Clinical and laboratory practice for lupus anticoagulant testing: An International Society of Thrombosis and Haemostasis Scientific and Standardization Committee survey

Background: Current guidelines have contributed to more uniformity in the performance and interpretation of lupus anticoagulant (LA ) testing. However, points to reconsider include testing for LA in patients on anticoagulation, cut‐off values, and interpretation of results. Objectives: The aim of this International Society of Thrombosis and Haemostasis Scientific and Standardization committee (ISTH SSC ) questionnaire was to capture the spectrum of clinical and laboratory practice in LA detection, focusing on variability in practice, so that the responses could inform further ISTH SSC recommendations. Methods: Members of the ISTH SSC on Lupus Anticoagulant/Antiphospholipid Antibodies and participants of the Lupus Anticoagulant/Antiphospholipid Antibodies Programme of the External quality Control of diagnostic Assays and Tests Foundation were invited to complete a questionnaire on LA testing that was placed on the ISTH website using RedCap, with data tallied using simple descriptive statistics. Results: There was good agreement on several key recommendations in the ISTH and other guidelines on LA testing, such as sample processing, principles of testing, choice of tests, repeat testing to confirm persistent positivity and the use of interpretative reporting. However, the results highlight that there is less agreement on some other aspects, including the timing of testing in relation to thrombosis or pregnancy, testing in patients on anticoagulation, cut‐off values, and calculation and interpretation of results. Conclusions: Although some of the variability in practice in LA testing reflects the lack of substantive data to underpin evidence‐based recommendations, a more uniform approach, based on further guidance, should reduce the inter‐center variability of LA testing

Comparison of acquired activated protein C resistance, using the CAT and ST-genesia® analysers and three thrombin generation methods, in APS and SLE patients

Background: Acquired activated protein C resistance (APCr) has been identified in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Objective: To assess agreement between the ST-Genesia® and CAT analysers in identifying APCr prevalence in APS/SLE patients, using three thrombin generation (TG) methods. Methods: APCr was assessed with the ST- Genesia using STG-ThromboScreen and with the CAT using recombinant human activated protein C and Protac® in 105 APS, 53 SLE patients and 36 thrombotic controls. Agreement was expressed in % and by Cohenʹs kappa coefficient. Results: APCr values were consistently lower with the ST- Genesia® compared to the CAT, using either method, in both APS and SLE patients. Agreement between the two analysers in identifying APS and SLE patients with APCr was poor (≤65.9%, ≤0.20) or fair (≤68.5%, ≥0.29), regardless of TG method, respectively; no agreement was observed in thrombotic controls. APCr with both the ST Genesia and the CAT using Protac®, but not the CAT using rhAPC, was significantly greater in triple antiphospholipid antibody (aPL) APS patients compared to double/single aPL patients (p <0.04) and in thrombotic SLE patients compared to non-thrombotic SLE patients (p < 0.05). Notably, the ST-Genesia®, unlike the CAT, with either method, identified significantly greater APCr in pregnancy morbidity (median, confidence intervals; 36.9%, 21.9–49.0%) compared to thrombotic (45.7%, 39.6–55.5%) APS patients (p = 0.03). Conclusion: Despite the broadly similar methodology used by CAT and ST-Genesia®, agreement in APCr was poor/fair, with results not being interchangeable. This may reflect differences in the TG method, use of different reagents, and analyser data handling

NGC 6153: a super-metal-rich planetary nebula?

