Adjunctive Rifampicin Increases Antibiotic Efficacy in Group A Streptococcal Tissue Infection Models.

Biofilm has recently been highlighted as a complicating feature of necrotizing soft tissue infections (NSTI) caused by Streptococcus pyogenes (i.e., group A Streptococcus [GAS]) contributing to a persistence of bacteria in tissue despite prolonged antibiotic therapy. Here, we assessed the standard treatment of benzylpenicillin and clindamycin with or without rifampin in a tissue-like setting. Antibiotic efficacy was evaluated by CFU determination in a human organotypic skin model infected for 24 or 48 h with GAS strains isolated from NSTI patients. Antibiotic effect was also evaluated by microcalorimetric metabolic assessment in in vitro infections of cellular monolayers providing continuous measurements over time. Adjunctive rifampin resulted in enhanced antibiotic efficacy of bacterial clearance in an organotypic skin tissue model, 97.5% versus 93.9% (P = 0.006). Through microcalorimetric measurements, adjunctive rifampin resulted in decreased metabolic activity and extended lag phase for all clinical GAS strains tested (P < 0.05). In addition, a case report is presented of adjunctive rifampin treatment in an NSTI case with persistent GAS tissue infection. The findings of this study demonstrate that adjunctive rifampin enhances clearance of GAS biofilm in an in vitro tissue infection model.

Aryl hydrocarbon receptor interacting protein (AIP) significantly influences prognosis of pancreatic carcinoma.

INTRODUCTION: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Aryl hydrocarbon receptor interacting protein (AIP) in one of AHR ligands. The aim of this study is to analyze the prognostic influence of AIP in pancreatic carcinoma. MATERIAL AND METHODS: Retrospective case series with immunohistochemical analysis of AIP. We have estimated a multivariate Cox's model for the outcome (progression free and overall survival). RESULTS: 204 patients were included in the study. As expected prognosis was poor and 67.8% died of disease. As for AIP 9.8% of the cases showed nuclear staining of the epithelial tumor cells and 59.4% a cytoplasmic one. Stroma was stained in 53.1% of the cases. Univariate survival analysis revealed a significantly worse prognosis of patients with cytoplasmic AIP expression (stroma and epithelium), but nuclear expression was associated to a better prognosis. In the multivariate analysis stromal AIP expression was an independent prognosticator of progression free survival, together with pT stage, histological grade and history of diabetes. DISCUSSION: AIP Is a conserved cochaperone protein binding to many proteins. AIP has been proposed as a potential tumor suppressor gene. To date, no study has analyzed the immunohistochemical expression of AIP in pancreatic carcinoma. Our results indicate that both epithelial and stromal cytoplasmic expression of AIP is associated to bad prognosis, while nuclear translocation seems to improve prognosis. CONCLUSION: Although we must deepen into the complex signaling pathways underlying this potential association, our results open a way to inhibiting AHR as a potential target against pancreatic carcinoma.

Primary resistance to integrase strand transfer inhibitors in Spain using ultrasensitive HIV-1 genotyping.

BACKGROUND: Transmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted. OBJECTIVES: We evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016. METHODS: Pre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%-19% of the virus population were considered to be low-frequency variants. RESULTS: From a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants. CONCLUSIONS: Transmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens.

Parenteral drug use as the main barrier to hepatitis C treatment uptake in HIV-infected patients.

OBJECTIVES: Our objective was to identify patient factors associated with being untreated for hepatitis C virus (HCV) infection in HIV-coinfected patients. METHODS: A prospective longitudinal study was carried out. HIV-infected patients with active chronic HCV infection included in the HERACLES cohort (NCT02511496) constituted the study population. The main study outcome was receipt of HCV direct-acting antiviral (DAA) treatment from 1 May 2015 to 1 May 2017. The population was divided into patients who were receiving HCV treatment during follow-up and those who were not. RESULTS: Of the 15 556 HIV-infected patients in care, 3075 (19.7%) presented with chronic HCV infection and constituted the study population. At the end of the follow-up, 1957 patients initiated HCV therapy (63.6%). Age < 50 years, absence of or minimal liver fibrosis, being treatment-naïve, HCV genotype 3 infection, being in the category of people who inject drugs using opioid substitutive therapy (OST-PWID), and being in the category of recent PWID were identified as significant independent risk factors associated with low odds of DAA implementation. When a multivariate analysis was performed including only the PWID population, both OST-PWID [odds ratio (OR) 0.552; 95% confidence interval (CI) 0.409-0.746) and recent PWID (OR 0.019; 95% CI 0.004-0.087) were identified as independent factors associated with low odds of treatment implementation. CONCLUSIONS: We identified factors, which did not include prioritization of a DAA uptake strategy, that limited access to HCV therapy. The low treatment uptake in several populations seriously jeopardizes the elimination of HCV infection in the coming years.

