic factors. In conclusion, identification of risk factors and predictors of a poor outcome in patients with cancer with BT candidemia may have important implications in early diagnosis and appropriate therapy of these patients.

Purification of metal plating rinse waters with chelating ion exchangers

A wide range of chelating ion exchangers was tested for their abilities to remove Zn, Ni, Cu and Cd from solutions simulating waste effluents from the metal-plating industry. The task was to reduce metal discharges to the environment so that metal-plating shops could keep up with the modern, more stringent regulations of waste effluents. The resins were tested by batch and mini-column experiments. Decontamination factors (DFs) as high as 700 and capacities up to 3.3 meq/mL were measured at the 5% breakthrough (BT) point in mini-column tests. Complexing agents, especially cyanide, considerably reduced the performance of the resins with only a few exceptions. Ammonium seemed to improve the ion-exchange performance of some chelating resins and capacities higher than the theoretical values, given by the manufacturer, were measured. Comparative experiments between chelating, strong acid and weak acid ion-exchange resins showed that the advantage of chelating exchangers over strong and weak acid exchangers is a very low metal BT level, even as low as 2 μg/L, which is very important, especially in the end-of-pipe polishing.

Study of Bi-layer Silylation Process for 193 nm Lithography.

The top surface imaging (TSI) process has been studied in order to extend the limit of photolithography down to 0.10um or smaller dimensions using 193nm or shorter wavelengths(1)-(10). We have been evaluating a bi-layer silylation process as one of the approaches to improve the lithographic performance of the silylation process. In this paper, we focus on the line edge roughness (LER) of the bi-layer silylation process, which is thought to be one of the serious issues limiting the lithographic performance of the silylation process. We chiefly investigated the effect of process conditions and the silylation resist material itself, and found several factors affecting the LER, such as the silylation film thickness, pre-baking conditions, the break-through (BT) etching conditions and the amount of cross-linker used for the chemically amplified (CA) resist. After optimization of these factors, the pattern quality after the dry-development was remarkably improved. The 0.11um L/S patterns were well fabricated and the LER was improved.

An Intermediate Dose of Alpha-Recombinant Interferon-2a for Chronic Hepatitis C with Nonsevere Histological Pattern

In the light of recent research, which suggests an interferon (IFN) therapy schedule on the basis of single patient characteristics (e.g. histological pattern, viral genotype) and the cost/benefits of such therapy, we studied the efficacy and tolerability of an intermediate dose (4.5MU 3 times a week) of alpha-recombinant interferon-2a (α-r IFN-2a) in 28 patients with histologically proven chronic hepatitis C. 20 were hepatitis C virus (HCV)-RNA +ve, 5 were HCV-RNA −ve, and in 3 patients HCV-RNA status was not carried out. The viral genotypes were: 13 (65%) 1b, 2 (10%) 1a, 1 (5%) 1a + 1b, 3 (15%) 2a, 1 (5%) 3a; histological pattern: 21 (75%) mild chronic active hepatitis (CAH), 7 (25%) moderate CAH. 4.5MU of α-r IFN-2a were given 3 times a week for 6 months, followed by 3MU 3 times a week for 6 months. Six patients (21.4%) had a biochemical and virological sustained response (SR), 8 patients (28%) had ALT normalisation during therapy (transient complete response [TCR]) followed by relapse, 3 patients (10.7%) had a TCR with breakthrough (BT), 4 patients (14.3%) had a partial response (PR) and 7 patients (25%) were nonresponders (NR). We observed persistent HCV-RNA serum loss in all patients with SR, transient HCV-RNA serum loss in 8 patients with TCR, TCR with BT and PR; in 5 patients who were NR no HCV-RNA serum loss occurred. The prevalence of HCV genotype 1b and the duration of disease in SR and NR groups showed a significant difference. Moreover, we found a significant correlation between prevalence of HCV genotype 1b and type of response (r = 0.899, p < 0.05) between mean age in the different patient response groups and prevalence of HCV genotype 1b (r = 0.881, p < 0.05), and between disease duration and type of response (r = 0.874, p < 0.05). The schedule we used can be considered as well tolerated and efficacious at least in chronic hepatitis C with nonsevere histological pattern, with an HCV genotype other than 1b.