We have obtained deep optical spectra of the planetary nebula NGC 6153, both along its minor axis and by uniformly scanning a long slit across the whole nebula. The scanned spectra, when combined with the nebular total Hβ flux, yield integrated fluxes for all the lines (∼400) in our spectra, which are rich in strong recombination lines from C, N, O and Ne ions A weak O VI λ 3811 emission line from the central star has been detected, suggesting that the nucleus of NGC 6153 has a hydrogen-deficient surface. The optical data, together with the ISO LWS 43-197 μm spectrum and the archival IUE and IRAS LRS spectra, are used to study the thermal and density structure and to derive the heavy-element abundances from lines produced by different excitation mechanisms. In all cases, the C2+/H+ N2+/H+, O2+/H+ and Ne2+/H+ abundances derived from multiple optical recombination lines (ORLs) are consistently higher, by about a factor of 10, than the corresponding values deduced from optical, UV or infrared (IR) collisionally excited lines (CELs). regardless of the excitation energies or critical densities of the latter. The agreement between the temperature-sensitive optical forbidden lines and the temperature-insensitive IR fine-structure lines rules out temperature fluctuations as the cause of the large difference between the ORL and CEL abundances. We present the results of a new calculation of recombination coefficients for [O II] which lead to good agreement between the observed and predicted [O II] λλ7320,7330 forbidden line intensities if these lines are solely excited by recombination at the Balmer jump temperature. Recombination excitation is also found to be important in exciting the [N II] λ5754 line, which, if unaccounted for, would lead to an overestimated [N II] temperature from the observed (λ6548 +λ6584)/λ5754 ratio. Analysis of a number of C II lines arising from levels as high as 7g in the recombination ladder reveals excellent agreement between their reddening-corrected relative intensities and those predicted by recombination theory. Spatial analysis of the long-slit spectra taken along the nebular minor axis yields a varying [O III] temperature, whereas the hydrogen Balmer jump temperature of 6000 K is approximately constant across the nebula, and is 2000-3000 K lower than the [O III] temperature The observed high-n Balmer line decrement indicates that the hydrogen lines arise from material having an electron density of 2000+2000-1000cm-3, consistent with the optical and IR forbidden-line density diagnostics, which yield average line-of-sight electron densities along the minor axis varying between 2000 and 4000 cm-3. While the He/H ratio mapped by He I and He II recombination lines is constant within 5 per cent across the nebula, the C2+/H+ and O2+/H+ recombination-line abundances decrease by a factor of 2-3 over a radius of 15 arcsec from the centre, pointing to the presence of abundance gradients. We consider a variety of hypotheses to account for the observed behaviour of the various thermal, density and abundance diagnostics. Empirical nebular models containing two components with differing densities and temperatures are able to account for many of the observed patterns, but only if one of the components is significantly hydrogen-deficient. One such model, which gives a good fit to the observed line intensities and patterns, has 500-K H-depleted material, presumed to be evaporating from dense neutral inclusions, embedded in 9500-K material with 'normal' abundances. An alternative model, which appears more physically plausible on a number of grounds, has high-density (2 × 106 cm-3), fully ionized, H-deficient knots embedded in the 'normal' component, although this model fails to account adequately for the observed low (6000 K) hydrogen Balmer jump temperature. However, the observed fact that the ORLs and CELs yield heavy-element abundance ratios that are identical within the uncertainties finds no obvious explanation in the context of H-deficient knot models

ISO LWS observations of planetary nebula fine-structure lines

We have obtained 43–198 μm far-infrared (IR) spectra for a sample of 51 Galactic planetary nebulae (PN) and protoplanetary nebulae (PPN), using the Long Wavelength Spectrometer (LWS) on board the Infrared Space Observatory (ISO). Spectra were also obtained of the former PN candidate Lo 14. The spectra yield fluxes for the fine-structure lines [N II] 122 μm, [N III] 57 μm and [O III] 52 and 88 μm emitted in the ionized regions and the [O I] 63- and 146-μm and [C II] 158-μm lines from the photodissociation regions (PDRs), which have been used to determine electron densities and ionic abundances for the ionized regions and densities, temperatures and gas masses for the PDRs. The strong [N III] and [O III] emission lines detected in the LWS spectrum taken centred on Lo 14 could be associated with the nearby strong radio and infrared source G 331.5–0.1. We find that the electron densities yielded by the [O III] 88 μm/52 μm doublet ratio are systematically lower than those derived from the optical [Ar IV] λ4740/λ4711 and [Cl III] λ5537/λ5517 doublet ratios, which have much higher critical densities than the 52- and 88-μm lines, suggesting the presence of density inhomogeneities in the nebulae. Ionic abundances, N+/H+,N2+/H+ and O2+/H+, as well as the N2+/O2+ abundance ratio, which provides a good approximation to the N/O elemental abundance ratio, are derived. Although ionic abundances relative to H+ deduced from the far-IR fine-structure lines are sensitive to the adopted electron density and the presence of density inhomogeneities, the strong dependence on the nebular physical conditions is largely cancelled out when N2+/O2+ is calculated from the 57 μm/(52 μm+88 μm) flux ratio, owing to the similarity of the critical densities of the lines involved. The temperatures and densities of the PDRs around 24 PN have been determined from the observed [O I] and [C II] line intensity ratios. Except for a few objects, the deduced temperatures fall between 200 and 500 K, peaking around 250 K. The densities of the PDRs vary from 104–105 cm−3, reaching 3×105 cm−3 in some young compact PN. With a derived temperature of 1600 K and a density of 105 cm−3, the PDR of NGC 7027 is one of the warmest and at the same time one of the densest amongst the nebulae studied. For most of the PN studied, the [C II]-emitting regions contain only modest amounts of material, with gas masses ≲0.1 M⊙. Exceptional large PDR masses are found for a few nebulae, including NGC 7027, the bipolar nebulae M2-9 and NGC 6302, the young dense planetary nebulae BD+30°3639, IC 418 and NGC 5315, and the old, probably recombining, nebulae IC 4406 and NGC 6072

