Percutaneous thermal ablation of primary and secondary lung tumors: Comparison between microwave and radiofrequency ablation.

PURPOSE: The purpose of this study was to retrospectively compare microwave (MWA) and radiofrequency (RFA) ablation in the percutaneous treatment of primary and secondary lung tumors. MATERIAL AND METHODS: A total of 115 patients with a total of 160 lung tumors (primary, n=41; secondary, n=119) were retrospectively included. There were 56 men and 59 women with a mean age of 67.8±12.7 (SD) years (range: 42-89 years) who underwent either MWA (61 patients; 79 tumors) or RFA (54 patients; 81 tumors). The primary study endpoints were local recurrence during follow-up and the incidence of complications during and following thermal ablation. The MWA and RFA groups were compared in terms of treatment efficacy and complication rates. RESULTS: Demographics were similar in the two groups. Mean tumor diameter was smaller in RFA group (13.1±5.1 [SD] mm; range: 4-27mm) than in MWA group (17.1±8.3 [SD] mm; range: 5-36mm) (P<0.001). Ablation volumes at one month were 24.1±21.7 (SD) cm3 (range: 2-97.8 cm3) in RFA group and 30.2±35.9 (SD) cm3 (range: 1.9-243.8 cm3) in MWA group (P=0.195). During a mean overall follow-up duration of 488±407 (SD) days (range: 30-1508 days), 9/160 tumors (5.6%) developed local recurrence: six (6/79; 7.6%) in the RFA group and three (3/81; 3.7%) in the MWA group (P=0.32). Pneumothoraces were more frequent in the RFA group (32/79; 40.5%) than in the MWA group (20/81; 24.7%) (P=0.049). The mean length of hospital stay was 4.5±3.7 (SD) days (range: 1-25 days) in the RFA group and 4.7±4.6 (SD) days (range: 2-25 days) in the MWA group (P=0.76). CONCLUSIONS: MWA favorably compares with RFA and can be considered as an effective and safe thermal ablation technique for lung tumors, especially in situations where RFA has limited efficacy.

Modified Appleby procedure for borderline resectable/locally advanced distal pancreatic adenocarcinoma: A major procedure for selected patients.

BACKGROUND: In distal pancreatic ductal adenocarcinoma (PDAC), distal pancreatectomy with en bloc splenectomy and celiac axis resection (DP-CAR) can allow curative resection in case of tumor extension to celiac axis. METHODS: From 2008 to 2013, of 102 patients with localized distal PDAC, 7 patients with celiac axis involvement were planned to undergo DP-CAR with curative intent. All patients received neoadjuvant treatment followed by preoperative coil embolization to enlarge collateral arterial pathways, except if a replaced right hepatic artery arising from superior mesenteric artery was present and sufficient for the blood supply. We herein analyzed indications, technique and outcomes of DP-CAR. RESULTS: After neoadjuvant treatment and arterial embolization, two patients experienced tumor progression and were not operated while five underwent DP-CAR. No patient required arterial reconstruction. Postoperative mortality was nil, but morbidity was 100%, mainly represented by pancreatic fistula. Postoperatively, there was a complete pain relief but chronic diarrhea was observed in all patients. Resections were R0 in three patients. One operated patient was alive and disease free at 60 months whereas median overall survival of patients who underwent resection was 24 months. CONCLUSIONS: DP-CAR for borderline resectable/locally advanced distal PDAC is associated with high morbidity and mixed long-term functional results. Neoadjuvant treatment may prevent from unnecessary surgery for patients with progressive disease and may facilitate resection with acceptable long-term survival.

Hepatic steatosis: a major trap in liver imaging.

Hepatic steatosis is a common condition, the prevalence of which is increasing along with non-alcoholic hepatic steatosis. In imaging, it can present in a typical homogeneous or heterogeneous way. Some forms create traps in imaging, whether localised steatosis is concerned or areas which have been spared by steatosis, and the purpose of this paper is to explain and illustrate them. The role of different imaging methods is described while emphasizing the importance of MRI.

Sulphide quinone reductase contributes to hydrogen sulphide metabolism in murine peripheral tissues but not in the CNS.