Effects of velocity loss during resistance training on athletic performance, strength gains and muscle adaptations.

We compared the effects of two resistance training (RT) programs only differing in the repetition velocity loss allowed in each set: 20% (VL20) vs 40% (VL40) on muscle structural and functional adaptations. Twenty-two young males were randomly assigned to a VL20 (n = 12) or VL40 (n = 10) group. Subjects followed an 8-week velocity-based RT program using the squat exercise while monitoring repetition velocity. Pre- and post-training assessments included: magnetic resonance imaging, vastus lateralis biopsies for muscle cross-sectional area (CSA) and fiber type analyses, one-repetition maximum strength and full load-velocity squat profile, countermovement jump (CMJ), and 20-m sprint running. VL20 resulted in similar squat strength gains than VL40 and greater improvements in CMJ (9.5% vs 3.5%, P < 0.05), despite VL20 performing 40% fewer repetitions. Although both groups increased mean fiber CSA and whole quadriceps muscle volume, VL40 training elicited a greater hypertrophy of vastus lateralis and intermedius than VL20. Training resulted in a reduction of myosin heavy chain IIX percentage in VL40, whereas it was preserved in VL20. In conclusion, the progressive accumulation of muscle fatigue as indicated by a more pronounced repetition velocity loss appears as an important variable in the configuration of the resistance exercise stimulus as it influences functional and structural neuromuscular adaptations.

Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents.

Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.

Desmoplastic astrocytoma: new insights into its clinical profile, diagnosis, and treatment.

BACKGROUND: Desmoplastic astrocytoma (DA) is a rare intracranial tumor which usually affects pediatric patients. The aim of this study is to describe the clinical features and management of DA based on a joint analysis of the cases reported in the scientific literature. MATERIAL AND METHODS: A thorough review was carried out, gathering those pathologically proven DAs reported since the first description of this entity. Two new own cases were included in order to illustrate this review. Epidemiological, clinical, radiological, therapeutic, and follow-up data were analyzed with the software SPSS version 20. RESULTS: A total of 52 DAs were recorded. Most cases occurred in the first 2 years of life, although older patients were also reported. Patients mainly presented symptoms and signs of elevated intracranial pressure. According to their radiological features, we were able to classify DAs in four main groups, with distinct differential diagnosis and prognosis. After treatment, 14.2 % of patients presented persistent neurological impairment and the mortality rate was close to 10 %. CONCLUSION: DAs can be diagnosed at any age from birth to adolescence. These neoplasms can show up a wider range of radiological morphologies than previously thought. Surgery represents the treatment of choice for DAs, although chemotherapy can also be useful in the setting of recurrence or progression of the disease. Those DAs lacking classic radiological features, especially type 4 tumors, were linked with a poorer clinical outcome.

Estimation of the Maximal Lactate Steady State in Endurance Runners.

This study aimed to predict the velocity corresponding to the maximal lactate steady state (MLSSV) from non-invasive variables obtained during a maximal multistage running field test (modified University of Montreal Track Test, UMTT), and to determine whether a single constant velocity test (CVT), performed several days after the UMTT, could estimate the MLSSV. Within 4-5 weeks, 20 male runners performed: 1) a modified UMTT, and 2) several 30 min CVTs to determine MLSSV to a precision of 0.25 km·h(-1). Maximal aerobic velocity (MAV) was the best predictor of MLSSV. A regression equation was obtained: MLSSV=1.425+(0.756·MAV); R(2)=0.63. Running velocity during the CVT (VCVT) and blood lactate at 6 (La6) and 30 (La30) min further improved the MLSSV prediction: MLSSV=VCVT+0.503 - (0.266·ΔLa30-6); R(2)=0.66. MLSSV can be estimated from MAV during a single maximal multistage running field test among a homogeneous group of trained runners. This estimation can be further improved by performing an additional CVT. In terms of accuracy, simplicity and cost-effectiveness, the reported regression equations can be used for the assessment and training prescription of endurance runners.

