Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience.

BACKGROUND: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL. PATIENTS AND METHODS: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed. RESULTS: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time. CONCLUSIONS: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment.

Opioid receptors expression in the skin of haemodialysis patients suffering from uraemic pruritus.

BACKGROUND: Uraemic pruritus is a common symptom in patients with chronic kidney disease undergoing haemodialysis (HD) treatment. Etiopathogenesis of uraemic pruritus is complex and not fully explained, but there are reports indicating a possible role of peripheral opioid system in its pathomechanism. OBJECTIVES: This study was undertaken to analyse the expression of mu- and kappa-opioid receptors in the skin of HD patients with and without uraemic pruritus. METHODS: Forty patients suffering from chronic kidney disease, treated with haemodialysis (21 pruritic and 19 non-pruritic), were included. The expression of mu- and kappa-opioid receptors in their skin was evaluated with immunohistochemistry. RESULTS: The significant (P < 0.02) decrease in kappa-opioid receptor expression was shown in the skin of pruritic patients in comparison with the skin of those without itch (1.07 ± 0.62 and 1.66 ± 0.85, respectively). Moreover, there was a significant negative correlation between intensity of pruritus and expression of kappa-opioid receptors (r = -0.63, P = 0.002). There was no difference in the expression of mu-opioid receptor expression in the skin of pruritic and non-pruritic HD patients. CONCLUSIONS: This study indicates that changes in peripheral opioid system may play an important role in the uraemic itch pathogenesis and that future studies are necessary to fully understand this mechanism.

Prognostic values of shear wave elastography in adolescent boys with varicocele.

INTRODUCTION: Shear wave elastography is an ultrasound technique for non-invasive quantification of tissue stiffness. It was used in assessing testis elasticity in some scrotal abnormalities, such as undescended pediatric testes or adult varicocele testes. In this study, its usefulness in adolescent patients with varicocele was examined. OBJECTIVE: The aim of this study was to quantify elasticity of testes with the use of elastography and comparison of the results with typical threshold values used in varicocele management in adolescent patients with varicoceles. STUDY DESIGN: In 30 patients with clinically diagnosed left varicoceles, quantitative 2D shear wave imaging of varicocele testes and contralateral ones were performed. RESULTS: The relationships between the grade of varicocele and elastography were calculated. The stiffness was 2.5 ± 0.49 kPa in testes with grade I of varicocele, 2.59 ± 0.81 in grade II and 2.80 ± 0.72 kPa in grade III. In contralateral testes, it was respectively grade I 2.39 ± 0.49 kPa, grade II 2.41 ± 0.61 kPa, and grade III 2.42 ± 0.85 kPa. The statistical significance was close to importance in grade III (P = 0.153). There was a statistically significant difference between elastography results in patients with volume difference over 20%. In testes with varicocele, it was 2.77 ± 0.75 kPa and in contralateral testes, 2.37 ± 0.65 kPa (P < 0.05). In patients with testis volume difference between 0 and 20%, elastography results were comparable, and it was 2.45 ± 0.57 kPa in testes with varicocele and 2.44 ± 0.61 kPa in contralateral testes (Table). DISCUSSION: Ultrasound is currently the most widely used imaging technique for the assessment of varicocele, but its role in the diagnostic algorithm is still controversial. Therefore, many attempts are made to determine the manifestations of testicular damage that precede morphological deterioration, which could increase the importance of imaging techniques in treatment planning. CONCLUSION: The changes of tissue elasticity due to varicocele seem to confirm the need of surgery in patients with testis volume difference more than 20% and in grade III of varicocele (Table). In case of validation of diffuse testis changes, they could indicate the need for surgery also in other stages.

Evaluation of Single-Chip, Real-Time Tomographic Data Processing on FPGA SoC Devices.

A novel approach to tomographic data processing has been developed and evaluated using the Jagiellonian positron emission tomography scanner as an example. We propose a system in which there is no need for powerful, local to the scanner processing facility, capable to reconstruct images on the fly. Instead, we introduce a field programmable gate array system-on-chip platform connected directly to data streams coming from the scanner, which can perform event building, filtering, coincidence search, and region-of-response reconstruction by the programmable logic and visualization by the integrated processors. The platform significantly reduces data volume converting raw data to a list-mode representation, while generating visualization on the fly.

Calculation of the time resolution of the J-PET tomograph using kernel density estimation.

