bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy
Authors: Phillips Gail D. Lewis , Fields Carter T. , Li Guangmin , Dowbenko Donald , Schaefer Gabriele , Miller Kathy , Andre Fabrice , Burris Howard A. , Albain Kathy S. , Harbeck Nadia , Dieras Veronique , Crivellari Diana , Fang Liang , Guardino Ellie , Olsen Steven R. , Crocker Lisa M. , Sliwkowski Mark X. 
Published: October 2013

Abstract
Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody–drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta).
Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3+3 phase Ib/II study design.
Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the maximum tolerated dose (MTD; 3.6 mg/kg every 3 weeks) with standard dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clinical activity.
Conclusions: Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456–68. ©2013 AACR.
A Novel Engineered Anti-CD20 Tracer Enables Early Time PET Imaging in a Humanized Transgenic Mouse Model of B-cell Non-Hodgkins Lymphoma
Authors: Natarajan Arutselvan , Hackel Benjamin J. , Gambhir Sanjiv Sam 
Published: October 2013

AbstractPurpose: The aim of this article was to evaluate the use of a novel engineered anti-CD20 protein based on the 10 kDa human fibronectin type 3 domain (FN3) and subsequently compare with 64Cu-rituximab for positron emission tomography (PET) imaging of CD20.Experimental Design: The engineered FN3CD20 and FN3WT were produced in Escherichia coli cells at 2 to 5 mg/L, conjugated to DOTA, labeled with 64Cu, and used for PET imaging of huCD20 expression in B cells. Humanized transgenic mice and subcutaneously xenografted mice each received intravenous 64Cu-FN3CD20 or FN3WT (3.7 MBq/4 μg Do-FN3 in 200 μL PBS). Control group received a blocking dose (50-fold excess) of unconjugated FN3CD20 two hours before radiotracer injection. PET imaging was carried out at 1 to 24 hours postinjections.Results: In vitro assay demonstrated FN3 binds CD20 with 20 nmol/L affinity on CD20-expressing cells. 64Cu-FN3CD20 showed clear, high-contrast visualization of huCD20-expressing B cells in the spleen of transgenic mice as early as 1 hour postinjection [38 ± 3% injected dose (ID)/g] and exhibited a spleen-to-blood ratio of 13 by 4 hours. This is higher uptake (P = 0.04) and 10-fold greater signal-to-background (P = 0.04) than the 64Cu-rituximab antibody radiotracer. Tumor uptake (16.8 ± 1.6 vs. 5.6 ± 1.4%ID/g) and tumor:background ratios were superior for FN3CD20 relative to rituximab in xenograft studies as well.Conclusions: The 64Cu-Do-FN3CD20 radiotracer represents a novel small, high-affinity binder for imaging human CD20, which may be well suited for B-cell non-Hodgkin's lymphoma imaging in patients at early time points. Clin Cancer Res; 19(24); 6820–9. ©2013 AACR.
Cabozantinib Inhibits Prostate Cancer Growth and Prevents Tumor-Induced Bone Lesions
Authors: Dai Jinlu , Zhang Honglai , Karatsinides Andreas , Keller Jill M. , Kozloff Kenneth M. , Aftab Dana T. , Schimmoller Frauke , Keller Evan T. 
Published: October 2013

Abstract
Purpose: Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both.
Experimental Design: Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2.
Results: Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively.
Conclusion: These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy. Clin Cancer Res; 20(3); 617–30. ©2013 AACR.
Bendamustine and Rituximab in Relapsed and Refractory Hairy Cell Leukemia
Authors: Burotto Mauricio , Stetler-Stevenson Maryalice , Arons Evgeny , Zhou Hong , Wilson Wyndham , Kreitman Robert J. 
Published: October 2013