Short-term Recovery Following Resistance Exercise Leading or not to Failure.

This study analyzed the time course of recovery following 2 resistance exercise protocols differing in level of effort: maximum (to failure) vs. half-maximum number of repetitions per set. 9 males performed 3 sets of 4 vs. 8 repetitions with their 80% 1RM load, 3×4(8) vs. 3×8(8), in the bench press and squat. Several time-points from 24 h pre- to 48 h post-exercise were established to assess the mechanical (countermovement jump height, CMJ; velocity against the 1 m·s(-1) load, V1-load), biochemical (testosterone, cortisol, GH, prolactin, IGF-1, CK) and heart rate variability (HRV) and complexity (HRC) response to exercise. 3×8(8) resulted in greater neuromuscular fatigue (higher reductions in repetition velocity and velocity against V1-load) than 3×4(8). CMJ remained reduced up to 48 h post-exercise following 3×8(8), whereas it was recovered after 6 h for 3×4(8). Significantly greater prolactin and IGF-1 levels were found for 3×8(8) vs. 3×4(8). Significant reductions in HRV and HRC were observed for 3×8(8) vs. 3×4(8) in the immediate recovery. Performing a half-maximum number of repetitions per set resulted in: 1) a stimulus of faster mean repetition velocities; 2) lower impairment of neuromuscular performance and faster recovery; 3) reduced hormonal response and muscle damage; and 4) lower reduction in HRV and HRC following exercise.

Rational application of adenosine deaminase activity in cerebrospinal fluid for the diagnosis of tuberculous meningitis.

PURPOSE: Tuberculous meningitis (TBM) is one of the most serious and difficult to diagnose manifestations of TB. An ADA value >9.5 IU/L has great sensitivity and specificity. However, all available studies have been conducted in areas of high endemicity, so we sought to determine the accuracy of ADA in a low endemicity area. METHODS: This retrospective study included 190 patients (105 men) who had ADA tested in CSF for some reason. Patients were classified as probable/certain TBM or non-TBM based on clinical and Thwaite's criteria. Optimal ADA cutoff was established by ROC curves and a predictive algorithm based on ADA and other CSF biochemical parameters was generated. RESULTS: Eleven patients were classified as probable/certain TBM. In a low endemicity area, the best ADA cutoff was 11.5 IU/L with 91 % sensitivity and 77.7 % specificity. We also developed a predictive algorithm based on the combination of ADA (>11.5 IU/L), glucose (<65 mg/dL) and leukocytes (≥13.5 cell/mm(3)) with increased accuracy (Se: 91 % Sp: 88 %). CONCLUSIONS: Optimal ADA cutoff value in areas of low TB endemicity is higher than previously reported. Our algorithm is more accurate than ADA activity alone with better sensitivity and specificity than previously reported algorithms.

Estimation of the Maximal Lactate Steady State in Junior Soccer Players.

This study aimed to predict the velocity corresponding to the maximal lactate steady state (MLSS(V)) from non-invasive variables obtained during an incremental maximal running test (University of Montreal Track Test, UMTT) and to determine whether a single constant velocity test (CVT), performed several days after the UMTT, could estimate the MLSS(V). During a period of 3 weeks, 20 male junior soccer players performed: (1) a UMTT, and (2) several 20-min CVTs to determine MLSS(V) to a precision of 0.35 km·h(-1). Maximal aerobic velocity (MAV) and velocity at 80% of maximum heart rate (V80%HRmax) were strong predictors of MLSS(V). A regression equation was obtained: MLSS(V)=(1.106·MAV) - (0.309·V(80%HRmax)) - 3.024; R2=0.60. Running velocity during CVT (V(CVT)) and blood lactate at 10 (La10) and 20 (La20) minutes further improved the MLSS(V) prediction: MLSS(V)=V(CVT)+0.26 - (0.812·ΔLa(20-10)); R2=0.66. MLSS(V) can be estimated from MAV and V(80%HRmax) during a single incremental maximal running test among a homogeneous group of soccer players. This estimation can be improved by performing an additional CVT. In terms of accuracy, simplicity and cost-effectiveness, the reported regression equations can be used for the assessment and training prescription of endurance in team sport players.

