Correlation of Non-tumoral Liver Dose with Treatment-Related Adverse Events in Patients with Hepatocellular Carcinoma Treated with Glass-Based Yttrium-90 Radioembolization.

PURPOSE: To evaluate the relationship between non-tumor liver (NTL) dose and adverse events (AE) in patients with hepatocellular carcinoma (HCC) treated with glass-based Yttrium-90 radioembolization (Y90-RE). MATERIALS AND METHODS: A retrospective analysis of patients with HCC treated with Y90-RE between 2013 and 2018 was performed. Baseline characteristics including demographics and Y90-RE treatment approach were captured. Common Terminology Criteria for Adverse Events v5 was assessed at months 3 and 6 post-treatment. Using voxel-based dosimetry with MIM Software V. 6.9, dose-volume histograms of treated area of liver were created. Receiver operator characteristic curve was used to determine NTL dose threshold predicting AEs. Multivariate analysis was used to determine independent clinical factors of predicting severe AEs. Chi-square analysis was used to compare proportions. RESULTS: Two hundred and twenty-nine consecutive patients (115(50.2%) lobar and 114(49.8%) segmental) were included. At 3 months, there was a lower rate of any grade AE (55(46%) segmental and 36(31%) lobar, p = 0.009) and increased rate of severe AEs for lobar compared to segmental (2(2%) segmental and 9(8%) lobar, p = 0.029). At 6 months, severe AEs were greater for lobar than segmental (1(1%) segmental vs 10(9%) lobar, p = 0.005). For lobar Y90-RE, mean NTL dose of 112 Gy predicted severe AE (89% sensitivity and 91% specificity (AUC = 0.95, p = < 0.0001) at 3 and 6 months. For the segmental group, no significant association was found between NTL dose and severe treatment-related AE at 3 and 6 months. CONCLUSION: In patients with HCC undergoing glass-based lobar Y90-RE, NTL dose of > 112 Gy is associated with severe treatment-related AEs at 3-6 months.

Determination of tumour dose response threshold and implication on survival in patients with HCC treated with Y90 radiation segmentectomy: a simple semi-quantitative analysis.

PURPOSE: To evaluate the relationship between Yttrium-90 (Y90) tumour dose and response rate in patients with hepatocellular carcinoma (HCC) who undergo Y90 radiation segmentectomy (Y90-RS) and to determine implication on overall survival (OS). MATERIALS AND METHODS: Post Y90-RS Bremsstrahlung single-photon emission computed tomography/CT of 105 HCC patients with 110 treatments performed with glass microspheres was retrospectively analysed. The dose-volume histogram of the targeted tumour was determined with commercially available dosimetry software. Tumour response at 3 months was evaluated using modified Response Evaluation Criteria in Solid Tumours. Tumour dose thresholds associated with the objective response with 80% specificity were then used to evaluate implication on OS using Kaplan-Meier estimation and log-rank analysis. RESULTS: Tumour dose thresholds to predict objective response with 80% specificity were the following: maximum tumour dose (748 Gy), mean tumour dose (568 Gy), minimum tumour dose of 30% tumour volume (608 Gy), minimum tumour dose of 50% tumour volume (565 Gy), minimum tumour dose of 70% tumour volume (464 Gy) and minimum tumour dose of 100% tumour volume (213 Gy). These parameters all significantly predicted tumour response with areas under the ROC curve of >0.6. Mean tumour dose of ≥250 Gy predicted median OS of 43.67 vs. 17.87 months for others (P = 0.026). Minimum dose ≥180 Gy to 100% of tumour volume predicted median OS of 44.93 vs. 35.87 months for others (P = 0.043). CONCLUSION: In patients with HCC undergoing Y90-RS, mean tumour dose ≥250 Gy and minimum tumour dose of ≥180 Gy to 100% of tumour volume are both significantly correlated with higher objective tumour response and prolonged survival.

