Solitary vulvar metastasis from early-stage endometrial cancer: Case report and literature review

Rationale:Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. It is usually diagnosed at early-stage and presents a favorable prognosis. Conversely, advanced or recurrent disease shows poor outcome. Most recurrences occur within 2 years postoperatively, typically in pelvic and para-aortic lymph nodes, vagina, peritoneum, and lungs. Vulvar metastasis (VM) is indeed anecdotal probably because of the different regional lymphatic drainage from corpus uteri.Patient concerns:A 3 cm, reddish, bleeding lesion of the posterior commissura/right labia was found in a 74-year-old woman treated with radical hysterectomy, surgical staging, and adjuvant radiotherapy 1 year before for a grade 2 endometrioid type, International Federation of Gynecology and Obstetrics Stage IB. Vulvar biopsy confirmed the EC recurrence. Pelvic magnetic resonance imaging and positron emission tomography excluded other metastases so VM was radically resected.Diagnosis:Postoperative histopathology confirmed the diagnosis of grade 2 EC VM.Interventions:A radical excision of VM was performed.Outcomes:Patient died from a severe sepsis 27 months after first surgery.Lessons:Vulvar metastases can show different appearance, occurring as single or diffuse lesions on healthy or injured skin. The surgical approach seems not to influence the metastatic risk, but tumor seeding and vaginal injuries should be avoided. Whether isolated or associated with recurrence in other locations, vulvar metastases imply poor prognosis despite radical treatment. Therefore, any suspected vulvar lesion arisen during EC follow-up should be biopsied and monitored closely, despite that the vulva represents an unusual metastatic site.     

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.     

A novel IVS2 -2A>T splicing mutation in the GH-1 gene in familial isolated growth hormone deficiency type II in the spectrum of other splicing mutations in the Russian population

Isolated GH deficiency (IGHD) is characterized by genetic heterogeneity, both in familial and sporadic cases. To determine if this statement can be applied to the Russian population, we performed screening for mutations in the GH-1 gene in children living in Russia with IGHD. Twenty-eight children from 26 families with total IGHD were studied. DNA fragments, covering each of four (2-5) exons of GH-1 were amplified using PCR. Single-strand conformation polymorphism analysis followed by direct DNA sequencing identified five heterozygous mutations of splicing in intron 2, intron 3, and exon 4 of GH-1; three of them were not previously reported. We concentrated here on dominant-negative mutations causing IGHD type II, which were as follows: 1) A>T transversion of the second base of the 3'-acceptor splice site of intron 2 (IVS2 -2A>T); 2) T>C transition of the second base of the 5'-donor splice site of intron 3 (IVS3 +2T>C); 3) G>A transition of the first base of the 5'-donor splice site of intron 3 (IVS3 +1G>A). Our data indicate allelic heterogeneity of IGHD type II (IGHD II). However, all mutations in Russian IGHD II patients affect splicing, a striking difference from the mutation spectrum of other IGHD forms. The IVS2 -2A>T mutation is the first identified mutation in intron 2 of GH-1. The 5'-donor splice site of intron 3 of GH-1 is a mutational hot spot, and the IVS3 +1G>A mutation can be considered to be a common molecular defect in IGHD II in Russian patients.     

The effect of alcohols as the third component on diffusion in mixtures of aromatics and ketones

With laboratory and numerical work, we demonstrate that one of the main diffusion coefficients and the smaller eigenvalue of the Fick diffusion matrix are invariant to the number of methylene groups of the alcohol in ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol). A critical analysis of the relationship between the kinetic and thermodynamic contributions to the diffusion coefficients allows us to explain this intriguing behaviour of this class of mixture. These findings are reflected by the diffusive behaviour of the according binary subsystems. Our approach provides a promising systematic framework for future investigations into the important and challenging problem of transport diffusion in multicomponent liquids.

The Fick diffusion coefficient matrix of three ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol) is investigated with laboratory and numerical work.

