Citations

Purpose Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. Patients and Methods Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m 2 ) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. Results Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. Conclusion The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.

Fasting results in the mobilization of adipose stores and the elevation of levels of free fatty acids (FFA). In humans, this process is driven by a release in GH. Little is known regarding the role of GH in modulating this process during early stages of fasting in the mouse. Confirmation of the role of GH in modulating FFA release in the fasting mouse is of particular importance given the frequent use of mouse models to study metabolic mechanisms. Here, we correlate the initial release of FFA throughout fasting in mice with pulsatile GH secretion. Observations illustrate the rapid release of FFA in response to food withdrawal. This does not correlate with a rise in GH secretion. Rather, we observed a striking loss in pulsatile secretion of GH throughout the first 6 h of fasting, suggesting that GH does not modulate the initial release of FFA in the mouse in response to fasting. This was confirmed in GH receptor knockout mice, in which we observed a robust fasting-induced rise in FFA. We further illustrate the dynamic relationship between the orexigenic and anorexigenic hormones ghrelin and leptin during fasting in the mouse. Our findings show an initial suppression of leptin and the eventual rise in circulating levels of acyl-ghrelin with fasting. However, altered acyl-ghrelin and leptin secretion occurs well after the rise in FFA and the suppression of GH secretion. Consequently, we conclude that although acyl-ghrelin and leptin may modulate the physiological response to drive food intake, these changes do not contribute to the initial loss of pulsatile GH secretion. Rather, it appears that the suppression of GH secretion in fasting may occur in response to an elevation in fasting levels of FFA or physiological stress. Observations highlight a divergent role for GH in modulating FFA release between man and mouse.

Impaired renal function with loss of nephron number in chronic renal disease (CKD) is associated with increased cardiovascular morbidity and mortality. However, the structural and functional cardiac response to early and mild reduction in renal mass is poorly defined. We hypothesized that mild renal impairment produced by unilateral nephrectomy (UNX) would result in early cardiac fibrosis and impaired diastolic function, which would progress to a more global left ventricular (LV) dysfunction. Cardiorenal function and structure were assessed in rats at 4 and 16 wk following UNX or sham operation (Sham); ( n = 10 per group). At 4 wk, blood pressure (BP), aldosterone, glomerular filtration rate (GFR), proteinuria, and plasma B-type natriuretic peptide (BNP) were not altered by UNX, representing a model of mild early CKD. However, UNX was associated with significantly greater LV myocardial fibrosis compared with Sham. Importantly, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis in the LV myocardium. Further, diastolic dysfunction, assessed by strain echocardiography, but with preserved LVEF, was observed. Changes in genes related to the TGF-β and apoptosis pathways in the LV myocardium were also observed. At 16 wk post-UNX, we observed persistent LV fibrosis and impairment in LV diastolic function. In addition, LV mass significantly increased, as did LVEDd, while there was a reduction in LVEF. Aldosterone, BNP, and proteinuria were increased, while GFR was decreased. The myocardial, structural, and functional alterations were associated with persistent changes in the TGF-β pathway and even more widespread changes in the LV apoptotic pathway. These studies demonstrate that mild renal insufficiency in the rat results in early cardiac fibrosis and impaired diastolic function, which progresses to more global LV remodeling and dysfunction. Thus, these studies importantly advance the concept of a kidney-heart connection in the control of myocardial structure and function.

Diabetic mastopathy is an uncommon, benign disease of the breast that can occur in women with diabetes and clinically mimic breast cancer. We describe a patient with long-standing type 1 diabetes who presented with a palpable breast mass with negative imaging findings on mammography, ultrasonography, and breast MRI. Surgical biopsy and histopathology confirmed diabetic mastopathy. We use this case to highlight the recognition, radiographic features, pathology, and management of this benign breast condition and emphasize that, in diabetic patients, the differential diagnosis of a new breast mass should include diabetic mastopathy.

Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.