In this paper we estimate the time resolution of the J-PET scanner built from plastic scintillators. We incorporate the method of signal processing using the Tikhonov regularization framework and the kernel density estimation method. We obtain simple, closed-form analytical formulae for time resolution. The proposed method is validated using signals registered by means of the single detection unit of the J-PET tomograph built from a 30 cm long plastic scintillator strip. It is shown that the experimental and theoretical results obtained for the J-PET scanner equipped with vacuum tube photomultipliers are consistent.

Postpartum two- and three-dimensional ultrasound evaluation of anal sphincter complex in women with obstetric anal sphincter injury.

OBJECTIVE: To compare the sensitivity and specificity of two- (2D) and three- (3D) dimensional transperineal ultrasound (TPUS) and 3D endovaginal ultrasound (EVUS) with the gold standard 3D endoanal ultrasound (EAUS) in detecting residual defects after primary repair of obstetric anal sphincter injuries (OASIS). METHODS: External (EAS) and internal (IAS) anal sphincters were evaluated by the four ultrasound modalities in women with repaired OASIS. 2D-TPUS was evaluated in real-time, whereas 3D-TPUS, 3D-EVUS and 3D-EAUS volumes were evaluated offline by six blinded readers. The presence/absence of any tear in EAS or IAS was recorded and defects were scored according to the Starck system. Sensitivity, specificity and predictive values were calculated, using 3D-EAUS as reference standard. Inter- and intraobserver analyses were performed for all 3D imaging modalities. Association between patients' symptoms (Wexner score) and ultrasound findings (Starck score) was calculated. RESULTS: Images from 55 patients were analyzed. Compared with findings on 3D-EAUS, the agreement for EAS evaluation was poor for 3D-EVUS (κ = 0.01), fair for 2D-TPUS (κ = 0.30) and good for 3D-TPUS (κ = 0.73). The agreement for IAS evaluation was moderate for both 3D-EVUS (κ = 0.41) and 2D-TPUS (κ = 0.52) and good for 3D-TPUS (κ = 0.66). Good intraobserver (3D-EAUS, κ = 0.73; 3D-TPUS, κ = 0.78) and interobserver (3D-EAUS, κ = 0.68; 3D-TPUS, κ = 0.60) agreement was reported. Significant association between Starck and Wexner scores was found only for 3D-EAUS (Spearman's rho = 0.277, P = 0.04). CONCLUSIONS: 2D-TPUS and 3D-EVUS are not accurate modalities for the assessment of anal sphincters after repair of OASIS. 3D-TPUS shows good agreement with the gold standard 3D-EAUS and a high sensitivity in detecting residual defects. It, thus, has potential as a screening tool after primary repair of OASIS. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Beneficial effects of enrichment of chicken meat with n-3 polyunsaturated fatty acids, vitamin E and selenium on health parameters: a study on male rats.

Consumption of chicken meat enriched with bioactive compounds such as n-3 polyunsaturated fatty acids (PUFAn-3), vitamin E (vE) and selenium (Se) can help prevent many diseases and can be used to deliver those substances to humans. This might be of importance as chicken meat consumption is increasing worldwide. The effects of enriching chicken meat with PUFAn-3, vE and Se through dietary interventions were studied in rats. Four groups of Ross 308 female broilers from day 22 to day 35 of age were fed control diet (L) that contained lard and 80 mg vE and 0.3 mg Se/kg, or diets that contained rape seeds and fish oil with the same level of Se and vE as in the control diet, the same level of Se as in the control and 150 mg vE/kg, or 150 mg of vE and 0.7 mg Se/kg. Broiler carcasses were boiled, deboned, lyophilized and pooled by group. Boiled edible components of chicken carcass (BECC) were included (240 g/kg) in the diets fed to four groups of ten 10-week-old Wistar male rats for 8 weeks. Inclusion of BECCs modulated dietary fatty acid profile in the rat diets. Feeding these diets did not influence parameters related to growth or relative weights of internal organs in the rats. Feeding BECCs with lower PUFAn-6/n-3 decreased the n-6/n-3 ratio in the rat brain and liver, and increased the proportion of docosahexaenoic acid in the brain lipids. Liver cholesterol level was similar among the experimental groups, whereas the concentration of vE in the liver of rats fed BECC with increased vE levels was higher than that in the rats fed BECC with the basal vE level. Haematological and biochemical parameters in blood were within the normal range for rats, but a few rats showed a tendency towards increased levels because of the higher vE and Se level. The health-promoting effect of feeding rats PUFAn-3 enriched BECC was more pronounced when an increased dietary level of vE was used, but the increased level of Se did not provide the rats with additional benefits. Thus, the findings indicate that BECC enriched with PUFAn-3 and vE by a dietary intervention is a functional food with great potential of implementation.