Determination of Tumor Dose Response Thresholds in Patients with Chemorefractory Intrahepatic Cholangiocarcinoma Treated with Resin and Glass-based Y90 Radioembolization.

PURPOSE: To compare the efficacies of glass and resin-based Yttrium-90 microspheres by comparing absorbed tumor dose (TD) with both tumor response (TR) and overall survival (OS) in patients with chemorefractory intrahepatic cholangiocarcinoma (ICC). METHODS: Post-Y90 treatment bremsstrahlung SPECT/CT of 38 consecutive patients receiving 45 treatments (21 resin microspheres, 24 glass microspheres) were analyzed retrospectively. MIM software v6.9.4 (MIM Software Inc, Cleveland, OH) was used to calculate targeted tumors' dose volume histogram. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor response 3 months post-treatment. Kaplan Meier estimation was used for survival analysis. T-test was used to compare the devices on various dosimetric parameters. RESULTS: Thresholds for TD to predict TR with ≥ 80% specificity were as follows: mean TD (Resin: 78.9 Gy; Glass: 254.7 Gy), maximum TD (Resin: 162.9 Gy; Glass: 591 Gy), minimum TD (Resin: 53.7 Gy; Glass: 149.1 Gy). Microsphere type had no effect on survival from first Y90 (Resin: 11.2 mo; Glass 10.9 mo [p = 0.548]). In patients receiving resin microspheres, mean TD ≥ 75 Gy or maximum TD ≥ 150 Gy was associated with median OS of 20.2 mo compared to 6.5 mo for those receiving less (p = 0.001, 0.002, respectively). For patients treated with glass microspheres, those receiving a mean TD ≥ 150 Gy had a median OS of 14.6 mo vs. 2.6 mo for those receiving less (p = 0.031). CONCLUSION: TD thresholds predictive of TR and OS differ significantly between glass and resin microspheres. However, microsphere type has no impact on survival in patients with chemorefractory ICC. LEVEL OF EVIDENCE: Level 3, Retrospective Study.

Is the Arrhenius-correction of biodegradation rates, as recommended through REACH guidance, fit for environmentally relevant conditions? An example from petroleum biodegradation in environmental systems.

Biodegradation is a major determinant of chemical persistence in the environment and an important consideration for PBT and environmental risk assessments. It is influenced by several environmental factors including temperature and microbial community structure. According to REACH guidance, a temperature correction based on the Arrhenius equation is recommended for chemical persistence data not performed at the recommended EU mean surface water temperature. Such corrections, however, can lead to overly conservative P/vP assessments. In this paper, the relevance of this temperature correction is assessed for petroleum hydrocarbons, using measured surface water (marine and freshwater) degradation half-time (DT50) and degradation half-life (HL) data compiled from relevant literature. Stringent screening criteria were used to specifically select data from biodegradation tests containing indigenous microbes and conducted at temperatures close to their ambient sampling temperature. As a result, ten independent studies were identified, with 993 data points covering 326 hydrocarbon constituents. These data were derived from tests conducted with natural seawater, or freshwater, at temperatures ranging from 5 to 21 °C. Regressions were performed on the full hydrocarbon dataset and on several individual hydrocarbons. The results were compared to the trend as predicted by the Arrhenius equation and using the activation energy (Ea) as recommend in the REACH Guidance. The comparison shows that the correction recommended in REACH Guidance over predicts the effect of temperature on hydrocarbon biodegradation. These results contrast with temperature manipulated inocula where the test temperature is different from the ambient sampling temperature. In these manipulated systems, the effect of temperature follows the Arrhenius equation more closely. In addition, a more striking effect of temperature on the lag phase was observed with longer lag phases more apparent at lower temperatures. This indicates that the effect of temperature may indeed be even lower when considering hydrocarbon biodegradation without the initial lag phase.

Maternal and pregnancy-related factors affecting human milk cytokines among Peruvian mothers bearing low-birth-weight neonates.