Feasibility of Photofrin II as a radiosensitizing agent in solid tumors - Preliminary results

Background: Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in in vitro and in vivo tumor models. We aimed to investigate the feasibility of a clinical application of Photofrin II. Material and Methods: 12 patients were included in the study (7 unresectable solid tumors of the pelvic region, 3 malignant gliomas, 1 recurrent oropharyngeal cancer, 1 recurrent adenocarcinoma of the sphenoid sinus). The dose of ionizing irradiation was 30-50.4 Gy; a boost irradiation of 14 Gy was added for the pelvic region. All patients were intravenously injected with 1 mg/kg Photofrin II 24 h prior to the commencement of radiotherapy. Magnetic resonance imaging (MRI) controls and in some cases positron emission tomography (PET) were performed in short intervals. The mean follow-up was 12.9 months. Results: No major adverse events were noted. Minor adverse events consisted of mild diarrhea, nausea and skin reactions. A complete remission was observed in 4/12 patients. A reduction in local tumor volume of > 45% was achieved in 4/12 patients. Stable disease was observed in 4/12 patients. 1 patient showed local disease progression after 5 months. Conclusion: The early follow-up results are encouraging regarding the feasibility of the application of Photofrin II as a radiosensitizing agent

High prevalence of activated protein C resistance associated with high avidity anti-protein C antibodies in various antiphospholipid syndrome clinical phenotypes

Background: Patritumab plus cetuximab with platinum as first-line therapy for patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) was evaluated for safety and to determine the recommended phase-II combination dose. Methods: Patients aged ≥18 years with confirmed R/M SCCHN received intravenous patritumab (18- mg/kg loading dose [LD]); 9-mg/kg maintenance dose [MD] every 3 weeks [q3w]) + cetuximab (400- mg/m2 LD; 250-mg/m2 MD weekly) + cisplatin (100 mg/m2 q3w) or carboplatin (area under the curve [AUC] of 5) for 6 cycles or until toxicity, disease progression, or withdrawal. Primary endpoints were dose-limiting toxicities (DLTs; grade ≥3 [21-day observation period]) and treatment-emergent adverse events (TEAEs). Pharmacokinetics, human antihuman antibodies (HAHA), tumor response, progression free survival (PFS), and overall survival (OS) were assessed. Results: Fifteen patients completed a median (range) of 8.7 (2.0-20.7) patritumab cycles. No DLTs were reported. Serious AEs were reported in 9 patients (patritumab-related n=4). TEAEs (N=15 patients) led to patritumab interruption in 7 patients. Patritumab-related dose reductions were reported in 1 patient. Patritumab (18 mg/kg) pharmacokinetics (N=15) showed mean (standard deviation) AUC0-21d of 2,619 (560) µg∙day/mL and maximum concentration of 499.9 (90.4) µg/mL. All patients were HAHA-negative at study end (single, transient low titer in 1 patient). Tumor response rate (complete plus partial response; N=15) was 47%. Median (95% confidence interval) PFS and OS (N=15) were 7.9 (3.7-9.7) and 13.5 (6.6- 17.5) months, respectively. Conclusion: Patritumab (18-mg/kg LD, 9-mg/kg MD) plus cetuximab/platinum was tolerable, active in SCCHN, and was selected as the phase II dose-regimen