A feasibility study of ortho-positronium decays measurement with the J-PET scanner based on plastic scintillators.

We present a study of the application of the Jagiellonian positron emission tomograph (J-PET) for the registration of gamma quanta from decays of ortho-positronium (o-Ps). The J-PET is the first positron emission tomography scanner based on organic scintillators in contrast to all current PET scanners based on inorganic crystals. Monte Carlo simulations show that the J-PET as an axially symmetric and high acceptance scanner can be used as a multi-purpose detector well suited to pursue research including e.g. tests of discrete symmetries in decays of ortho-positronium in addition to the medical imaging. The gamma quanta originating from o-Ps decay interact in the plastic scintillators predominantly via the Compton effect, making the direct measurement of their energy impossible. Nevertheless, it is shown in this paper that the J-PET scanner will enable studies of the [Formula: see text] decays with angular and energy resolution equal to [Formula: see text] and [Formula: see text], respectively. An order of magnitude shorter decay time of signals from plastic scintillators with respect to the inorganic crystals results not only in better timing properties crucial for the reduction of physical and instrumental background, but also suppresses significantly the pile-ups, thus enabling compensation of the lower efficiency of the plastic scintillators by performing measurements with higher positron source activities.

Time resolution of the plastic scintillator strips with matrix photomultiplier readout for J-PET tomograph.

Recent tests of a single module of the Jagiellonian Positron Emission Tomography system (J-PET) consisting of 30 cm long plastic scintillator strips have proven its applicability for the detection of annihilation quanta (0.511 MeV) with a coincidence resolving time (CRT) of 0.266 ns. The achieved resolution is almost by a factor of two better with respect to the current TOF-PET detectors and it can still be improved since, as it is shown in this article, the intrinsic limit of time resolution for the determination of time of the interaction of 0.511 MeV gamma quanta in plastic scintillators is much lower. As the major point of the article, a method allowing to record timestamps of several photons, at two ends of the scintillator strip, by means of matrix of silicon photomultipliers (SiPM) is introduced. As a result of simulations, conducted with the number of SiPM varying from 4 to 42, it is shown that the improvement of timing resolution saturates with the growing number of photomultipliers, and that the [Formula: see text] configuration at two ends allowing to read twenty timestamps, constitutes an optimal solution. The conducted simulations accounted for the emission time distribution, photon transport and absorption inside the scintillator, as well as quantum efficiency and transit time spread of photosensors, and were checked based on the experimental results. Application of the [Formula: see text] matrix of SiPM allows for achieving the coincidence resolving time in positron emission tomography of [Formula: see text]0.170 ns for 15 cm axial field-of-view (AFOV) and [Formula: see text]0.365 ns for 100 cm AFOV. The results open perspectives for construction of a cost-effective TOF-PET scanner with significantly better TOF resolution and larger AFOV with respect to the current TOF-PET modalities.

Perineal body anatomy seen by three-dimensional endovaginal ultrasound of asymptomatic nulliparae.

AIM: The perineal body (PB) plays an important role in supporting the pelvic floor and the posterior vaginal wall, but its attachments and relationships are still debated. This study aimed to assess the normal anatomy of the PB using high-resolution three-dimensional endovaginal ultrasound (3D-EVUS) in asymptomatic nulliparae. METHOD: To validate the identification of perineal structures, 3D-EVUS was initially performed on nulliparous cadavers. Fresh frozen pelves were prepared and echogenic structures thought to be the PB, the external anal sphincter, the superficial and deep transverse perineii, pubovaginalis, puboperinealis, puboanalis, puborectalis and iliococcygeus muscles were tagged with biopsy needles, and marked with indigo carmine dye for localization during dissection. In the second part of the study, consecutive asymptomatic nulliparae were prospectively imaged with the same ultrasound modality. Interrater reproducibility was assessed off-line from stored 3D US volumes using a standardized technique. RESULTS: Five fresh frozen pelves and 44 asymptomatic nulliparae were assessed with 3D-EVUS. The PB was seen as an ovoid structure of mixed echogenicity between the rectum and vagina. It appeared to be divided into a superficial level, in contact with the external anal sphincter, the bulbospongiousus and the superficial transverse perineii muscle and a deep level, in contact with puboperinealis and puboanalis muscles. Interobserver repeatability was excellent for the measurements of PB height [intraclass correlation coefficient (ICC) 0.927], PB depth (ICC 0.969) and PB width (ICC 0.932). CONCLUSION: The PB is divided into two levels with different anatomical relationships with the pelvic floor muscles. 3D-EVUS yields reproducible assessment of this complex structure.