Several cytokines have been detected in human milk but their relative concentrations differ among women and vary over time in the same person. The drivers of such differences have been only partially identified, while the effect of luminal cytokines in the fine-regulation of the intestinal immune system is increasingly appreciated. The aim of this study was to investigate the associations between obstetrical complications and human milk cytokine profiles in a cohort of Peruvian women giving birth to Low Birth Weight (LBW) infants. Colostrum and mature human milk samples were collected from 301 Peruvian women bearing LBW infants. The concentration of twenty-three cytokines was measured using the Luminex platform. Ninety-nine percent of women had at least one identified obstetrical complication leading to intra-uterine growth restriction and/or preterm birth. Median weight at birth was 1,420g; median gestational age 31 weeks. A core of 12 cytokines, mainly involved in innate immunity and epithelial cell integrity, was detectable in most samples. Maternal age, maternal infection, hypertensive disorders, preterm labor, and premature rupture of membranes were associated with specific cytokine profiles both in colostrum and mature human milk. Mothers of Very LBW (VLBW) neonates had significantly higher concentrations of chemokines and growth factor cytokines both in their colostrum and mature milk compared with mothers of larger neonates. Thus, maternal conditions affecting pregnancy duration and in utero growth are also associated with specific human milk cytokine signatures.

Oxacillin disk diffusion testing for the prediction of penicillin resistance in Streptococcus pneumoniae.

Objective To 1) describe the correlation between the zones of inhibition in 1-µg oxacillin disk diffusion (ODD) tests and penicillin and ceftriaxone minimum inhibitory concentrations (MICs) of meningeal and non-meningeal strains of Streptococcus pneumoniae and 2) evaluate the usefulness of the ODD test as a predictor of susceptibility to penicillin in S. pneumoniae and as a quick and cost-effective method easily implemented in a routine clinical laboratory setting. Methods S. pneumoniae isolates from healthy nasopharyngeal carriers less than 2 years old, obtained in a multicentric cross-sectional study conducted in various Peruvian hospitals and health centers from 2007 to 2009, were analyzed. Using Clinical and Laboratory Standards Institute (CLSI) breakpoints, the correlation between the zones of inhibition of the ODD test and the MICs of penicillin and ceftriaxone was determined. Results Of the 571 S. pneumoniae isolates, 314 (55%) showed resistance to penicillin (MIC ≥ 0.12 µg/mL) and 124 (21.7%) showed resistance to ceftriaxone (MIC ≥ 1 µg/mL). Comparison of the ODD test zones of inhibition and the penicillin MICs, using the CLSI meningeal breakpoints, showed good correlation (Cohen's kappa coefficient = 0.8239). Conclusions There was good correlation between ODD zones of inhibition and penicillin meningeal breakpoints but weak correlation between the ODD results and non-meningeal breakpoints for both penicillin and ceftriaxone. Therefore, the ODD test appears to be a useful tool for predicting penicillin resistance in cases of meningeal strains of S. pneumoniae, particularly in low- and middle- income countries, where MIC determination is not routinely available.

Oxacillin disk diffusion testing for the prediction of penicillin resistance in Streptococcus pneumoniae / Prueba de difusión con discos de oxacilina para predecir la resistencia a la penicilina de Streptococcus pneumoniae