AbstractPurpose: To determine tolerability and for the first time explore efficacy of bendamustine–rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using two different dose levels of bendamustine.Experimental Design: Patients with HCL with ≥2 prior therapies requiring treatment received rituximab 375 mg/m2 days 1 and 15 plus bendamustine 70 (n = 6) or 90 (n = 6) mg/m2, days 1 and 2, for six cycles at 4-week intervals.Results: At 70 and 90 mg/m2/dose of bendamustine, overall response rate was 100%, with three (50%) and four (67%) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67% and 100% of CRs, respectively. All six without MRD remain in CR at 30 to 35 (median, 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/mL at baseline to undetectable and 2 ng/mL after CR, respectively (P &lt; 0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83%), lymphopenia (75%), leukopenia (58%), and neutropenia (42%). Grade III and IV hematologic toxicity included lymphopenia and thrombocytopenia (each 75%), leukopenia (58%), and neutropenia (25%). No significant dose-related differences were detected in response or toxicity.Conclusion: BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m2/dose was highly effective in multiply relapsed/refractory HCL and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. As it was not dose-limiting, 90 mg/m2/dose was chosen for future testing. Clin Cancer Res; 19(22); 6313–21. ©2013 AACR.
Phase I Study of Panobinostat plus Everolimus in Patients with Relapsed or Refractory Lymphoma
Authors: Oki Yasuhiro , Buglio Daniela , Fanale Michelle , Fayad Luis , Copeland Amanda , Romaguera Jorge , Kwak Larry W. , Pro Barbara , de Castro Faria Silvana , Neelapu Sattva , Fowler Nathan , Hagemeister Fredrick , Zhang Jiexin , Zhou Shouhao , Feng Lei , Younes Anas 
Published: October 2013

Abstract
Purpose: To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity.
Experimental Design: This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed.
Results: Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021).
Conclusions: Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination. Clin Cancer Res; 19(24); 6882–90. ©2013 AACR.
It Takes Two to Tango: Dual Inhibition of PI3K and MAPK in Rhabdomyosarcoma
Authors: Jahangiri Arman , Weiss William A. 
Published: October 2013

Abstract
The PI3K/AKT/mTOR and RAS/RAF/MAPK pathways play essential roles in rhabdomyosarcoma. Singular targeting of each pathway is ineffective due to extensive cross-talk and compensatory feedback between these two pathways. Dual blockade with inhibitors of PI3K and MAPK in combination synergistically inhibits growth of rhabdomyosarcoma both in vitro and in vivo. Clin Cancer Res; 19(21); 5811–3. ©2013 AACR.
Harnessing Immune Responses in the Tumor Microenvironment: All Signals Needed
Authors: Le Dung T. , Jaffee Elizabeth M. 
Published: October 2013

Abstract
An agonist CD40 monoclonal antibody (CP-870,893), in combination with gemcitabine, is well tolerated in patients with advanced pancreatic adenocarcinoma. The combination results in induction of cytokines, B cell activation, and clinical responses. These findings support testing of immunotherapies in combination with other established and targeted therapies. Clin Cancer Res; 19(22); 6061–3. ©2013 AACR.
Test-Firing Ammunition for Spliceosome Inhibition in Cancer
Authors: Dehm Scott M. 
Published: October 2013

Abstract
E7107 is a derivative of the pladienolide family of natural product spliceosome inhibitors, which targets the U2 small nuclear ribonucleoprotein (snRNP) subunit SF3b. The results of a first-in-human trial with E7107 have been reported, representing an important translational step toward the goal of modulating RNA splicing for cancer therapy. Clin Cancer Res; 19(22); 6064–6. ©2013 AACR.
Clinical, Electrocardiographic, Echocardiographic Characteristics and Long-Term Follow-Up of Elite Soccer Players With J-Point Elevation
Authors: Biasco Luigi , Cristoforetti Yvonne , Castagno Davide , Giustetto Carla , Astegiano Piero , Ganzit Gianpasquale , Gribaudo Carlo Gabriele , Gaita Fiorenzo 
Published: October 2013

Background—
J-point elevation is common in athletes; nevertheless, the influence of structural changes associated with the athlete’s heart and its prognostic impact are still debated. Our aim was to investigate the prevalence of J-point elevation, the associated clinical, electrocardiographic, and echocardiographic characteristics and its impact on long-term outcome in elite soccer players.

Methods and Results—

Clinical, electrocardiographic, and cardiopulmonary exercise test data from 332 male professional soccer players were retrospectively analyzed. For 235 (70.7%) athletes echocardiographic data were also available. J-point elevation was defined as an elevation ≥1 mm in ≥2 contiguous leads. Long-term follow-up data were obtained for all athletes, whereas univariate and multivariable analyses were performed to assess the associated characteristics. Overall, 118 (35.6%) athletes showed a J-point elevation ≥1 mm. At multivariable analysis a significant direct association of interventricular septum thickness (odds ratio for 1 SD increase, 1.361; 95% confidence interval, 1.019–1.817;
P
=0.036) and Sokolow–Lyon index (odds ratio for 1 SD increase, 1.367; 95% confidence interval, 1.026–1.822;
P
=0.033) and an inverse association of baseline heart rate (odds ratio for 1 SD increase, 0.686; 95% confidence interval, 0.508–0.927;
P
=0.011) with J-point elevation were observed. During a long-term follow-up (median, 13.3 years; first and third quartiles, 10.1–17.0 years), a low mortality rate was observed, not related to cardiovascular causes.