Changes in the anaerobic threshold in an annual cycle of sport training of young soccer players.

The aim of the study was to assess changes in the anaerobic threshold of young soccer players in an annual training cycle. A group of highly trained 15-18 year old players of KKS Lech Poznan were tested. The tests included an annual training macrocycle, and its individual stages resulted from the time structure of the sports training. In order to assess the level of exercise capacities of the players, a field exercise test of increasing intensity was carried out on a soccer pitch. The test made it possible to determine the 4 millimolar lactate threshold (T LA 4 mmol · l(-1)) on the basis of the lactate concentration in blood [LA], to establish the threshold running speed and the threshold heart rate [HR]. The threshold running speed at the level of the 4 millimolar lactate threshold was established using the two-point form of the equation of a straight line. The obtained indicators of the threshold running speed allowed for precise establishment of effort intensity used in individual training in developing aerobic endurance. In order to test the significance of differences in mean values between four dates of tests, a non-parametric Friedman ANOVA test was used. The significance of differences between consecutive dates of tests was determined using a post-hoc Friedman ANOVA test. The tests showed significant differences in values of selected indicators determined at the anaerobic threshold in various stages of an annual training cycle of young soccer players. The most beneficial changes in terms of the threshold running speed were noted on the fourth date of tests, when the participants had the highest values of 4.01 m · s(-1) for older juniors, and 3.80 m · s(-1) for younger juniors. This may be indicative of effective application of an individualized programme of training loads and of good preparation of teams for competition in terms of players' aerobic endurance.

3-D high-frequency endovaginal ultrasound of female urethral complex and assessment of inter-observer reliability.

OBJECTIVES: Assessment of the urethral complex and defining its morphological characteristics with 3-dimensional endovaginal ultrasonography with the use of high frequency rotational 360° transducer. Defining inter-observer reliability of the performed measurements. MATERIALS AND METHODS: Twenty-four asymptomatic, nulliparous females (aged 18-55, mean 32 years) underwent high-frequency (12MHz) endovaginal ultrasound with rotational 360° and automated 3D data acquisition (type 2050, B-K Medical, Herlev, Denmark). Measurements of the urethral thickness, width and length, bladder neck-symphysis distance, intramural part of the urethra as well as rhabdosphincter thickness, width and length were taken by three investigators. Descriptive statistics for continuous data was performed. The results were given as mean values with standard deviation. The relationships among different variables were assessed with ANOVA for repeated measures factors, as well as T-test for dependent samples. Intraclass correlation (ICC) was calculated for each parameter. Intra- and interobserver reliability was assessed. Statistical significance was assigned to a P value of <0.05 (two-tailed). RESULTS: Excellent reliability was observed for urethral measurements (length, width, thickness and volume) (ICC>0.8) and good reliability for rhabdosphincter measurements (ICC>0.6) between all three investigators. CONCLUSIONS: Advanced EVUS provides detailed information on anatomy and morphology of the female urethral complex. Our results show that 360° rotational transducer with automated 3D acquisition, currently routinely used for proctological scanning is suitable for the reliable assessment of the urethral complex and can be applied in a routine diagnostics of pelvic floor disturbances in females.

The differences in testicular volumes in boys 8-36 months old with undescended, retractile and hydrocele testis--usefulness of scrotal screening ultrasound.

PURPOSE: The aim of the study was quantitative and qualitative assessments of scrotal abnormalities diagnosed in boys 8 to 36 months old during ultrasound screening and estimation if these abnormalities influence testes volume. MATERIALS AND METHODS: High frequency scrotal ultrasound was performed in 1448 patients aged 8-36 months as additional exam during screening ultrasound program for children including cervical and abdominal ultrasound. The mean age of examined boys was 17 months. For further analysis the children were divided in 5 age groups. RESULTS: The abnormalities in scrotal ultrasound were found in 20.1% of boys. Undescended, cryptorchid testes were found in 4.8% of patients, mobile testicle in 7.6% and hydrocele in 2.8%. The volume of undescended testes was statistically lower than volume of the descended testes in 3 youngest groups of boys (p=0.003-0.011). The volume of mobile testicles did not increase with age, while in patients with hydrocele the testicular volume decreased with age. CONCLUSION: Scrotal screening ultrasound performed in boys up to 3 years old may deliver information about the number and type of existing pathologies as well as their influence on the testicular volume. The volume of the pathological testes was lower than the volume of the normal ones. Improper growth of testes may potentially have important clinical implication for the function of testes in the future.

