Technical assessment of resolution of handheld ultrasound devices and clinical implications.

PURPOSE: Since handheld ultrasound devices are becoming increasingly ubiquitous, objective criteria to determine image quality are needed. We therefore conducted a comparison of objective quality measures and clinical performance. MATERIAL AND METHODS: A comparison of handheld devices (Butterfly IQ+, Clarius HD, Clarius HD3, Philips Lumify, GE VScan Air) and workstations (GE Logiq E10, Toshiba Aplio 500) was performed using a phantom. As a comparison, clinical investigations were performed by two experienced ultrasonographers by measuring the resolution of anatomical structures in the liver, pancreas, and intestine in ten subjects. RESULTS: Axial full width at half maximum resolution (FWHM) of 100µm phantom pins at depths between one and twelve cm ranged from 0.6-1.9mm without correlation to pin depth. Lateral FWHM resolution ranged from 1.3-8.7mm and was positively correlated with depth (r=0.6). Axial and lateral resolution differed between devices (p<0.001) with the lowest median lateral resolution observed in the E10 (5.4mm) and the lowest axial resolution (1.6mm) for the IQ+ device. Although devices showed no significant differences in most clinical applications, ultrasonographers were able to differentiate a median of two additional layers in the wall of the sigmoid colon and one additional structure in segmental portal fields (p<0.05) using cartwheel devices. CONCLUSION: While handheld devices showed superior or similar performance in the phantom and routine measurements, workstations still provided superior clinical imaging and resolution of anatomical substructures, indicating a lack of objective measurements to evaluate clinical ultrasound devices.

The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy. EXPERIMENTAL DESIGN: We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated. RESULTS: AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6-42 pmol/L. In vivo, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68-labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs. CONCLUSIONS: The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.See related commentary by Kamat et al., p. 2675.

The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models.

We investigated here the novel immunomodulation and anti-multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell-dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, <46.6 pM). Besides inducing T-cell proliferation and cytolytic activity, AMG 701 also promoted differentiation of patient T cells to central memory, effector memory, and stem cell-like memory (scm) phenotypes, more so in CD8 vs CD4 T subsets, resulting in increased CD8/CD4 ratios in 7-day ex vivo cocultures. IMiDs and AMG 701 synergistically induced TDCC against MM cell lines and autologous RRMM patient cells, even in the presence of immunosuppressive bone marrow stromal cells or osteoclasts. IMiDs further upregulated AMG 701-induced patient T-cell differentiation toward memory phenotypes, associated with increased CD8/CD4 ratios, increased Tscm, and decreased interleukin 10-positive T and T regulatory cells (CD25highFOXP3high), which may downregulate T effector cells. Importantly, the combination of AMG 701 with lenalidomide induced sustained inhibition of MM cell growth in SCID mice reconstituted with human T cells; tumor regrowth was eventually observed in cohorts treated with either agent alone (P < .001). These results strongly support AMG 701 clinical studies as monotherapy in patients with RRMM (NCT03287908) and the combination with IMiDs to improve patient outcomes in MM.

Author Correction: Key Role of the Ocean Western Boundary currents in shaping the Northern Hemisphere climate.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Key Role of the Ocean Western Boundary currents in shaping the Northern Hemisphere climate.

The individual impact of North Atlantic and Pacific Ocean Western Boundary Currents (OWBCs) on the tropospheric circulation has recently been studied in depth. However, their simultaneous role in shaping the hemisphere-scale wintertime troposphere/stratosphere-coupled circulation and its variability have not been considered. Through semi-idealized Atmospheric General-Circulation-Model experiments, we show that the North Atlantic and Pacific OWBCs jointly maintain and shape the wintertime hemispheric circulation and its leading mode of variability Northern Annular Mode (NAM). The OWBCs energize baroclinic waves that reinforce quasi-annular hemispheric structure in the tropospheric eddy-driven jetstreams and NAM variability. Without the OWBCs, the wintertime NAM variability is much weaker and its impact on the continental and maritime surface climate is largely insignificant. Atmospheric energy redistribution caused by the OWBCs acts to damp the near-surface atmospheric baroclinicity and compensates the associated oceanic meridional energy transport. Furthermore, the OWBCs substantially weaken the wintertime stratospheric polar vortex by enhancing the upward planetary wave propagation, and thereby affecting both stratospheric and tropospheric NAM-annularity. Whereas the overall impact of the extra-tropical OWBCs on the stratosphere results mainly from the Pacific, the impact on the troposphere results from both the Pacific and Atlantic OWBCs.

EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video).

BACKGROUND AND AIMS: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce. METHODS: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis. RESULTS: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10-4). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10-14). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10-9). CONCLUSIONS: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.