Multicomponent diffusion plays a crucial role in various natural and industrial processes involving mass transfer.^1–3 Liquids appearing in nature and technical applications are essentially multicomponent. However, only data on binary diffusion coefficients are relatively abundant because the diffusion behavior of ternary and higher mixtures is much more complex.^4,5 Describing the isothermal–isobaric diffusion of a ternary mixture by Fick’s law requires four different diffusion coefficients that are composition dependent. The presence of cross diffusion coefficients aggravates the interpretation and data processing in experimental work, resulting in large uncertainties.^6,7 Thus, efforts are being made to develop new methods for analysis of multicomponent diffusion explicitly addressing various degrees of complexity.^8–10 Predictive equations for multicomponent diffusion of liquids mostly rely on extensions of the Darken relation,^11–13 which is only valid for ideal mixtures.¹⁴ The underlying physical phenomena in non-ideal mixtures are not well understood and the lack of experimental data impedes the development and verification of new predictive equations.The objective of this study was not only to measure and predict the Fick diffusion coefficient matrix for a series of ternary liquid mixtures, rather, the emphasis lied on understanding common features and whether they can be related to the behavior of the pure components and binary subsystems. Three ternary mixtures that are composed of organic compounds were selected, i.e. an aromatic, a ketone and an alcohol. Throughout, the first two components were benzene (1) and acetone (2) and the third component was one of the alcohols, methanol, ethanol or 2-propanol. For each mixture, nine state points along a composition path with a constant content of benzene, x₁ = 0.33 mol mol⁻¹, were studied under ambient conditions (298.15 K and 0.1 MPa). Seven of the state points were ternary mixtures and two were binary subsystems. To obtain reliable results for the Fick diffusion coefficient matrix, two complementary approaches were used, i.e. experiments and predictive molecular simulations. This combination allows for a critical analysis and leads to a deeper understanding of the underlying phenomena.^14,15The Taylor dispersion technique was utilized for the experiments.^16,17 In this method, a small quantity of mixture with a slightly different composition is injected into a laminar stream. It disperses due to convection and diffusion while flowing through a capillary tube and the refractive index is measured at its end to sample the concentration distribution. We have used the same apparatus as in previous works.^6,7 The Fick diffusion matrix is obtained by fitting working equations to the measured signal, i.e. the Taylor peak. The mathematical model of the Taylor dispersion technique was originally developed on the basis of Fick’s law in the volume reference frame. In a ternary mixture, two molar fluxes J^v_i relative to a volume averaged velocity are related to gradients of molar concentration ∇C_i with four diffusion coefficients D^v_ij. Alternatively, fluxes expressed in the molar reference frame J_i are relative to a molar averaged velocity and the mole fraction gradients ∇x_i act as a driving force1with molar density ρ. The fluxes of all three components are constrained by ΣJ_i = 0. The main diffusion coefficients D₁₁ and D₂₂ relate the flux of one component to its own mole fraction gradient and the cross diffusion coefficients D₁₂ and D₂₁ describe the coupling of the flux of one component with the gradient of the other. The third component does not appear in eqn (1) explicitly, but in general it affects all four diffusion coefficients. The transformation of experimental data from the volume to the molar reference frame (D^v_ij to D_ij) could be done here on the basis of the pure component volumes (see the ESI^†).Equilibrium molecular dynamics (MD) simulations were employed in this work, allowing for examination at the microscopic scale. The underlying molecular models were rigid, non-polarizable force fields of united atom type, consisting of a varying number of Lennard–Jones, point charge, dipole and quadrupole sites (see the ESI^†). Note that the force field parameters were adjusted to pure fluid properties only so that all simulation results for the mixtures are strictly predictive. Diffusion coefficients were sampled with the Green–Kubo formalism, based on integrated correlation functions of net velocities of the contained species.^11,15 Thereby, phenomenological coefficients Δ_ij were obtained, associating the diffusive fluxes with the chemical potential gradients ∇μ_i2with gas constant R and temperature T. Fluxes J_i correspond to the molar reference frame as in eqn (1).The diffusion coefficients from experiment and simulation are related to different driving forces so that the chemical potential gradients have to be transformed to the mole fraction gradients for their comparison.¹⁸ This transformation is contained in the thermodynamic factor matrix Γ3with the activity coefficient of species i being γ_i, which expresses the non-ideality of a mixture with respect to the composition. This relationship shows that the Fick diffusion coefficients are actually the product of two contributions, a kinetic Δ_ij and a thermodynamic Γ_ij. The separate observation of these two contributions promotes understanding of the underlying physical phenomena. In the present study, the thermodynamic factor was calculated using the Wilson excess Gibbs energy (g^E) model, using parameters fitted to experimental vapor–liquid equilibrium data of the binary subsystems (see the ESI^†). This combination of MD simulation results with a g^E model was successfully used in previous work to predict Fick diffusion coefficients, including several binary subsystems of the ternary mixtures studied here.¹⁹The four elements of the Fick diffusion coefficient matrix were determined for the three ternary mixtures, benzene + acetone + methanol/ethanol/2-propanol, for nine different compositions, each at ambient temperature and pressure.Results for the first main element of the diffusion matrix D₁₁, which relates the flux of benzene to its own mole fraction gradient, are shown in Fig. 1(a). The experimental data agree quantitatively with the molecular simulation data. D₁₁ increases with the acetone content in the ternary mixture. Since mixtures with a constant mole fraction of benzene (x₁ = 0.33 mol mol⁻¹) were studied throughout, the left edge of Fig. 1(a) corresponds to the binary limit of benzene + alcohol, while the right edge corresponds to that of benzene + acetone. Analysis of the ternary diffusive fluxes implies the following asymptotic behavior of the diffusion coefficients towards the binary limits:⁷ (i) at the infinite dilution limit, x₂ → 0, the ternary coefficient D₁₁ tends to the binary Fick diffusion coefficient of benzene + alcohol; (ii) at the other limit, x₃ → 0, D₁₁ − D₁₂ = D₂₂ − D₂₁ → D_bin (benzene + acetone) should hold. The present experimental and simulation results for D₁₁ are consistent with these asymptotic limits.Open in a separate windowFig. 1Top: The main Fick diffusion coefficient (molar reference frame) of benzene D₁₁ in the three ternary mixtures benzene (1) + acetone (2) + alcohol (3) at a constant benzene mole fraction x₁ = 0.33 mol mol⁻¹ from experiment (triangles) and MD simulation combined with the Wilson g^E model (circles). Both data sets were sampled at the same compositions, but are slightly shifted in the plot for visibility reasons. The symbols at the edges of this plot are the binary diffusion coefficients of benzene + alcohol (x₂ → 0) and of benzene + acetone (x₃ → 0). Bottom: The binary Fick diffusion coefficient of the subsystems benzene + alcohol and benzene + acetone. Most of the binary experimental data were taken from the literature.^20–27An inspection of Fig. 1(a) provides an unexpected finding: the main element D₁₁ is almost identical for all three mixtures along the examined composition path, i.e. it is independent of the contained type of alcohol. To explain this intriguing behavior of D₁₁, the properties of the pure components are considered first (see

