Detection of cell-free tumor DNA in the blood has offered promise as a cancer biomarker, but practical clinical implementations have been impeded by the lack of a sensitive and accurate method for ...quantitation that is also simple, inexpensive, and readily scalable. Here we present an approach that uses next-generation sequencing to quantify the small fraction of DNA molecules that contain tumor-specific mutations within a background of normal DNA in plasma. Using layers of sequence redundancy designed to distinguish true mutations from sequencer misreads and PCR misincorporations, we achieved a detection sensitivity of approximately 1 variant in 5,000 molecules. In addition, the attachment of modular barcode tags to the DNA fragments to be sequenced facilitated the simultaneous analysis of more than 100 patient samples. As proof-of-principle, we showed the successful use of this method to follow treatment-associated changes in circulating tumor DNA levels in patients with non-small cell lung cancer. Our findings suggest that the deep sequencing approach described here may be applied to the development of a practical diagnostic test that measures tumor-derived DNA levels in blood.
To report the clinical outcome and late side effect profile of proton radiotherapy in the treatment of children with parameningeal rhabdomyosarcoma (PM-RMS).
Seventeen consecutive children with ...PM-RMS were treated with proton radiotherapy at Massachusetts General Hospital between 1996 and 2005. We reviewed the medical records of all patients and asked referring physicians to report specific side effects of interest.
Median patient age at diagnosis was 3.4 years (range, 0.4-17.6). Embryonal (n = 11), alveolar (n = 4), and undifferentiated (n = 2) histologies were represented. Ten patients (59%) had intracranial extension. Median prescribed dose was 50.4 cobalt gray equivalents (GyRBE) (range, 50.4-56.0 GyRBE) delivered in 1.8-2.0-GyRBE daily fractions. Median follow-up was 5.0 years for survivors. The 5-year failure-free survival estimate was 59% (95% confidence interval, 33-79%), and overall survival estimate was 64% (95% confidence interval, 37-82%). Among the 7 patients who failed, sites of first recurrence were local only (n = 2), regional only (n = 2), distant only (n = 2), and local and distant (n = 1). Late effects related to proton radiotherapy in the 10 recurrence-free patients (median follow-up, 5 years) include failure to maintain height velocity (n = 3), endocrinopathies (n = 2), mild facial hypoplasia (n = 7), failure of permanent tooth eruption (n = 3), dental caries (n = 5), and chronic nasal/sinus congestion (n = 2).
Proton radiotherapy for patients with PM-RMS yields tumor control and survival comparable to that in historical controls with similar poor prognostic factors. Furthermore, rates of late effects from proton radiotherapy compare favorably to published reports of photon-treated cohorts.
Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has ...rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
Angiosarcoma is an aggressive malignancy with endothelial differentiation and notoriously poor prognosis despite aggressive therapy. Limited data are available to guide management decisions. To ...address this limitation, we present a large retrospective analysis of angiosarcoma patients treated at a single institution over a 25-year period.
To identify factors that impact angiosarcoma outcomes, we reviewed demographic, tumor, and treatment characteristics of angiosarcoma patients evaluated at the University of Wisconsin Hospital between 1987 and 2012.
The cohort included 81 patients diagnosed at ages 19 to 90 years (median, 67 y). Fifty-five (68%) patients presented with localized disease, whereas 26 (32%) presented with metastases. The primary sites were visceral/deep soft tissue (42%), head and neck/cutaneous (37%), breast (16%), and limbs in the setting of Stewart-Treves (5%). The 5-year overall survival was 40% with a median of 16 months. By univariate analysis, significant adverse predictors of survival included metastases at presentation, visceral/deep soft tissue tumor location, tumor size > 5 cm, tumor necrosis, and the absence of surgical excision. A trend toward prolonged survival was observed with radiation therapy and for chemotherapy in patients with metastases. Age, sex, and prior radiation showed no correlation with survival.
Our large single institution series confirms the poor prognosis of angiosarcoma, supports a central role for surgical excision in management, and highlights the need for novel therapies particularly in patients who present with metastatic disease.
We compared tumor and normal tissue dosimetry of proton radiation therapy with intensity-modulated radiation therapy (IMRT) for pediatric parameningeal rhabdomyosarcomas (PRMS).
To quantify ...dosimetric differences between contemporary proton and photon treatment for pediatric PRMS, proton beam plans were compared with IMRT plans. Ten patients treated with proton radiation therapy at Massachusetts General Hospital had IMRT plans generated. To facilitate dosimetric comparisons, clinical target volumes and normal tissue volumes were held constant. Plans were optimized for target volume coverage and normal tissue sparing.
Proton and IMRT plans provided acceptable and comparable target volume coverage, with at least 99% of the CTV receiving 95% of the prescribed dose in all cases. Improved dose conformality provided by proton therapy resulted in significant sparing of all examined normal tissues except for ipsilateral cochlea and mastoid; ipsilateral parotid gland sparing was of borderline statistical significance (p = 0.05). More profound sparing of contralateral structures by protons resulted in greater dose asymmetry between ipsilateral and contralateral retina, optic nerves, cochlea, and mastoids; dose asymmetry between ipsilateral and contralateral parotids was of borderline statistical significance (p = 0.05).
For pediatric PRMS, superior normal tissue sparing is achieved with proton radiation therapy compared with IMRT. Because of enhanced conformality, proton plans also demonstrate greater normal tissue dose distribution asymmetry. Longitudinal studies assessing the impact of proton radiotherapy and IMRT on normal tissue function and growth symmetry are necessary to define the clinical consequences of these differences.
Primary Cardiac Sarcoma Hamidi, Maryam, MD; Moody, John S., MD, PhD; Weigel, Tracey L., MD ...