ABSTRACT Objective To 1) describe the correlation between the zones of inhibition in 1-µg oxacillin disk diffusion (ODD) tests and penicillin and ceftriaxone minimum inhibitory concentrations (MICs) of meningeal and non-meningeal strains of Streptococcus pneumoniae and 2) evaluate the usefulness of the ODD test as a predictor of susceptibility to penicillin in S. pneumoniae and as a quick and cost-effective method easily implemented in a routine clinical laboratory setting. Methods S. pneumoniae isolates from healthy nasopharyngeal carriers less than 2 years old, obtained in a multicentric cross-sectional study conducted in various Peruvian hospitals and health centers from 2007 to 2009, were analyzed. Using Clinical and Laboratory Standards Institute (CLSI) breakpoints, the correlation between the zones of inhibition of the ODD test and the MICs of penicillin and ceftriaxone was determined. Results Of the 571 S. pneumoniae isolates, 314 (55%) showed resistance to penicillin (MIC ≥ 0.12 µg/mL) and 124 (21.7%) showed resistance to ceftriaxone (MIC ≥ 1 µg/mL). Comparison of the ODD test zones of inhibition and the penicillin MICs, using the CLSI meningeal breakpoints, showed good correlation (Cohen’s kappa coefficient = 0.8239). Conclusions There was good correlation between ODD zones of inhibition and penicillin meningeal breakpoints but weak correlation between the ODD results and non-meningeal breakpoints for both penicillin and ceftriaxone. Therefore, the ODD test appears to be a useful tool for predicting penicillin resistance in cases of meningeal strains of S. pneumoniae, particularly in low- and middle- income countries, where MIC determination is not routinely available.

RESUMEN Objetivo 1) Describir la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos de oxacilina de 1 µg y la concentración inhibitoria mínima (CIM) de penicilina y ceftriaxona frente a cepas meníngeas y no meníngeas de Streptococcus pneumoniae y 2) evaluar si la prueba de difusión con discos de oxacilina permite predecir la sensibilidad de S. pneumoniae a la penicilina y sirve como método rápido y eficaz en función de los costos, y resulta fácil de aplicar en los laboratorios clínicos ordinarios. Métodos Se analizaron colonias de S. pneumoniae aisladas de la nasofaringe de portadores sanos menores de 2 años obtenidas en un estudio transversal multicéntrico realizado en diversos hospitales y centros de salud del Perú entre los años 2007 y 2009. Se determinó la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos y la CIM de la penicilina y la ceftriaxona utilizando los valores críticos definidos por el Instituto de Estándares Clínicos y de Laboratorio. Resultados De las 571 colonias aisladas de S. pneumoniae, 314 (55 %) presentaron resistencia a la penicilina (CIM ≥ 0,12 µg/ml) y 124 (21,7%), resistencia a la ceftriaxona (CIM ≥ 1 µg/ml). Se observó una buena correlación (coeficiente κ de Cohen = 0,8239) entre las zonas de inhibición de la prueba de difusión con discos y la CIM de la penicilina utilizando los valores críticos del Instituto respecto de las cepas meníngeas. Conclusiones Se encontró una buena correlación entre las zonas de inhibición de la prueba de difusión con discos y los valores críticos de CIM de la penicilina respecto de las cepas meníngeas, pero una correlación débil entre los resultados de la prueba de difusión y los valores críticos tanto de la penicilina como de la ceftriaxona respecto de las cepas no meníngeas. Por consiguiente, la prueba de difusión con discos es un método de utilidad para predecir la resistencia a la penicilina de las cepas meníngeas de S. pneumoniae, en particular en los países de ingresos bajos y medianos, donde no suele ser posible determinar la CIM.

Oxacillin disk diffusion testing for the prediction of penicillin resistance in Streptococcus pneumoniae / Prueba de difusión con discos de oxacilina para predecir la resistencia a la penicilina de Streptococcus pneumoniae

Objective. To 1) describe the correlation between the zones of inhibition in 1-μg oxacillin disk diffusion (ODD) tests and penicillin and ceftriaxone minimum inhibitory concentrations (MICs) of meningeal and non-meningeal strains of Streptococcus pneumoniae and 2) evaluate the usefulness of the ODD test as a predictor of susceptibility to penicillin in S. pneumoniae and as a quick and cost-effective method easily implemented in a routine clinical laboratory setting. Methods. S. pneumoniae isolates from healthy nasopharyngeal carriers less than 2 years old, obtained in a multicentric cross-sectional study conducted in various Peruvian hospitals and health centers from 2007 to 2009, were analyzed. Using Clinical and Laboratory Standards Institute (CLSI) breakpoints, the correlation between the zones of inhibition of the ODD test and the MICs of penicillin and ceftriaxone was determined. Results. Of the 571 S. pneumoniae isolates, 314 (55%) showed resistance to penicillin (MIC ≥ 0.12 μg/mL) and 124 (21.7%) showed resistance to ceftriaxone (MIC ≥ 1 μg/mL). Comparison of the ODD test zones of inhibition and the penicillin MICs, using the CLSI meningeal breakpoints, showed good correlation (Cohen’s kappa coefficient = 0.8239). Conclusions. There was good correlation between ODD zones of inhibition and penicillin meningeal breakpoints but weak correlation between the ODD results and non-meningeal breakpoints for both penicillin and ceftriaxone. Therefore, the ODD test appears to be a useful tool for predicting penicillin resistance in cases of meningeal strains of S. pneumoniae, particularly in low- and middle- income countries, where MIC determination is not routinely available