Pelvic floor disorders: role of new ultrasonographic techniques.

The paper presents the role of various ultrasound modalities in the diagnostics of female pelvic floor disorders (PFD). It describes the use of two/three/four-dimensional transperineal ultrasound and endocavitary transducers, which, up to now, have been used for proctological examinations and prostate cancer brachytherapy. Ultrasonography is the most widely available imaging modality. As a result of technical progress, novel transducers and more sophisticated software have recently been introduced to the market providing more information about the anatomy of pelvic organs. Some features of these transducers, such as higher frequency and multiplanar imaging, enable better visualisation of pelvic floor organs. In-depth knowledge of the technical and physical properties of modern ultrasonography, as well as its advantages and limitations, could provide an integrated approach to imaging of PFD. Technical modalities, the wide availability of ultrasonographic techniques, and an understanding of the imaging possible with modern ultrasonography could improve our understanding of PFD and allow better assessment in pre- and post-surgical management.

State of the art: an integrated approach to pelvic floor ultrasonography.

Surgical management of pelvic floor disorders depends on a comprehensive understanding of the structural integrity and function of the pelvic floor. For visualizing this region, ultrasonography has emerged as a procedure that is relatively easy to perform, cost-effective and widely available. In this review, pelvic floor ultrasonography, including two-dimensional (2D), three-dimensional (3D) and 4D imaging as well as transvaginal, endoanal and transperineal techniques, is discussed from a global and multicompartmental perspective, rather than using a compartmentalized approach. The role of the different sonographic modalities in the major disorders of the pelvic floor-urinary and fecal incontinence, pelvic organ prolapse and obstructed defecation syndrome-is evaluated critically.

Innate immunity as orchestrator of stem cell mobilization.

Hematopoietic stem and progenitor cells (HSPCs), as well as other types of stem cells, circulate under steady-state conditions at detectable levels in peripheral blood (PB), with their numbers increasing in response to stress, inflammation and tissue/organ injury. This mobilization process may be envisioned as a danger-sensing response mechanism triggered by hypoxia or mechanical or infection-induced tissue damage that recruits into PB different types of stem cells that have a role in immune surveillance and organ/tissue regeneration. Mobilization is also significantly enhanced by the administration of pharmacological agents, which has been exploited in hematological transplantology as a means to obtain HSPCs for hematopoietic reconstitution. In this review we will present mounting evidence that innate immunity orchestrates this evolutionarily conserved mechanism of HSPC mobilization.

Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex.

The complement cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemoattractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the bone marrow (BM). We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal-derived factor-1 (SDF-1)-independent manner because (i) plasma SDF-1 level does not correlate with mobilization efficiency; (ii) the chemotactic plasma gradient is not affected in the presence of AMD3100 and (iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested the involvement of bioactive lipids and we focused on sphingosine-1-phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P (i) creates in plasma a continuously present gradient for BM-residing HSPCs; (ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1 and (iii) its plasma level increases during mobilization due to CC activation and interaction of the membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC through MAC induces the release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

CFU-megakaryocytic progenitors expanded ex vivo from cord blood maintain their in vitro homing potential and express matrix metalloproteinases.

BACKGROUND: In patients transplanted with cord blood (CB), prolonged thrombocytopenia is a major complication. However, this could be alleviated by supplementing the CB graft with ex vivo-expanded megakaryocytic progenitors (CFU-Meg), provided that the homing properties of these cells are not affected negatively by expansion. METHODS AND RESULTS: We assessed the in vitro homing potential of CFU-Meg progenitors expanded from CB and showed that the combination of thrombopoietin (TPO) with interleukin-3 (IL-3) used for expansion not only results in optimal proliferation of CFU-Meg but also protects these cells from apoptosis. Moreover, we found that ex vivo-expanded CFU-Meg maintained expression of the CXCR4 receptor throughout a 9-day culture and were chemoattracted towards a stromal cell-derived factor-1 (SDF-1) gradient. They also expressed matrix metalloproteinase-9 (MMP-9) and membrane-type (MT) 1-MMP, and transmigrated across the reconstituted basement membrane Matrigel. Finally, we observed that SDF-1 up-regulated the expression of both MMP-9 and MT1-MMP in CB CD34(+) cells and ex vivo-expanded CFU-Meg. DISCUSSION: We suggest that CB-expanded CFU-Meg, in particular those from day 3 of expansion, when their proliferation and in vitro homing potential are maximal, could be employed to supplement CB grafts and speed up platelet recovery in transplant recipients.