Citations

Key Points Heme, released from hemoglobin, elicits vaso-occlusion in transgenic sickle mice via endothelial TLR4 signaling. Heme/TLR4 signaling activates NF-κB and triggers vaso-occlusion through Weibel-Palade body degranulation and adhesion molecule expression.

SummaryAutologous stem‐cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant‐related mortality rates are high, and a recent randomized trial suggested that non‐transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant‐related mortality occurred in 11·5%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain‐type natriuretic peptide (BNP) >300 pg/ml (17·5 months vs. not‐reached) (P = 0·0004), troponin‐I >0·07 ng/ml (13·5 months vs. not‐reached) (P = 0·00001) and those not achieving a complete haematological response (88 months vs. not‐reached) (P = 0·0345); high BNP and troponin‐I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP <300 pg/ml and/or normal levels of troponin‐I should be considered transplant candidates.

Abstract Aims Prognostic benefit from CRT compared with controls is well established. Symptomatic response rates, however, are controversial and have never been systematically evaluated with standard subtraction of control rates to establish the incremental symptomatic response effect of CRT pacing. Methods and results First, we identified 150 consecutive CRT papers and assessed researchers’ perceptions of the symptomatic response to CRT. The mean quoted response rate was 66%. Only 26 studies acknowledged the existence of response without the device. Secondly, we examined actual symptomatic response rates in the randomized trials (CARE-HF, COMPANION, CONTAK-CD, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, MUSTIC, and REVERSE) totalling 3904 patients. The NYHA status improved in 51% of those randomized to CRT vs. 35% of controls (incremental effect 16%). This incremental improvement was significantly greater in open studies (with no device for controls) than in blinded studies (control arm receiving a device but no CRT, such as a defibrillator or a CRT programmed off), 20% vs. 13%, P &lt; 0.001. Conclusions Quoting CRT responder rates in isolation without recognizing spontaneous ‘response’ is common but unwise. The incremental symptomatic response rate from CRT pacing is ∼16%, much lower than widely reported. This value is similar to that for drugs in heart failure and should not be considered disappointing: they both exert powerful prognostic benefits. For scientific purposes, e.g. to explore potential improvements, symptomatic benefit from CRT should be quantified, like all other effects, by comparison with a control.

We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC) tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.

Purpose Indications for sentinel lymph node biopsy (SLNB) for thin melanoma are continually evolving. We present a large multi-institutional study to determine factors predictive of sentinel lymph node (SLN) metastasis in thin melanoma. Patients and Methods Retrospective review of the Sentinel Lymph Node Working Group database from 1994 to 2012 identified 1,250 patients who had an SLNB and thin melanomas (≤ 1 mm). Clinicopathologic characteristics were correlated with SLN status and outcome. Results SLN metastases were detected in 65 (5.2%) of 1,250 patients. On univariable analysis, rates of Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, ulceration, and absence of regression differed significantly between positive and negative SLN groups (all P < .05). These four variables and mitotic rate were used in multivariable analysis, which demonstrated that Breslow thickness ≥ 0.75 mm (P = .03), Clark level ≥ IV (P = .05), and ulceration (P = .01) significantly predicted SLN metastasis with 6.3%, 7.0%, and 11.6% of the patients with these respective characteristics having SLN disease. Melanomas < 0.75 mm had positive SLN rates of < 5% regardless of Clark level and ulceration status. Median follow-up was 2.6 years. Melanoma-specific survival was significantly worse for patients with positive versus negative SLNs (P = .001). Conclusion Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, and ulceration significantly predict SLN disease in thin melanoma. Most SLN metastases (86.2%) occur in melanomas ≥ 0.75 mm, with 6.3% of these patients having SLN disease, whereas in melanomas < 0.75 mm, SLN metastasis rates are < 5%. By using a 5% metastasis risk threshold, SLNB is indicated for melanomas ≥ 0.75 mm, but further study is needed to define indications for SLNB in melanomas < 0.75 mm.

We validate a technique for model-free measurement of shear wave velocity and attenuation. A mechanical shaker was used to excite harmonic plane and cylindrical waves in phantoms and excised tissue. Radiation force was used to excite impulsive cylindrical waves. 2D FFT of the displacement yielded the k-space whose coordinates are frequency and the wave number. The shear wave velocity at each frequency was obtained by finding the maximum at the given frequency in k-space and dividing the frequency coordinate by the wave number coordinate. The attenuation (α) at a given frequency was calculated using α = FWHM × π/√3, where FWHM is the full width at half maximum of the k-space peak along the given frequency. This method was applied to measure shear wave velocity and attenuation of transplanted kidneys and livers, and in the thyroid tumor, and compare it to the healthy tissues. The velocities and attenuations at each frequency for various excitation methods agree within one standard deviation. The k-space estimates of velocity and attenuation agreed with those obtained using the phase gradient (velocity) and amplitude decay (attenuation). The transplanted organs and the thyroid tumor had higher velocity and lower attenuation than healthy tissues.