BACKGROUND AND PURPOSE: Hydrogen sulphide (H(2) S) is gaining acceptance as a gaseous signal molecule. However, mechanisms regarding signal termination are not understood. We used stigmatellin and antimycin A, inhibitors of sulphide quinone reductase (SQR), to test the hypothesis that the catabolism of H(2) S involves SQR. EXPERIMENTAL APPROACH: H(2) S production and consumption were determined in living and intact mouse brain, liver and colonic muscularis externa using gas chromatography and HPLC. Expressions of SQR, ethylmalonic encephalopathy 1 (Ethe1) and thiosulphate transferase (TST; rhodanese) were determined by RT-PCR and immunohistochemistry. KEY RESULTS: In the colonic muscularis externa, H(2) (35) S was catabolized to [(35) S]-thiosulphate and [(35) S]-sulphate, and stigmatellin reduced both the consumption of H(2) (35) S and formation of [(35) S]-thiosulphate. Stigmatellin also enhanced H(2) S release by the colonic muscularis externa. In the brain, catabolism of H(2) (35) S to [(35) S]-thiosulphate and [(35) S]-sulphate, which was stigmatellin-insensitive, partially accounted for H(2) (35) S consumption, while the remainder was captured as unidentified (35) S that was probably bound to proteins. Levels of mRNA encoding SQR were higher in the colonic muscularis externa and the liver than in the brain. CONCLUSIONS AND IMPLICATIONS: These data support the concept that termination of endogenous H(2) S signalling in the colonic muscularis externa occurs via catabolism to thiosulphate and sulphate partially via a mechanism involving SQR. In the brain, it appears that H(2) S signal termination occurs partially through protein sequestration and partially through catabolism not involving SQR. As H(2) S has beneficial effects in animal models of human disease, we suggest that selective inhibition of SQR is an attractive target for pharmaceutical development.

Factors for graft-versus-host disease after donor lymphocyte infusions with an escalating dose regimen: lack of association with cell dose.

We investigated the risk factors for graft-versus-host disease (GVHD) in 82 patients treated with donor lymphocyte infusions (DLI) using an escalating dose regimen for chronic myeloid leukaemia in relapse following conventional allografting. Two factors emerged as predictors of both acute and chronic GVHD: the infusion of male recipients with lymphocytes from a female donor and the interval between transplant and last DLI, but only the first remained significant at multivariate analysis. Surprisingly, lymphocyte dose did not influence the incidence of GVHD. Our results suggest that DLI can be given in large cell doses without increasing the risk of GVHD.

In vitro--in vivo evaluation of tableted caseinchitosan microspheres containing diltiazem hydrochloride.

Casein-chitosan microspheres containing diltiazem hydrochloride (DTZ.HCL) were prepared using aqueous coacervation technique. The formed microspheres were not suitable for tableting by direct compression due to their poor binding properties. The effect of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carbopol 940 and egg albumin as dry binders at different concentrations on the properties of the tablets was studied. Each blend of microspheres with dry binder and 2% w/w magnesium stearate as glidant was hand-filled into the die cavity of a single punch tablet machine to ensure constant amount of drug (90 mg) in each tablet. The compression force was adjusted to produce tablets with hardness value about 7.73 +/- 0.79 Kp. The prepared tablets showed good appearance and low friability. The tested binders HPMC (10 and 30% w/w) and EC (20 and 30% w/w) gave fast tablet disintegration with high initial drug release (burst effect) while, carbopol 940 (5 and 10% w/w) and egg albumin (30% w/w) gave non-disintegrating tablets with low initial drug release. Tableted microspheres prepared with 30% egg albumin showed drug release profile similar to one of the commercial tablets (Dilzem retard, 90 mg) and was chosen for in-vivo study. Tableted microspheres and commercial tablets were administered orally in different occasions to six beagle dogs and diltiazem was assayed in dog plasma. The pharmacokinetic parameters including maximum drug concentration (Cmax) and time to reach that maximum (Tmax) were 106.24 +/- 17.96 ng.ml-1 and 5.8 +/- 2.04 hours, respectively, for the commercial sustained release DTZ tablets while, those were 107.9 +/- 12.89 ng.ml-1 and 3.6 +/- 1.36 hours, respectively for tableted microspheres. The elimination half-lives were nearly the same for the commercial and the formulated tablets (8.22 +/- 4.19 and 7.95 +/- 4.28 hours, respectively). No statistical differences (P > 0.05) were found between the two treatments for area under the plasma concentration curve (AUC0 infinity), mean residence time (MRT) and rate of drug absorption (Cmax/AUC0 infinity) indicating comparable extent and rate of drug absorption for both formulations. It was concluded that the formulated tableted microspheres provide an acceptable delivery for DTZ over an extended period of time.