Velocity- and power-load relationships of the bench pull vs. bench press exercises.

This study compared the velocity- and power-load relationships of the antagonistic upper-body exercises of prone bench pull (PBP) and bench press (BP). 75 resistance-trained athletes performed a progressive loading test in each exercise up to the one-repetition maximum (1RM) in random order. Velocity and power output across the 30-100% 1RM were significantly higher for PBP, whereas 1RM strength was greater for BP. A very close relationship was observed between relative load and mean propulsive velocity for both BP (R2=0.97) and PBP (R2=0.94) which enables us to estimate %1RM from velocity using the obtained prediction equations. Important differences in the load that maximizes power output (Pmax) and the power profiles of both exercises were found according to the outcome variable used: mean (MP), peak (PP) or mean propulsive power (MPP). When MP was considered, the Pmax load was higher (56% BP, 70% PBP) than when PP (37% BP, 41% PBP) or MPP (37% BP, 46% PBP) were used. For each variable there was a broad range of loads at which power output was not significantly different. The differing velocity- and power-load relationships between PBP and BP seem attributable to the distinct muscle architecture and moment arm levers involved in these exercises.

Effect of movement velocity during resistance training on neuromuscular performance.

This study aimed to compare the effect on neuromuscular performance of 2 isoinertial resistance training programs that differed only in actual repetition velocity: maximal intended (MaxV) vs. half-maximal (HalfV) concentric velocity. 21 resistance-trained young men were randomly assigned to a MaxV (n=10) or HalfV (n=11) group and trained for 6 weeks using the full squat exercise. A complementary study (n=8) described the acute metabolic and mechanical response to the protocols used. MaxV training resulted in a likely more beneficial effect than HalfV on squat performance: maximum strength (ES: 0.94 vs. 0.54), velocity developed against all (ES: 1.76 vs. 0.88), light (ES: 1.76 vs. 0.75) and heavy (ES: 2.03 vs. 1.64) loads common to pre- and post-tests, and CMJ height (ES: 0.63 vs. 0.15). The effect on 20-m sprint was unclear, however. Both groups attained the greatest improvements in squat performance at their training velocities. Movement velocity seemed to be of greater importance than time under tension for inducing strength adaptations. Slightly higher metabolic stress (blood lactate and ammonia) and CMJ height loss were found for MaxV vs. HalfV, while metabolite levels were low to moderate for both conditions. MaxV may provide a superior stimulus for inducing adaptations directed towards improving athletic performance.

Evaluation of a soil incubation method to characterize nitrogen release patterns of slow- and controlled-release fertilizers.

Several technologies have been proposed to characterize the nutrient release patterns of slow-release fertilizers (SRF) and controlled-release fertilizers (CRF) during the last few decades. These technologies have been developed mainly by manufacturers, and are product-specific, based on the regulation and analysis of each SRF and CRF product. Despite previous efforts to characterize SRF and CRF materials, no standardized, validated method exists to assess their nutrient release patterns. However, the increased production and distribution of these materials in specialty and nonspecialty markets requires an appropriate method to verify product claims and material performance. A soil incubation column leaching procedure was evaluated to determine its suitability as a standard method to estimate nitrogen (N) release patterns of SRFs and CRFs during 180 days. The influence of three soil/sand ratios, three incubation temperatures, and four soils on method behavior was assessed using five SRFs and three CRFs. In general, the highest soil/sand ratio increased the N release rate of all materials, but this effect was more marked for the SRFs. Temperature had the greatest influence on N release rates. For CRFs, the initial N release rates and the percentage N released/day increased as temperature increased. For SRFs, raising the temperature from 25 to 35 degreesC increased initial N release rate and the total cumulative N released, and almost doubled the percentage released/day. The percentage N released/day from all products generally increased as the texture of the soil changed from sandy to loamy (lowa>California>Pennsylvania>Florida). The soil incubation technique was demonstrated to be robust and reliable for characterizing N release patterns from SRFs and CRFs. The method was reproducible, and variations in soil/sand ratio, temperature, and soil had little effect on the results.