Diagnostic and prognostic significance of cardiovascular magnetic resonance native myocardial T1 mapping in patients with pulmonary hypertension

Background

Native T1 may be a sensitive, contrast-free, non-invasive cardiovascular magnetic resonance (CMR) marker of myocardial tissue changes in patients with pulmonary artery hypertension. However, the diagnostic and prognostic value of native T1 mapping in this patient group has not been fully explored. The aim of this work was to determine whether elevation of native T1 in myocardial tissue in pulmonary hypertension: (a) varies according to pulmonary hypertension subtype; (b) has prognostic value and (c) is associated with ventricular function and interaction.

Methods

Data were retrospectively collected from a total of 490 consecutive patients during their clinical 1.5 T CMR assessment at a pulmonary hypertension referral centre in 2015. Three hundred sixty-nine patients had pulmonary hypertension [58?±?15 years; 66% female], an additional 39 had pulmonary hypertension due to left heart disease [68?±?13 years; 60% female], 82 patients did not have pulmonary hypertension [55?±?18; 68% female]. Twenty five healthy subjects were also recruited [58 ±4 years); 51% female]. T1 mapping was performed with a MOdified Look-Locker Inversion Recovery (MOLLI) sequence. T1 prognostic value in patients with pulmonary arterial hypertension was assessed using multivariate Cox proportional hazards regression analysis.