The Annals of thoracic surgery,
07/2010, Letnik:
90, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Background The presentation, management, and outcome of patients with primary cardiac sarcomas are not well defined. Furthermore, the role of adjuvant therapy has not been delineated in the ...management of primary cardiac sarcomas. Methods Patients with primary cardiac sarcoma and noncardiac sarcoma, diagnosed between 1988 and 2005, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics and outcomes of primary cardiac sarcoma were defined and compared with the characteristics of noncardiac sarcomas. Univariate and multivariate methods were used to identify factors associated with primary cardiac sarcoma survival. Results Compared with noncardiac sarcomas, primary cardiac sarcomas were found to occur in a younger age group and were more likely to present with advanced disease. Primary cardiac sarcomas were ten times more likely to be vessel-derived (eg, angiosarcoma), comprising almost half of all cases. Median overall survival for cardiac sarcoma patients was 6 months whereas that for noncardiac sarcoma patients was significantly longer at 93 months ( p < 0.001). Furthermore, cardiac sarcoma patients who underwent surgery had a median survival of 12 months whereas those who did not undergo surgery had a median survival of 1 month ( p < 0.001). Conclusions Cardiac sarcomas are a distinct, rare subset of soft tissue sarcomas with a poor prognosis. Surgery continues to be the central component of successful management. Future clinical efforts should be directed at developing approaches to permit safe radical excision and, potentially, developing effective adjuvant therapy.
A variety of drugs inhibit the conversion of arachidonic acid to prostaglandin G2 by the cyclooxygenase (COX) activity of prostaglandin endoperoxide synthases. Several modes of inhibitor binding in ...the COX active site have been described including ion pairing of carboxylic acid containing inhibitors with Arg-120 of COX-1 and COX-2 and insertion of arylsulfonamides and sulfones into the COX-2 side pocket. Recent crystallographic evidence suggests that Tyr-385 and Ser-530 chelate polar or negatively charged groups in arachidonic acid and aspirin. We tested the generality of this binding mode by analyzing the action of a series of COX inhibitors against site-directed mutants of COX-2 bearing changes in Arg-120, Tyr-355, Tyr-348, and Ser-530. Interestingly, diclofenac inhibition was unaffected by the mutation of Arg-120 to alanine but was dramatically attenuated by the S530A mutation. Determination of the crystal structure of a complex of diclofenac with murine COX-2 demonstrates that diclofenac binds to COX-2 in an inverted conformation with its carboxylate group hydrogen-bonded to Tyr-385 and Ser-530. This finding represents the first experimental demonstration that the carboxylate group of an acidic non-steroidal anti-inflammatory drug can bind to a COX enzyme in an orientation that precludes the formation of a salt bridge with Arg-120. Mutagenesis experiments suggest Ser-530 is also important in time-dependent inhibition by nimesulide and piroxicam.
Triolimus is a first-in-class, multidrug-loaded micelle containing paclitaxel, rapamycin, and 17-AAG. In this study, we examine the antitumor mechanisms of action, efficacy, and toxicity of Triolimus ...in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin, and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/mitogen-activated protein kinase and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity, and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared with paclitaxel-containing micelles. Enhanced antitumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and antitumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anticancer agents.
Abstract Angiosarcomas are malignant endothelial cell tumors with few effective systemic treatments. Despite a unique endothelial origin, molecular candidates for targeted therapeutic intervention ...have been elusive. In this study, we explored the tunica internal endothelial cell kinase 2 (Tie2) receptor as a potential therapeutic target in angiosarcoma. Human angiosarcomas from diverse sites were shown to be universally immunoreactive for Tie2. Tie2 and vascular endothelial growth factor receptor (VEGFR) antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro . In the high-grade SVR cell line, Tie2 and VEGF antagonists inhibited cell survival synergistically, whereas effects were largely additive in the low-grade MS1-VEGF cell line. Xenograft modeling using these cell lines closely recapitulated the human disease. In vivo , Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay. The combination proved more effective than either agent alone. Tie2 inhibition seemed to elicit tumor growth delay through increased tumor cell apoptosis, whereas VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation. These data identify Tie2 antagonism as a potential novel, targeted therapy for angiosarcomas and provide a foundation for further investigation of Tie2 inhibition, alone and in combinations, in the management of this disease.
Cyclooxygenase-2 (COX-2) action on the endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), generates prostaglandin
glycerol esters (PG-G) and ethanolamides (PG-EA), respectively. The ...diversity of PG-Gs and PG-EAs that can be formed enzymatically
following COX-2 oxygenation of endocannabinoids was examined in cellular and subcellular systems. In cellular systems, glycerol
esters and ethanolamides of PGE 2 , PGD 2 , and PGF 2α were major products of the endocannabinoid-derived COX-2 products, PGH 2 -G and PGH 2 -EA. The sequential action of purified COX-2 and thromboxane synthase on AEA and 2-AG provided thromboxane A 2 ethanolamide and glycerol ester, respectively. Similarly, bovine prostacyclin synthase catalyzed the isomerization of the
intermediate endoperoxides, PGH 2 -G and PGH 2 -EA, to the corresponding prostacyclin derivatives. Quantification of the efficiency of prostaglandin and thromboxane synthase-directed
endoperoxide isomerization demonstrated that PGE, PGD, and PGI synthases catalyze the isomerization of PGH 2 -G at rates approaching those observed with PGH 2 . In contrast, thromboxane synthase was far more efficient at catalyzing PGH 2 isomerization than at catalyzing the isomerization of PGH 2 -G. These results define the in vitro diversity of endocannabinoid-derived prostanoids and will permit focused investigations into their production and potential
biological actions in vivo .
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