Optimization and validation of an accelerated laboratory extraction method to estimate nitrogen release patterns of slow- and controlled-release fertilizers.

Several technologies have been proposed to characterize the nutrient release and availability patterns of enhanced-efficiency fertilizers (EEFs), especially slow-release fertilizers (SRFs) and controlled-release fertilizers (CRFs) during the last few decades. These technologies have been developed mainly by manufacturers and are product-specific based on the regulation and analysis of each EEF product. Despite previous efforts to characterize EEF materials, no validated method exists to assess their nutrient release patterns. However, the increased use of EEFs in specialty and nonspecialty markets requires an appropriate method to verify nutrient claims and material performance. A series of experiments were conducted to evaluate the effect of temperature, fertilizer test portion size, and extraction time on the performance of a 74 h accelerated laboratory extraction method to measure SRF and CRF nutrient release profiles. Temperature was the only factor that influenced nutrient release rate, with a highly marked effect for phosphorus and to a lesser extent for nitrogen (N) and potassium. Based on the results, the optimal extraction temperature set was: Extraction No. 1-2:00 h at 25 degrees C; Extraction No. 2-2:00 h at 50 degrees C; Extraction No. 3-20:00 h at 55 degrees C; and Extraction No. 4-50:00 h at 60 degrees C. Ruggedness of the method was tested by evaluating the effect of small changes in seven selected factors on method behavior using a fractional multifactorial design. Overall, the method showed ruggedness for measuring N release rates of coated CRFs.

Statistical correlation of the soil incubation and the accelerated laboratory extraction methods to estimate nitrogen release rates of slow- and controlled-release fertilizers.

Several technologies have been proposed to characterize the nutrient release patterns of enhanced-efficiency fertilizers (EEFs) during the last few decades. These technologies have been developed mainly by manufacturers and are product-specific based on the regulation and analysis of each EEF product. Despite previous efforts to characterize nutrient release of slow-release fertilizer (SRF) and controlled-release fertilizer (CRF) materials, no official method exists to assess their nutrient release patterns. However, the increased production and distribution of EEFs in specialty and nonspecialty markets requires an appropriate method to verify nutrient claims and material performance. Nonlinear regression was used to establish a correlation between the data generated from a 180-day soil incubation-column leaching procedure and 74 h accelerated lab extraction method, and to develop a model that can predict the 180-day nitrogen (N) release curve for a specific SRF and CRF product based on the data from the accelerated laboratory extraction method. Based on the R2 > 0.90 obtained for most materials, results indicated that the data generated from the 74 h accelerated lab extraction method could be used to predict N release from the selected materials during 180 days, including those fertilizers that require biological activity for N release.

Radiosensitization of cervical cancer cells with epigenetic drugs hydralazine and valproate.

PURPOSE: To evaluate the radiosensitizing effects of the DNA methylation inhibitor hydralazine in combination with valproic acid, a histone deacetylase inhibitor in cervical cancer cells. MATERIALS AND METHODS: Cell viability assays were performed in the SiHa cervical cancer cell line treated with hydralazine and valproic acid for five days with and without cisplatin. Cell irradiation was performed using teletherapy (1.25 MV). RESULTS: Neither hydralazine, valproic acid or cisplatin as single agents increased the cytotoxicity from radiation, however, the combination of hydralazine with valproic acid at ten microM and one mM, respectively, did induce radiosensitization (p = 0.046). Interestingly, this effect was further increased with the triple combination of hydralazine, valproic acid, and cisplatin (p = 0.041), where cell viability decreased more than 50% as compared to radiation alone. CONCLUSIONS: The present results demonstrate that epigenetic drugs increase the efficacy of cisplatin chemoradiation in cervical cancer cells.