Results

Patients with pulmonary artery hypertension had elevated T1 in the right ventricular (RV) insertion point (pulmonary hypertension patients: T1?=?1060?±?90 ms; No pulmonary hypertension patients: T1?=?1020?±?80 ms p <?0.001; healthy subjects T1?=?940?±?50 ms p <?0.001) with no significant difference between the major pulmonary hypertension subtypes. The RV insertion point was the most successful T1 region for discriminating patients with pulmonary hypertension from healthy subjects (area under the curve?=?0.863) however it could not accurately discriminate between patients with and without pulmonary hypertension (area under the curve?=?0.654). T1 metrics did not contribute to prediction of overall mortality (septal: p =?0.552; RV insertion point: p =?0.688; left ventricular free wall: p =?0.258). Systolic interventricular septal angle was a significant predictor of T1 in patients with pulmonary hypertension (p <?0.001).

Conclusions

Elevated myocardial native T1 was found to a similar extent in pulmonary hypertension patient subgroups and is independently associated with increased interventricular septal angle. Native T1 mapping may not be of additive value in the diagnostic or prognostic evaluation of patients with pulmonary artery hypertension.

     

T1 and T2 mapping in myocarditis: seeing beyond the horizon of Lake Louise criteria and histopathology

Introduction: Myocarditis and its sequelae remain an unconquered clinical problem, disproportionately affecting the young. Several hurdles beset myocarditis, including non-specific symptoms, heterogeneous clinical presentation, dynamic disease stages, underscored by an absence of an easy diagnostic test or a specific treatment.

Areas covered: The current diagnostic means are poorly equipped to counter the challenge; the gold standard by invasive endomyocardial biopsy relies on availability of expert procedural and reading skill. The tissue diagnostic criteria were developed to improve readers agreement with clinical diagnosis, and not based on evidence for differential treatment or improved prognosis. The Lake-Louise Criteria represented a first step towards a non-invasive diagnosis. They require extensive imaging, which is insufficiently robust with poor diagnostic confidence and tissue pathophysiological validation; they similarly lack evidence of improved outcome by guiding clinical management. T1 and T2 mapping are a step-change, providing robust, short and quantifiable imaging application, which can veritably reflect the dynamic and heterogeneous underlying disease.

Expert commentary: T1 and T2 mapping harbours a unique potential for an objective non-invasive disease recognition and treatment discovery in myocarditis. These measures should enter independently into clinical experimentation, with a high priority for outcome and therapeutic studies.     

Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results

UK Biobank, a large cohort study, plans to acquire 100,000 cardiac MRI studies by 2020. Although fully-automated left ventricular (LV) analysis was performed in the original acquisition, this was not designed for unsupervised incorporation into epidemiological studies. We sought to evaluate automated LV mass and volume (Siemens syngo InlineVF versions D13A and E11C), against manual analysis in a substantial sub-cohort of UK Biobank participants. Eight readers from two centers, trained to give consistent results, manually analyzed 4874 UK Biobank cases for LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass (LVM). Agreement between manual and InlineVF automated analyses were evaluated using Bland–Altman analysis and the intra-class correlation coefficient (ICC). Tenfold cross-validation was used to establish a linear regression calibration between manual and InlineVF results. InlineVF D13A returned results in 4423 cases, whereas InlineVF E11C returned results in 4775 cases and also reported LVM. Rapid visual assessment of the E11C results found 178 cases (3.7%) with grossly misplaced contours or landmarks. In the remaining 4597 cases, LV function showed good agreement: ESV ?6.4?±?9.0 ml, 0.853 (mean?±?SD of the differences, ICC) EDV ?3.0?±?11.6 ml, 0.937; SV 3.4?±?9.8 ml, 0.855; and EF 3.5?±?5.1%, 0.586. Although LV mass was consistently overestimated (29.9?±?17.0 g, 0.534) due to larger epicardial contours on all slices, linear regression could be used to correct the bias and improve accuracy. Automated InlineVF results can be used for case-control studies in UK Biobank, provided visual quality control and linear bias correction are performed. Improvements between InlineVF D13A and InlineVF E11C show the field is rapidly advancing, with further improvements expected in the near future.     

Early PREdiction of sepsis using leukocyte surface biomarkers: the ExPRES-sepsis cohort study

Purpose

Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score?≥?2 at 24 h and/or 72 h following ED presentation).

Methods

In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3).

Results

Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23–2.57); P?=?0.002], higher monocyte CD279 [1.32 (1.03–1.70); P?=?0.03], and lower monocyte HLA-DR [0.73 (0.55–0.97); P?=?0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity.

Conclusions

From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection.

Clinical trial registration

NCT02188992.