Motesanib diphosphate in progressive differentiated thyroid cancer.
ABSTRACT Background The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. Methods In an open-label, single-group, phase 2 study, we treated 93 patients who had pro- gressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radio- graphic review. Additional end points included the duration of the response, pro- gression-free survival, safety, and changes in serum thyroglobulin concentration. Results Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective re- sponse rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval (CI) was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). Conclusions Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)
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ABSTRACT: This paper presents a novel pipeline leak detection scheme based on gradient and slope turns rejection (GSTR). Instead of monitoring the pipeline under constant working pressure, GSTR introduces a new testing method which obtains data during the transient periods of different working pressures. A novel pipeline leak detection method based on those transient data without failure history is proposed. Wavelet packet analysis (WPA) is applied to extract features which capture the dynamic characteristics from the non-stationary pressure data. Principal component analysis (PCA) is used to reduce the dimension of the feature space. Gaussian mixture model (GMM) is utilized to approximate the density distribution of the lower-dimensional feature space which consists of the major principal components. Bayesian information criterion (BIC) is used to determine the number of mixtures for the GMM and a density boosting method is applied to achieve better accuracy of the distribution estimation. An experimental case study for oil pipeline system is used as an example to validate the effectiveness of the proposed method.Journal of Loss Prevention in the Process Industries 01/2012; · 1.35 Impact Factor
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ABSTRACT: Thyroid cancer is one of the most rapidly increasing cancers in many countries. Although most thyroid cancers are differentiated cancers and easily treated with radioiodine (RI), a portion of differentiated and undifferentiated cancers is refractory not only to RI therapy, but also to radiotherapy and chemotherapy. Thus, various alternative therapies have been tested in RI-refractory thyroid cancers. These alternative therapies include two major categories: redifferentiation therapy and recent molecular target therapy. Several clinical trials have investigated these therapies. They demonstrated potential effects of the therapies, although the results have been somewhat limited so far. Thus, the future strategy for undifferentiated thyroid cancers will involve individualized, lesion-specific, and combined therapy. In this review, the basic mechanism of each redifferentiation and molecular target therapy is discussed, and results of recent clinical trials using these therapeutic agents are summarized.Nuclear Medicine and Molecular Imaging. 12/2011; 45(4).
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ABSTRACT: Das große Interesse an der Behandlung lokal fortgeschrittener oder bereits metastasierter Schilddrüsenkarzinome spiegelt sich durch die hohe Anzahl an eingereichten und bewilligten Kongressbeiträgen auf dem Jahreskongress der „American Society of Clinical Oncology“ (ASCO-Kongress) 2011 wider. Viele Patienten mit differenzierten, undifferenzierten und medullären Schilddrüsenkarzinomen sprechen auf bisher etablierte Therapieverfahren nicht mehr ausreichend an, sodass Hoffnung in neuere Therapiestrategien gesetzt wird. Bei diesen Therapieverfahren handelt es sich vor allem um Targettherapeutika, die biologisch gezielt zentrale Signalkaskaden in den veränderten Zellen bekämpfen, insbesondere die Angiogenese dieser Tumoren. Der Kliniker sollte die Möglichkeiten dieser Therapie kennen und mit den typischen Nebenwirkungen vertraut seien.HNO 05/2012; 60(5). · 0.54 Impact Factor
n engl j med 359;25 www.nejm.org december 18, 2008
Motesanib Diphosphate in Progressive Differentiated
To the Editor: Sherman et al. (July 3 issue)1
highlight the importance of selecting patients for
alternative therapies, such as motesanib diphos-
phate, in the treatment of progressive differenti-
ated thyroid carcinomas. Although radiographic
findings are useful criteria for predicting a re-
sponse to motesanib, they can be supplemented
by the microscopical findings — in particular,
growth pattern, necrosis, and desmoplastic reac-
tion — which have been correlated with progres-
sion prediction.2 The genotypic alterations de-
scribed in follicular-cell neoplasms control the
mitogen-activated protein (MAP) kinase pathway
and proliferation. Was any correlation found with
proliferation markers? Which radiographic crite-
ria were used to define progression in metastatic
neoplasms? As for tumor progression, it normal-
ly refers to the acquisition of invasive capabilities
in intraepithelial lesions or metastatic potential
in invasive cancers.3
Salvador J. Diaz-Cano, M.D., Ph.D.
King’s College Hospital
London SE5 9RS, United Kingdom
Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate
in progressive differentiated thyroid cancer. N Engl J Med 2008;
Arif S, Patel J, Blanes A, Diaz-Cano SJ. Cytoarchitectural and
kinetic features in the histological evaluation of follicular thy-
roid neoplasms. Histopathology 2007;50:750-63.
Diaz-Cano SJ. General morphological and biological fea-
tures of neoplasms: integration of molecular findings. Histopa-
The author replies: We agree with Diaz-Cano
that careful selection of patients for treatment with
investigational therapies for differentiated thyroid
cancer is essential. As is standard in cancer-thera-
py trials, in our trial progression was defined by
application of the Response Evaluation Criteria in
Solid Tumors (RECIST) for determination of both
eligibility and response.1 The microscopical fea-
tures referenced by Diaz-Cano may certainly be
valuable in characterizing follicular neoplasms but
have not yet been established as predictors of re-
sponses to therapy. Future studies of molecularly
targeted therapies in thyroid cancer may well ben-
efit from serial assessment of cellular responses
to treatment, including proliferation markers and
signaling intermediates, as he suggests.
Steven I. Sherman, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77230-1402
for the Motesanib Thyroid Cancer Study Group
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines
to evaluate the response to treatment in solid tumors: European
Organization for Research and Treatment of Cancer, National
Cancer Institute of the United States, National Cancer Institute
of Canada. J Natl Cancer Inst 2000;92:205-16.
Platelets and the Vascular Wall
To the Editor: In their review of the importance
of platelets in maintaining the integrity of the vas-
cular wall, Nachman and Rafii (Sept. 18 issue)1
provide evidence that maintenance of the endo-
thelial barrier depends on a reciprocal communi-
cation between endothelial cells and platelets and
the formation of zipper structures at adherens
junctions. A protein that is central in the activa-
tion status of platelets and endothelial zipper struc-
tures is vasodilator-stimulated phosphoprotein
(VASP). VASP is crucial for the polymerization of
the actin cytoskeleton and is intimately linked to
several proteins forming adherens junctions, such
as α-catenin. Endothelial cells deficient in VASP
are leaky, and platelets lacking VASP demonstrate
severe abnormalities in the platelet interaction with
the endothelium.2,3 Therefore, we wonder what the
authors think about the role of VASP in the cross-
talk between platelets and endothelial cells.
Valbona Mirakaj, M.D.
David Köhler, Ph.D.
Peter Rosenberger, M.D., Ph.D.
University Hospital Tübingen
72076 Tübingen, Germany
The New England Journal of Medicine
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