Objective For robot-assisted coronary artery bypass graft interventions, surgeons typically use a preoperative thoracic computed tomography scan of the patient to plan the procedure. However, the cardiac anatomy is prone to changes induced perioperatively in the effort to access the heart and surgical targets, which, in turn, may invalidate the initial plan. This article presents a method to estimate the perioperative heart migration, information which can be further exploited to refine the preoperative surgical plan. Methods Tracked transesophageal ultrasound images of four patients’ hearts were acquired at each stage in the procedure: before lung deflation, after lung deflation, and after both lung deflation and CO 2 thoracic insufflation. Anatomic features of interest—the mitral and aortic valves—were identified from each dataset, and their movement between the different procedure stages was recorded and used to estimate the global heart displacement. Moreover, the local morphology of the features of interest was investigated to provide insight on the extent of the deformation the heart has undergone during the workflow. Results The study suggested that the heart does undergo substantial displacement—on the order of 10 to 15 mm in each direction (axial, coronal, and sagittal) after lung deflation and CO 2 thoracic insufflation. However, no significant differences (P > 0.1) were observed in the morphologic characteristics of the features of interest across the multiple workflow stages, suggesting that local deformations occur at a much smaller scale compared with the global migration. Conclusions The quantification of the perioperatively induced changes is critical to track the displacement of the heart and surgical targets. The recorded migration patterns should not be ignored but rather be used to update the surgical plan to better suit the intraoperative environment.

Tissue mechanical properties can be obtained by algebraic direct inversion (ADI) of the shear-wave motion differential equation, which is insensitive to reflection and geometry of the pushing beam. Shear waves normally generated by a focused ultrasound pushing beam have limited spatial extent in depth and are transient in time, leading to noisy and unstable ADI results. A comb-shape acoustic radiation force distribution can generate shear waves with longer spatial extent and time duration, facilitating more robust ADI. For 400 μs, a linear array transducer simultaneously transmitted four unfocused pushing beams (12 on elements for each pushing beam, 8 off elements between beams) into a tissue-mimicking phantom (∼1.5 kPa) with a cylindrical inclusion (∼4 kPa). The ultrasound system (Verasonics Inc.) then immediately switched to flash imaging mode (frame rate = 2 kHz, spatial resolution = 0.31 mm) to measure shear-wave displacements in a 38 mm by 30 mm domain that was used for ADI. The reconstructed 2D shear elasticity map provides accurate shear elasticity estimates (background = 1.5 kPa with 7% variance; inclusion = 3.9 kPa with 15% variance) and excellent contrast between the background and inclusion.

The acoustic radiation force (ARF), which signifies the average transfer of momentum from the sound wave to the propagating medium, is nowadays frequently used to compute the mean displacement field in soft tissues due to the action of a focused ultrasound beam. In situations when the sound field used to generate the ARF is modulated, the latter depends on both spatial and temporal derivatives of the acoustic intensity. Unfortunately, the numerical computation of the nonlinear acoustic solution due to modulated focused ultrasound beam is complicated by the presence of two disparate time scales in the formulation. To deal with the problem, the KZK-type spatial scaling is complemented by its dual-time-scale companion, where the temporal coordinate is split into its “fast” and “slow” components, allowing one to track the ultrasound-scale oscillations and modulation-scale variations separately in the solution. In this case, the nonlinear acoustic solution (and consequently the ARF) can be effectively computed in the “fast” frequency domain and “slow” time domain for any given modulation envelope, transient, or steady-state. The proposed developments are both validated by the experimental results and illustrated via numerical examples that show the effectiveness of the computational scheme.

In the field of tissue engineering, monitoring the elasticity of developing tissue cultures is important for evaluating their growth and maturation. In this work, we used wave propagation methods to measure the elasticity of thin tissue-mimicking layers to test the feasibility of measuring the elasticity of developing tissue cultures. We developed finite element and analytical models for investigating this problem and found good agreement between the results from both models. We used ultrasound radiation force to induce propagating waves, and the waves are measured using high frame rate ultrasound imaging at 10 kHz. The wave modes were identified and compared with an analytic model for Rayleigh wave propagation in a thin elastic layer bound to a solid substrate. The same gelatin mixture was used to make phantoms 1, 4, and 50 mm thick, where the phantom with 50 mm thickness was used as control and evaluated with shear wave imaging methods. The analytic model was used to fit data from experiments in the large block and thin layers of 1 and 4 mm thick, and the measured shear moduli were 22.7, 21.8, and 22.5 kPa, respectively. These results provide a validation for measurement of elasticity in thin elastic layers.

Propagating shear waves in tissue can be measured with high frame rate Doppler or correlation methods. The measured characteristics of the shear waves, such as speed versus frequency, can be used to deduce material properties such as complex viscoelastic modulus using physics models appropriate to the geometry and properties of the tissue. This inverse problem is characterized by calculating the storage and loss modulus as a function of frequency and requires appropriate tissue motion, which in turn requires optimized dynamic radiation force distributions. We will discuss novel radiation force distributions that provide enhanced tissue motions appropriate to dealing with the inverse problem of determining tissue material properties from ultrasonically measured tissue motion.