Objetivo. 1) Describir la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos de oxacilina de 1 μg y la concentración inhibitoria mínima (CIM) de penicilina y ceftriaxona frente a cepas meníngeas y no meníngeas de Streptococcus pneumoniae y 2) evaluar si la prueba de difusión con discos de oxacilina permite predecir la sensibilidad de S. pneumoniae a la penicilina y sirve como método rápido y eficaz en función de los costos, y resulta fácil de aplicar en los laboratorios clínicos ordinarios. Métodos. Se analizaron colonias de S. pneumoniae aisladas de la nasofaringe de portadores sanos menores de 2 años obtenidas en un estudio transversal multicéntrico realizado en diversos hospitales y centros de salud del Perú entre los años 2007 y 2009. Se determinó la correlación entre las zonas de inhibición observadas en la prueba de difusión con discos y la CIM de la penicilina y la ceftriaxona utilizando los valores críticos definidos por el Instituto de Estándares Clínicos y de Laboratorio.. Resultados. De las 571 colonias aisladas de S. pneumoniae, 314 (55 %) presentaron resistencia a la penicilina (CIM ≥ 0,12 μg/ml) y 124 (21,7%), resistencia a la ceftriaxona (CIM ≥ 1 μg/ml). Se observó una buena correlación (coeficiente κ de Cohen = 0,8239) entre las zonas de inhibición de la prueba de difusión con discos y la CIM de la penicilina utilizando los valores críticos del Instituto respecto de las cepas meníngeas. Conclusiones. Se encontró una buena correlación entre las zonas de inhibición de la prueba de difusión con discos y los valores críticos de CIM de la penicilina respecto de las cepas meníngeas, pero una correlación débil entre los resultados de la prueba de difusión y los valores críticos tanto de la penicilina como de la ceftriaxona respecto de las cepas no meníngeas. Por consiguiente, la prueba de difusión con discos es un método de utilidad para predecir la resistencia a la penicilina de las cepas meníngeas de S. pneumoniae, en particular en los países de ingresos bajos y medianos, donde no suele ser posible determinar la CIM.

Dimeric Organization of Blood Coagulation Factor VIII bound to Lipid Nanotubes.

Membrane-bound Factor VIII (FVIII) has a critical function in blood coagulation as the pro-cofactor to the serine-protease Factor IXa (FIXa) in the FVIIIa-FIXa complex assembled on the activated platelet membrane. Defects or deficiency of FVIII cause Hemophilia A, a mild to severe bleeding disorder. Despite existing crystal structures for FVIII, its membrane-bound organization has not been resolved. Here we present the dimeric FVIII membrane-bound structure when bound to lipid nanotubes, as determined by cryo-electron microscopy. By combining the structural information obtained from helical reconstruction and single particle subtomogram averaging at intermediate resolution (15-20 Å), we show unambiguously that FVIII forms dimers on lipid nanotubes. We also demonstrate that the organization of the FVIII membrane-bound domains is consistently different from the crystal structure in solution. The presented results are a critical step towards understanding the mechanism of the FVIIIa-FIXa complex assembly on the activated platelet surface in the propagation phase of blood coagulation.