Conclusions—
The correlation between J-point elevation and interventricular septum thickness suggests a possible mechanistic role of exercise-induced left ventricular hypertrophy as the basis for J-point elevation. After a long-term follow-up, no cardiac death was observed.
Unipolar Signal Modification as a Guide for Lesion Creation During Radiofrequency Application in the Left Atrium
Authors: Bortone Agustín , Appetiti Anthony , Bouzeman Abdeslam , Maupas Eric , Ciobotaru Vlad , Boulenc Jean-Marc , Pujadas-Berthault Pénélope , Rioux Philippe 
Published: October 2013

Background—
In patients treated for paroxysmal atrial fibrillation, the pulmonary vein (PV) reconnection rate is substantial and may be related to the lack of transmurality achievement while performing PV isolation (PVI). It has been experimentally demonstrated that positive unipolar atrial electrogram completion, when applying radiofrequency energy, was associated with transmural lesions. In this regard, we seek to determine whether the unipolar signal modification may be an appropriate end point for point-by-point radiofrequency application and find out whether it could improve the paroxysmal atrial fibrillation ablation results in humans.

Methods and Results—

Fifty consecutive patients (61±8 years old, 41 men) with paroxysmal atrial fibrillation underwent PVI using Carto and Lasso. Each radiofrequency application lasted until development of a completely positive unipolar electrogram. Fifty patients (63±9 years old, 40 men), who previously underwent PVI following the standard approach of our institution, corresponded to the control group. All PVs were isolated in all patients of both groups. However, the procedural and ablation times were significantly lower in the unipolar group compared with those of the control group, whereas the PV reconnection rate, after 30 minutes of waiting time, was not significantly different. Overall, 21±4 months after 1 PVI session, the sinus rhythm maintenance rate without antiarrhythmic drugs was significantly higher (
P
=0.027) in the unipolar group (88%) compared with that of the control group (70%).

Conclusions—
Unipolar signal modification is a useful end point for radiofrequency energy delivery in patients with paroxysmal atrial fibrillation who undergo PVI and leads to a substantial midterm sinus rhythm maintenance rate.
Accuracy of Conventional Oximetry for Flow Estimation in Patients With Superior Cavopulmonary Connection
Authors: Downing Tacy E. , Whitehead Kevin K. , Dori Yoav , Gillespie Matthew J. , Harris Matthew A. , Fogel Mark A. , Rome Jonathan J. , Glatz Andrew C. 
Published: October 2013

Background—
Cardiac catheterization is routinely used as a diagnostic tool in single ventricle patients with superior cavopulmonary connection. This physiology presents inherent challenges in applying the Fick principle to estimate flow. We sought to quantitatively define the error in oximetry-derived flow parameters using phase-contrast cardiac MRI (CMR) as a reference.

Methods and Results—

Thirty patients with superior cavopulmonary connection who underwent combined CMR and catheterization between July 2008 and June 2012 were retrospectively analyzed. Estimates of flow and resistance calculated using the Fick equation were compared with CMR measurements. Oximetry underestimated CMR-measured pulmonary blood flow (
Q
p
) by an average of 1.1 L/min per m
2
or 32% of the CMR value (
P
<0.0001). Oximetry overestimated systemic blood flow (
Q
s
) by an average of 0.5 L/min per m
2
or 15% of the CMR value (
P
=0.009). There was no correlation between the
Q
p
:
Q
s
ratio derived by Fick and that measured by CMR (
ρ
c
=0.01). The error in the Fick
Q
p
correlated moderately with the measured systemic-to-pulmonary arterial collateral flow (
r
=0.39). The median total oxygen consumption calculated using combined CMR and oximetry data was 173 mL/min per m
2
, higher than the assumed values used to calculate flows by the Fick equation. The upper body circulation received on average 51% of systemic blood flow while conducting only 39% of total body metabolism.