Separation of lidocaine and its metabolites by capillary electrophoresis using volatile aqueous and nonaqueous electrolyte systems.

The separation of the basic drug lidocaine and six of its metabolites has been investigated both by using volatile aqueous electrolyte system, at low pH and by employing non-aqueous electrolyte systems. In aqueous systems, the best separation of the compounds under the investigated conditions was achieved by using the electrolyte 60 mM trifluoroacetic acid (TFA)/triethylamine (TEA) at pH 2.5 containing 15% methanol. With this electrolyte, all seven compounds were well separated with high efficiency and migration time repeatability. The separations with bare fused-silica capillaries and polyacrylamide-coated capillaries were compared with higher separation efficiency with the latter. On the other hand, near baseline separation of all the seven compounds was also obtained by employing the non-aqueous electrolyte, 40 mM ammonium acetate in methanol and TFA (99:1, v/v), with comparable migration time repeatability but lower separation efficiency relative to the aqueous system.

Serum antibodies to group A streptococcal extracellular and cell-associated antigens in Egyptians with post-streptococcal diseases.

We investigated serum antibodies to a comprehensive array of group A streptococcal antigens and superantigens in Egyptian subjects. Antibodies to Streptococcus pyogenes cell-associated proteins and to proteins released by rapidly dividing S. pyogenes were compared in four patient groups with different post-streptococcal diseases and in healthy controls. Enzyme-linked immunosorbent assays showed that total Ig and IgG to extracellular antigens were significantly higher in patients with acute rheumatic fever (ARF) compared to healthy controls, but no differences were found in either total Ig or IgG titres to cell-associated proteins between any of the groups. Western blotting showed that multiple extracellular and cell-associated antigens, covering a wide range of molecular masses, were recognised by all sera, including healthy controls. No evidence was obtained for putative dominant antigens associated with any disease group, although a low molecular mass cell-associated protein (approximately 4 kDa) was clearly recognised by two-thirds of subjects irrespective of disease status. These findings demonstrate that raised serum Ig and IgG titres to extracellular, but not cell-associated, S. pyogenes antigens are a feature of ARF in this population, and suggest that multiple S. pyogenes antigens contribute to this response.

Direct injection of human plasma samples after ultrafiltration into programmed temperature vaporiser-gas chromatography-mass spectrometry with packed liner.

The direct injection of plasma samples after ultrafiltration into a gas chromatograph using a packed injector liner was investigated. Ropivacaine, a local anaesthetic of the amide type and one of its metabolites (PPX) were used as model compounds in this evaluation. Phosphoric acid was added to the plasma to minimize the protein binding. After ultrafiltration, 50 microl of the sample was directly injected into the chromatographic system. No interfering peaks or damage to the GC or MS system were observed using ultrafiltration as a sample-preparation method. The validation of the method demonstrated good linearity and selectivity. The limits of quantification were 1.1 nM (301 pg/ml) and 1.4 nM (325 pg/ml) for ropivacaine and PPX, respectively. The liner had to be changed after 20 injections.

Evaluation of solid-phase microextraction for the study of protein binding in human plasma samples.

Solid-phase microextraction (SPME) in combination with capillary gas chromatography and a nitrogen-phosphorous detector is used to study protein binding in human plasma samples. Local anesthetics of the amide-type (ropivacaine, bupivacaine, mepivacaine, prilocaine, and lidocaine) are used as model compounds in this evaluation. Carbowax/divinylbenzene (CW/DVB), polyacrylate, and polydimethylsiloxane fibers are tested. Sampling on CW/DVB fibers give the highest recovery in plasma samples compared with other fibers. Ultrafiltrate spiked with each of the substances is used for the construction of calibration curves. The protein binding is investigated at four different total concentrations from 0.5 to 15.0 microM. The degree of protein binding increases when the solute concentration decreases. Protein binding of the five solutes is investigated at four pH levels (6.4, 7.4, 8.4, and 9.4). It is found that protein binding increased with increasing pH. The influence of temperature variation (from 32 degrees C to 40 degrees C) on protein binding is also investigated. The protein binding decreases when the temperature increases. The methodology is validated and good correlation and precision are obtained. Back-calculated quality control samples give accuracy within 20% of theoretical values for all five substances. This study shows that SPME as a sample-preparation method gives the same protein binding for the studied local anesthetics as that achieved using earlier presented methods.

High-performance liquid chromatography-tandem electrospray mass spectrometry for the determination of lidocaine and its metabolites in human plasma and urine.