Stress induced polarization of immune-neuroendocrine phenotypes in Gallus gallus

Immune-neuroendocrine phenotypes (INPs) stand for population subgroups differing in immune-neuroendocrine interactions. While mammalian INPs have been characterized thoroughly in rats and humans, avian INPs were only recently described in Coturnix coturnix (quail). To assess the scope of this biological phenomenon, herein we characterized INPs in Gallus gallus (a domestic hen strain submitted to a very long history of strong selective breeding pressure) and evaluated whether a social chronic stress challenge modulates the individuals’ interplay affecting the INP subsets and distribution. Evaluating plasmatic basal corticosterone, interferon-γ and interleukin-4 concentrations, innate/acquired leukocyte ratio, PHA-P skin-swelling and induced antibody responses, two opposite INP profiles were found: LEWIS-like (15% of the population) and FISCHER-like (16%) hens. After chronic stress, an increment of about 12% in each polarized INP frequency was found at expenses of a reduction in the number of birds with intermediate responses. Results show that polarized INPs are also a phenomenon occurring in hens. The observed inter-individual variation suggest that, even after a considerable selection process, the population is still well prepared to deal with a variety of immune-neuroendocrine challenges. Stress promoted disruptive effects, leading to a more balanced INPs distribution, which represents a new substrate for challenging situations.Fil: Nazar, Franco Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Estevez, Inma. Centro de Investigación. Neiker - Tecnalia; EspañaFil: Correa, Silvia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Marin, Raul Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentin

Recovery of renal function in dialysis patients

BACKGROUND: Although recovery of renal functions in dialysis dependent patients is estimated to be greater than 1%, there are no indicators that actually suggest such revival of renal function. Residual renal function in dialysis patients is unreliable and seldom followed. Therefore renal recovery (RR) in dialysis dependent patients may remain unnoticed. We present a group of dialysis dependent patients who regained their renal functions. The aim of this project is to determine any indicators that may identify the recovery of renal functions in dialysis dependent patients. METHODS: All the discharges from the chronic dialysis facilities were identified. Among these discharges deaths, transplants, voluntary withdrawals and transfers either to another modality or another dialysis facility were excluded in order to isolate the patients with RR. The dialysis flow sheets and medical records of these patients were subsequently reviewed. RESULTS: Eight patients with a mean age of 53.8 ± 6.7 years (± SEM) were found to have RR. Dialysis was initiated due to uremic symptoms in 6 patients and fluid overload in the remaining two. The patients remained dialysis dependent for 11.1 ± 4.2 months. All these patients had good urine output and 7 had symptoms related to dialysis. Their mean pre-initiation creatinine and BUN levels were 5.21 ± 0.6 mg/dl and 72.12 ± 11.12 mg/dl, respectively. Upon discontinuation, they remained dialysis free for 19.75 ± 5.97 months. The mean creatinine and BUN levels after cessation of dialysis were 2.85 ± 0.57 mg/dl and 29.62 ± 5.26 mg/dl, respectively, while the mean creatinine clearance calculated by 24-hour urine collection was 29.75 ± 4.78 ml/min. One patient died due to HIV complications. One patient resumed dialysis after nine months. Remaining continue to enjoy a dialysis free life. CONCLUSION: RR must be considered in patients with good urine output and unresolved acute renal failure. Dialysis intolerance may be an indicator of RR among such patients

Ecmo-assisted carinal resection and reconstruction after left pneumonectomy

Extracorporeal Membrane Oxygenation (ECMO) has become an increasingly important technique for patients with respiratory or cardiac failure for a variety of causes. In addition, there are many reports about the use of ECMO in surgical operation on neonates and children patients with tracheal obstruction. In this report we present a case about an adult patient who underwent a carinal resection and reconstruction after left pneumonectomy with ECMO assistance successfully. To our knowledge, this case is the first of its kind to use ECMO in adult carinal resection and reconstruction after pneumonectomy. In this report, we try to illustrate that ECMO is effective in operations of this kind

Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation-Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study

PURPOSE: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. PATIENTS AND METHODS: Patients ages 1 to <18 years who had BRAF V600-mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2. RESULTS: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26-62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64-94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). CONCLUSIONS: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600-mutant pLGG