Evaluation and selection of indicators for land degradation and desertification monitoring: types of degradation, causes, and implications for management.

Indicator-based approaches are often used to monitor land degradation and desertification from the global to the very local scale. However, there is still little agreement on which indicators may best reflect both status and trends of these phenomena. In this study, various processes of land degradation and desertification have been analyzed in 17 study sites around the world using a wide set of biophysical and socioeconomic indicators. The database described earlier in this issue by Kosmas and others (Environ Manage, 2013) for defining desertification risk was further analyzed to define the most important indicators related to the following degradation processes: water erosion in various land uses, tillage erosion, soil salinization, water stress, forest fires, and overgrazing. A correlation analysis was applied to the selected indicators in order to identify the most important variables contributing to each land degradation process. The analysis indicates that the most important indicators are: (i) rain seasonality affecting water erosion, water stress, and forest fires, (ii) slope gradient affecting water erosion, tillage erosion and water stress, and (iii) water scarcity soil salinization, water stress, and forest fires. Implementation of existing regulations or policies concerned with resources development and environmental sustainability was identified as the most important indicator of land protection.

Evaluation and selection of indicators for land degradation and desertification monitoring: methodological approach.

An approach to derive relationships for defining land degradation and desertification risk and developing appropriate tools for assessing the effectiveness of the various land management practices using indicators is presented in the present paper. In order to investigate which indicators are most effective in assessing the level of desertification risk, a total of 70 candidate indicators was selected providing information for the biophysical environment, socio-economic conditions, and land management characteristics. The indicators were defined in 1,672 field sites located in 17 study areas in the Mediterranean region, Eastern Europe, Latin America, Africa, and Asia. Based on an existing geo-referenced database, classes were designated for each indicator and a sensitivity score to desertification was assigned to each class based on existing research. The obtained data were analyzed for the various processes of land degradation at farm level. The derived methodology was assessed using independent indicators, such as the measured soil erosion rate, and the organic matter content of the soil. Based on regression analyses, the collected indicator set can be reduced to a number of effective indicators ranging from 8 to 17 in the various processes of land degradation. Among the most important indicators identified as affecting land degradation and desertification risk were rain seasonality, slope gradient, plant cover, rate of land abandonment, land-use intensity, and the level of policy implementation.

First-line chemotherapy with liposomal doxorubicin plus cisplatin for patients with advanced malignant pleural mesothelioma: phase II trial.

BACKGROUND: Chemotherapy based on platinum is the standard treatment for unresectable malignant pleural mesothelioma (MPM). Liposomal doxorubicin (LD) consists of pegylated phospholipid vesicles that encapsulate doxorubicin-enhancing liposome deposition in the tumour. We evaluated the toxicity profile and anti-tumour activity of cisplatin plus LD in untreated patients with MPM, as well as (99m)Tc-LD distribution in MPM lesions after chemotherapy administration. METHODS: A total of 38 patients with non-resectable MPM received LD 40 mg m(-2) and cisplatin 60 mg m(-2) every 21 days. Gamma camera images of (99m)Tc-LD were acquired to evaluate LD accumulation in measurable tumour tissue. The study was registered in Clinical Trials (NCT00886028). RESULTS: In all, 72% of patients were stage III and 28% were stage IV. Eighty four percent and 16% have high and low risk acording EORTC respectively. The median time to progression was 4.6 months (95% confidence interval (95% CI: 3.4-5.9 months), and median overall survival (OS) was 19.6 months (15.2-37.2 months). Patients that responded to chemotherapy treatment had better survival than patients who did not. Functional physical scales, dysnea, cough, and chest/arm pain demonstrated improvement. The accumulation ratio of LD in tumour and soft tissues vs liver was 0.78±0.16 and 0.29±0.09, respectively. After 1 h of administration, LD uptake in tumour tissue was higher than in soft tissue (P< 0.001). CONCLUSION: The combination of LD and cisplatin results in an active therapeutic regimen for unresectable MPM, with an acceptable toxicity profile and improvement in quality of life. (99m)Tc-LD showed higher levels of tumour uptake as compared with surrounding tissues.