Efficacy of Endoscopic Dilation of Gastroduodenal Crohn's Disease Strictures: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND & AIMS: Little is known about the effects of endoscopic balloon dilation (EBD) for strictures of the upper gastrointestinal (UGI) tract in patients with Crohn's disease (CD). We performed a pooled analysis of the efficacy and safety of EBD for UGI CD-associated strictures. METHODS: We searched Embase, Medline, and the Cochrane library, as well as bibliographies of relevant articles, for cohort studies of adults with CD and strictures of the stomach or duodenum (up to the ligament of Treitz) who underwent EBD through December 2016. We obtained data from 7 international referral centers on 94 patients who underwent 141 EBDs. We performed a patient-level meta-analysis of data from published and unpublished cohort studies to determine mechanical and clinical success. We performed a time-to-event analysis to assess symptom recurrence and need for redilation or surgery. The patients analyzed had strictures of the duodenum (n = 107), stomach (n = 30), or spanning both (n = 4). RESULTS: The rate of technical success for EBD was 100%, with 87% short-term clinical efficacy; major complications arose from 2.9% of all procedures. During a median follow-up period of 23.1 months, 70.5% of patients had a recurrence of symptoms, 59.6% required redilation, and 30.8% required surgical intervention. Patients whose disease was located in the small bowel had a higher risk for symptom recurrence (hazard ratio [HR], 2.1; P = .003). Asian race (HR, 2.8; P < .001) and location of disease in the small bowel (HR, 1.9; P = .004) increased the need for redilation. Prestenotic dilation was a risk factor for needing surgery earlier (HR, 1.9; P = .001). CONCLUSIONS: In a meta-analysis, we found EBD for CD-associated strictures of the UGI to be an effective alternative to surgery, with a high rate of short-term technical and clinical success, moderate long-term efficacy, and an acceptable rate of complications.

Decadal variability of tropical tropopause temperature and its relationship to the Pacific Decadal Oscillation.

Tropopause temperatures (TPTs) control the amount of stratospheric water vapour, which influences chemistry, radiation and circulation in the stratosphere, and is also an important driver of surface climate. Decadal variability and long-term trends in tropical TPTs as well as stratospheric water vapour are largely unknown. Here, we present for the first time evidence, from reanalysis and state-of-the-art climate model simulations, of a link between decadal variability in tropical TPTs and the Pacific Decadal Oscillation (PDO). The negative phase of the PDO is associated with anomalously cold sea surface temperatures (SSTs) in the tropical east and central Pacific, which enhance the zonal SST gradient across the equatorial Pacific. The latter drives a stronger Walker Circulation and a weaker Hadley Circulation, which leads to less convection and subsequently a warmer tropopause over the central equatorial Pacific. Over the North Pacific, positive sea level pressure anomalies occur, which damp vertical wave propagation into the stratosphere. This in turn slows the Brewer-Dobson circulation, and hence warms the tropical tropopause, enabling more water vapour to enter the stratosphere. The reverse chain of events holds for the positive phase of the PDO. Such ocean-troposphere-stratosphere interactions may provide an important feedback on the Earth's global surface temperature.

Molecular adsorbent recirculating system and single-pass albumin dialysis in liver failure--a prospective, randomised crossover study.

BACKGROUND: The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure. METHODS: Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4% albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model. RESULTS: Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median -68 µmol/L, interquartile range [IQR] -107.5 to -33.5, p = 0.001; SPAD: -59 µmol/L, -84.5 to +36.5, p = 0.001). However, bile acids (MARS: -39 µmol/L, -105.6 to -8.3, p < 0.001; SPAD: -9 µmol/L, -36.9 to +11.4, p = 0.131), creatinine (MARS: -24 µmol/L, -46.5 to -8.0, p < 0.001; SPAD: -2 µmol/L, -9.0 to +7.0/L, p = 0.314) and urea (MARS: -0.9 mmol/L, -1.93 to -0.10, p = 0.024; SPAD: -0.1 mmol/L, -1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10%, -0.8 to +20.9%, p < 0.001; SPAD: +7%, -7.5 to +15.5%, p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD. CONCLUSIONS: Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation. TRIAL REGISTRATION: German Clinical Trials Register ( www.drks.de) DRKS00000371. Registered 8 April 2010.

Solar forcing synchronizes decadal North Atlantic climate variability.

Quasi-decadal variability in solar irradiance has been suggested to exert a substantial effect on Earth's regional climate. In the North Atlantic sector, the 11-year solar signal has been proposed to project onto a pattern resembling the North Atlantic Oscillation (NAO), with a lag of a few years due to ocean-atmosphere interactions. The solar/NAO relationship is, however, highly misrepresented in climate model simulations with realistic observed forcings. In addition, its detection is particularly complicated since NAO quasi-decadal fluctuations can be intrinsically generated by the coupled ocean-atmosphere system. Here we compare two multi-decadal ocean-atmosphere chemistry-climate simulations with and without solar forcing variability. While the experiment including solar variability simulates a 1-2-year lagged solar/NAO relationship, comparison of both experiments suggests that the 11-year solar cycle synchronizes quasi-decadal NAO variability intrinsic to the model. The synchronization is consistent with the downward propagation of the solar signal from the stratosphere to the surface.

Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia.

There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3ε of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC(50) values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-γ, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML.

Amplifying the Pacific climate system response to a small 11-year solar cycle forcing.

One of the mysteries regarding Earth's climate system response to variations in solar output is how the relatively small fluctuations of the 11-year solar cycle can produce the magnitude of the observed climate signals in the tropical Pacific associated with such solar variability. Two mechanisms, the top-down stratospheric response of ozone to fluctuations of shortwave solar forcing and the bottom-up coupled ocean-atmosphere surface response, are included in versions of three global climate models, with either mechanism acting alone or both acting together. We show that the two mechanisms act together to enhance the climatological off-equatorial tropical precipitation maxima in the Pacific, lower the eastern equatorial Pacific sea surface temperatures during peaks in the 11-year solar cycle, and reduce low-latitude clouds to amplify the solar forcing at the surface.