Measurements of viscoelasticity with shear wave velocity dispersion requires measurements over a large bandwidth. In this study, we explored the parameters that modulate the frequency characteristics of shear waves induced using radiation force push beams. We used a Verasonics ultrasound scanner equipped with a linear array transducer. We performed measurements of shear wave motion induced using both focused and unfocused ultrasound beams. Measurements were made in elastic phantoms with shear moduli of 1, 4, and 16 kPa. The number of elements used for the unfocused beams were varied from 8 to 24, and for the focused beams from 16 to 128. The shear wave motion was tracked using plane wave imaging, and a one-dimensional autocorrelation algorithm applied to the acquired in-phase/quadrature data. At each pixel we calculated the fast Fourier transform of the data and found the center frequency, center-of-gravity, and −3 dB bandwidth. We compared the frequency characteristics from the different push beams. The frequency characteristics were found to be spatially variant and dependent on the number of elements used as well as the shear modulus of the medium. The center frequency, center-of-gravity, and the bandwidth were found to be correlated to one another, and strongly associated with the stiffness of the medium.

Robust shear-wave motion detection is essential for producing reliable shear elasticity measurements for ultrasound shear-wave elastography (SWE). However, because shear-wave motion is extracted from radiofrequency signals which can be heavily contaminated by noise, shear-wave motion detection can be very challenging, especially for in vivo applications. This study investigated the implementation of harmonic imaging (HI) to facilitate more robust shear-wave tracking based on HI’s effectiveness in suppressing imaging noise associated with ultrasound reverberation, phase aberration, and clutter noise. A HI shear-wave tracking sequence was developed combining the pulse-inversion HI method with the plane wave imaging technique to transmit phase-inverted pulses at a high frame rate of several kilohertz. The backscattered ultrasound signals from phase-inverted pulses were added to suppress the fundamental and enhance the second harmonic component, from which the shear-wave motion was extracted. A pork belly phantom experiment showed that HI could significantly improve shear-wave motion detection by producing almost three-fold less underestimation of shear-wave motion and over ten-fold more precision for shear-wave speed measurements than fundamental imaging. An in vivo transthoracic case study of a human heart showed that HI substantially improved the success rate of shear-wave motion detection and could provide consistent estimates of the left ventricle myocardium stiffness.

Thyroid cancer is the fastest growing age and gender adjusted cancer in 2011 according the American Cancer Society. The majority of the clinically diagnosed thyroid nodules are benign while less than 5% represent intrathyroidal cancers. Currently, the clinical gold-standard procedure for assessing the thyroid nodules is needle biopsy, a procedure that is associated with significant financial burden as well as pain and risk for patients. Therefore, a noninvasive, affordable, and potentially widely available method to differentiate between benign and malignant thyroid nodules can play an important role in reducing the number of unnecessary biopsies. In this study, we investigate the feasibility of two acoustic radiation force elastography techniques, shear wave dispersion ultrasound vibrometry (SDUV) and comb-push ultrasound shear wave elastography (CUSE imaging), in identifying thyroid nodules (imaging) and differentiating between benign and malignant pathologies based on their elasticity and viscosity (SDUV measurements). Our preliminary results show that the measured shear elasticity and shear viscosity parameters depend on tissue type; hence, these measurements may be utilized to differentiate between healthy normal thyroid tissue, benign nodules, and malignant nodules. Further studies on a large population of patients is required to better evaluate the role of the combination of elasticity and viscosity properties of tissue in differentiating various thyroid nodules.

Ultrasound stimulated vibroacoustography has been used to image tissues using the acoustic response of tissues to localized harmonic radiation pressure. The method provides high resolution and high dynamic range images of tissues. The parameter being imaged is a complex combination of scattering, attenuation, and nonlinearity. However, specific use of harmonic or pulsed radiation pressure and subsequent measurement of the tissue response can be used to measure fundamental material properties of tissue. The measurement of shear wave dispersion can be used to estimate elastic shear moduli of tissue. Fundamental model free properties such as elastic storage and loss constants can also be measured. Ultrasound radiation pressure is used to induce free propagating shear waves. The measurable properties of the shear waves are sensitive to only the material properties of the tissue under certain circumstances. Shear moduli in tissue are measured with high accuracy and precision given appropriate models of wave propagation within the geometry of the tissue. Careful use of shear wave propagation and subsequent measurements can provide fundamental measurements of tissue mechanical properties if models are accurate.