Image-guided radiation therapy for post-operative gynaecologic cancer: patient set up verification with and without implanted fiducial markers

<p><b>Background:</b> Intensity modulated radiotherapy (IMRT) is increasingly being used to treat gynaecological malignancies in the postoperative setting. The purpose of this study was to evaluate the use of image-guided radiotherapy (IGRT) using cone-beam computed tomography (CBCT) with fiducial markers for daily localization.</p> <p><b>Material and methods:</b> A single institution study was performed of consecutive cervical or endometrial cancer patients receiving adjuvant external beam radiotherapy (<i>n</i> = 15). Patients were set up at treatment using daily CBCT and alignment of implanted fiducial markers. Image registration was retrospectively completed based on soft tissue matching and the resulting couch shifts from each IGRT method were compared (<i>n</i> = 122).</p> <p><b>Results:</b> The median shift between IGRT methods was 2 mm, 1 mm and 1 mm in the anterior-posterior (A-P), superior-inferior (S-I), and lateral directions, respectively. The largest deviations were observed in the A-P direction; however, more than 90% were within 5 mm and 63.9% were within 2.5 mm.</p> <p><b>Conclusions:</b> IGRT based on soft tissue match provides a noninvasive convenient method for daily localization and is accurate within treatment uncertainty for the majority of cases.</p

Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells

<p>Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial. We demonstrate that genetic ablation of ERBB4, but not ERBB1-3, led to apoptosis in lapatinib-resistant cells, suggesting that the efficacy of pan-ERBB inhibitors was, at least in part, mediated by the inhibition of ERBB4. Moreover, ERBB4 was upregulated at the protein level in ERBB2+ breast cancer cell lines selected for acquired lapatinib resistance <i>in vitro</i> and in <i>MMTV-Neu</i> mice following prolonged lapatinib treatment. Knockdown of ERBB4 caused a decrease in AKT phosphorylation in resistant cells but not in sensitive cells, suggesting that ERBB4 activated the PI3K/AKT pathway in lapatinib-resistant cells. Importantly, ERBB4 knockdown triggered apoptosis not only in lapatinib-resistant cells but also in trastuzumab-resistant cells. Our results suggest that although ERBB4 is dispensable for naïve ERBB2+ breast cancer cells, it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors, lapatinib and trastuzumab.</p

Additional file 2: of Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas

Mice Null for the Deubiquitinase USP18 Spontaneously Develop Leiomyosarcoma. (DOCX 115 kb

Additional file 1: Table S1. of Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas

Antibodies used for immunohistochemistry studies. Table S2. Immunohistochemical staining of USP18 in clinical leiomyosarcoma samples. Figure S1. A: Dystrophic calcifications in USP18 null mice. A representative image of a USP18-/- mouse is shown. B: KHC-2 cells with reconstituted USP18 expression maintained expression for the duration of growth in mice. Immunoblot analysis of protein isolated from 4 control and 4 USP18 overexpressing independent orthotopic sarcomas harvested from mice. The immunoblot showed representative analysis of KHC-2 cells and this finding was also seen in KHC-1 cells (data not shown). Figure S2. USP18 null leiomyosarcoma cell lines are sensitive to treatment with the JAK2-STAT3 inhibitor, JSI-124. A: Immunoblot analysis of pSTAT3, STAT3, CDK4 and USP18 levels in KHC-1 cells with and without stably restored USP18 activity. B: Growth analysis of KHC-1 cells with JAK2-STAT3 inhibitor, JSI-124. Similar effects were seen in KHC-2 cells (data not shown). Validation of JSI-124 repression of JAK2-STAT3 pathway C: Immunoblot analyses of phosphorylated JAK2 (pJAK2), JAK2, and actin with relative level of pJAK2/JAK2 calculated relative to control. D: Immunoblot analysis of phosphorylated STAT3 (pSTAT3), STAT3, cyclin D1 and actin levels. Figure S3. USP18 null leiomyosarcoma cell line KHC-1 and human leiomyosarcoma cell line SK-LMS-1 growth in response to interferon-β (500Units/ml IFNB) or doxycycline (0.2ΟM Dox) treatment over 3 days. Results expressed as fold relative to vehicle treated cells. Each experiment was performed in triplicate 3 separate times. Figure S4. USP18 null leiomyosarcoma cell line KHC-1 with restored USP18 expression did not affect response to IFNb (500Units/ml). Results expressed as fold relative to vehicle treated cells. (N.S. = not significant). (PPTX 2131 kb