Conclusions—
Fick-derived estimates of flow are inherently unreliable in patients with superior cavopulmonary connections. Integrating flows measured by CMR and pressures measured by catheter will provide the best characterization of superior cavopulmonary connection physiology.
Occult Cardiotoxicity in Childhood Cancer Survivors Exposed to Anthracycline Therapy
Authors: Toro-Salazar Olga H. , Gillan Eileen , O’Loughlin Michael T. , Burke Georgine S. , Ferranti Joanna , Stainsby Jeffrey , Liang Bruce , Mazur Wojciech , Raman Subha V. , Hor Kan N. 
Published: October 2013

Background—
More than 50% of >270 000 childhood cancer survivors in the United States have been treated with anthracyclines and are therefore at risk of developing cardiotoxicity. Cardiac magnetic resonance (CMR) has demonstrated utility to detect diffuse interstitial fibrosis and changes in regional myocardial function. We hypothesized that CMR would identify occult cardiotoxicity characterized by structural and functional myocardial abnormalities in a cohort of asymptomatic pediatric cancer survivors with normal global systolic function.

Methods and Results—

Forty-six long-term childhood cancer survivors with a cumulative anthracycline dose ≥200 mg/m
2
and normal systolic function were studied 2.5 to 26.9 years after anthracycline exposure. Subjects underwent transthoracic echocardiography, CMR with routine cine acquisition, tissue characterization, and left ventricular strain analysis using a modified 16-segment model. Extracellular volume was measured in 27 subjects, all of whom were late gadolinium enhancement negative. End-systolic fiber stress was elevated in 45 of 46 subjects. Low average circumferential strain magnitude (
ε
cc
) −14.9±1.4;
P
<0.001, longitudinal strain magnitude (
ε
ll
) −13.5±1.9;
P
<0.001, and regional peak circumferential strain were seen in multiple myocardial segments, despite normal global systolic function by transthoracic echocardiography and CMR. The mean T1 values of the myocardium were significantly lower than that of control subjects at 20 minutes (458±69 versus 487±44 milliseconds;
P
=0.01). Higher mean extracellular volume was observed in female subjects (0.34 versus 0.22;
P
=0.01).

Conclusions—
Asymptomatic postchemotherapy pediatric patients have abnormal myocardial characteristics and strain parameters by CMR despite normal global cardiac function by standard transthoracic echocardiography and CMR measures.
Macrophage Migration Inhibitory Factor for the Early Prediction of Infarct Size
Authors: Chan William , White David A. , Wang Xin‐Yu , Bai Ru‐Feng , Liu Yang , Yu Hai‐Yi , Zhang You‐Yi , Fan Fenling , Schneider Hans G. , Duffy Stephen J. , Taylor Andrew J. , Du Xiao‐Jun , Gao Wei , Gao Xiao‐Ming , Dart Anthony M. 
Published: October 2013

Background

Early diagnosis and knowledge of infarct size is critical for the management of acute myocardial infarction (
MI
). We evaluated whether early elevated plasma level of macrophage migration inhibitory factor (
MIF
) is useful for these purposes in patients with
ST
‐elevation
MI
(
STEMI
).

Methods and Results

We first studied
MIF
level in plasma and the myocardium in mice and determined infarct size.
MI
for 15 or 60 minutes resulted in 2.5‐fold increase over control values in plasma
MIF
levels while
MIF
content in the ischemic myocardium reduced by 50% and plasma
MIF
levels correlated with myocardium‐at‐risk and infarct size at both time‐points (
P
<0.01). In patients with
STEMI
, we obtained admission plasma samples and measured
MIF
, conventional troponins (
TnI
,
TnT
), high sensitive
TnI
(
hsTnI
), creatine kinase (
CK
),
CK
‐
MB
, and myoglobin. Infarct size was assessed by cardiac magnetic resonance (
CMR
) imaging. Patients with chronic stable angina and healthy volunteers were studied as controls. Of 374
STEMI
patients, 68% had elevated admission
MIF
levels above the highest value in healthy controls (>41.6 ng/mL), a proportion similar to
hsTnI
(75%) and
TnI
(50%), but greater than other biomarkers studied (20% to 31%, all
P
<0.05 versus
MIF
). Only admission
MIF
levels correlated with
CMR
‐derived infarct size, ventricular volumes and ejection fraction (n=42, r=0.46 to 0.77, all
P
<0.01) at 3 day and 3 months post‐
MI
.

Conclusion

Plasma
MIF
levels are elevated in a high proportion of
STEMI
patients at the first obtainable sample and these levels are predictive of final infarct size and the extent of cardiac remodeling.