A sensitive, selective and accurate high-performance liquid chromatographic-tandem mass spectrometric assay was developed and validated for the determination of lidocaine and its metabolites 2,6-dimethylaniline (2,6-xylidine), monoethylglycinexylidide and glycinexylidide in human plasma and urine. A simple sample preparation technique was used for plasma samples. The plasma samples were ultrafiltered after acidification with phosphoric acid and the ultrafiltrate was directly injected into the LC system. For urine samples, solid-phase extraction discs (C(18)) were used as sample preparation. The limit of quantification (LOQ) was improved by at least 10 times compared to the methods described in the literature. The LOQ was in the range 1.6-5 nmol/l for the studied compounds in plasma samples.

The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity.

Busulphan and cyclophosphamide (Bu/CP) are widely used in preparative regimens for bone marrow transplantation. Many studies have shown a wide variation in busulphan pharmacokinetics. Moreover, higher rates of liver toxicity were reported in Bu/CP protocols than in a total body irradiation (TBI)-containing regimen. In the present paper we investigated the effect of the time interval between the last dose of busulphan and the first dose of cyclophosphamide on the pharmacokinetics of CP and its cytotoxic metabolite 4-hydroperoxycyclophosphamide (4-OHCP). Thirty-six patients undergoing bone marrow transplantation (BMT) were included in the study. We also investigated the occurrence of veno-occlusive disease, mucositis and graft-versus-host disease. Ten patients conditioned with CP followed by TBI served as a control group (TBI). Twenty-six patients were conditioned with Bu/CP. The patients received Bu (1 mg/kg x 4 for 4 days), followed by CP (60 mg/kg for 2 days) administered as a 1-h infusion. Patients received their CP therapy either 7-15 h (group A, n = 12) or 24-50 h (group B, n = 14) after the last dose of Bu. None of the patients were given phenytoin or any other drug known to enhance CP metabolism. The administration of CP less than 24 h after the last dose of Bu resulted in: (1) a significantly (P = 0.003) lower clearance for cyclophosphamide was observed in group A (0.036 l/h/kg) compared to 0.055 and 0.055 l/h/kg, in the B and TBI groups, respectively; (2) significantly (P = 0.002) longer elimination half-life in group A (10.93 h) than in groups B and TBI (6.87 and 7.52 h, respectively); (3) significantly (P < 0.001) lower exposure to the cytotoxic metabolite (4-OHCP), expressed as the ratio AUC4-OHCP/AUCCP, in group A (0.0053) than that obtained in group B (0.013) and group TBI (0.012); (4) the patients in group A had a significantly (P < 0.05) higher incidence of VOD (seven of 12) than the other groups, B and TBI (2/14 and 1/10, respectively); and (5) mucositis was significantly higher in group A patients (8/12), being seen in only one patient in group B and none in the TBI group. The present study has shown that the interval between busulphan and cyclophosphamide administration can negatively affect the pharmacokinetics of cyclophosphamide and its cytotoxic metabolite. We conclude that the timing of CP administration must be considered in order to improve drug efficacy and reduce conditioning-related toxicity.

A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients.

AIMS: This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. METHODS: Fourteen patients received a combination of CP (6 g m-2 ), thiotepum (500 mg m-2 ) and carboplatin (800 mg m-2 ) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. RESULTS: CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 l h-1 (90% C.I. 0.92-2.58) and 1.14 l h-1 (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. CONCLUSIONS: The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.

Determination of amide-type local anaesthetics by direct injection of plasma in a column-switching high-performance liquid chromatographic system using a pre-column with a semipermeable surface.

A high-performance liquid chromatographic method using column switching was applied to the direct determination of two local anaesthetics, ropivacaine and bupivacaine, in human plasma. The method is intended to be used in a combined LC-GC system; here only the LC-part is described. After addition of internal standard, the samples were filtered and directly injected into a semipermeable surface (SPS) pre-column where the analytes were strongly retained and separated from many endogenous compounds by a short washing step. The retained analytes were transferred by a buffered methanol phase from the pre-column into a carbonaceous HPLC column and they were detected by UV detection at 254 nm. The SPS pre-column could withstand numerous (> 200) direct injections of plasma samples (10 microliters). The method has a detection limit of 8.2 ng and requires a total assay time of 15 min per plasma sample. Quantitative recoveries were obtained over the range 3.3-114 micrograms/ml with inter-day precisions of 1.6-5.2% (C.V.).