tbuckley/cabot-search huggingface dataset:
An economic analysis of single fraction radiotherapy for treatment of hospice patients with symptomatic bone metastasis
Authors: S. Lutz, E. Chow, M. Kerr, S. Connor
Journal: Journal of Clinical Oncology (2004)

8031 Background: Fifty percent of hospice patients have cancer, though few receive palliative radiotherapy. The Medicare hospice per diem of $114 may inhibit the use of more costly treatments. Recent trials have confirmed equal efficacy of single versus multiple fraction radiotherapy in the palliation of painful bony metastasis, and here we present an economic model estimating the range of costs for single fraction radiotherapy. Methods: We model Medicare reimbursement for single fraction radiotherapy to two hypothetical patients, each with one site of painful bony metastasis. We first choose a situation that allows use of the most economical consultation, treatment planning, and treatment delivery. We then investigate a case with a radiation sensitive normal structure adjacent to the treated area that necessitates more complex intervention. We assume no charge for a single follow-up visit 4 weeks after treatment. Results: Assuming a conversion factor of $36.70 per relative value unit and the 2003 fee schedule, the lower complexity treatment costs $630 and includes charges for codes related to limited consultation ($88), treatment management ($93), simple simulation ($168), basic dosimetry ($83), simple isodose plan ($107), pre-treatment port film ($23), and simple 6 MV treatment delivery ($68). For the more complex case, the total cost is $1154 and reflects increases in charges for codes representing more complex consultation ($173), simulation ($327), 6MV treatment delivery ($89), and isodose plan ($180), as well as the addition of a complex treatment device ($186). Using the same assumptions, the estimated cost for ten fractions ranges from $1508 to $2221. Conclusions: Though single fraction radiotherapy is more economical than the commonly used ten fraction schedule, that single treatment still costs 5 to 10 times more than the average hospice per diem. Single fraction therapy is not likely to be offered unless it leads to earlier referral to hospice, allowing the hospice program to recover some of the cost of treatment. Alternatively, we recommend adding an outlier payment system for delivery of radiotherapy to hospice patients. No significant financial relationships to disclose.
Abstract 1456: Dexamethasone suppresses cytokine-induced dual oxidase 2 (Duox2) and VEGF-A expression in human pancreatic cancer cells <i>in vitro</i> and pancreatic cancer growth in xenografts
Authors: Yongzhong Wu, Smitha Antony, Jennifer L. Meitzler, Jiamo Lu, Agnes Juhasz, Guojian Jiang, Krishnendu Roy, James H. Doroshow
Journal: Cancer Research (2016)

Abstract Chronic pancreatic inflammation is strongly associated with pancreatic cancer. We previously demonstrated that inflammatory cytokines interact to produce a Duox2 (one of 7 members of the NADPH Oxidase family)-dependent, reactive oxygen species (ROS)-related, pro-oxidant milieu that could increase the pathologic potential of pancreatic inflammation, enhancing malignant transformation. Furthermore, we have shown that Duox2 expression is upregulated in patients with chronic pancreatitis as well as pancreatic ductal adenocarcinoma (PDAC). Dexamethasone (Dex) has been reported to inhibit PDAC invasiveness, the formation of pancreatic intraepithelial neoplasia in genetically-engineered mouse models of pancreatic cancer, as well as epithelial to mesenchymal transition, and local tumor recurrence and metastasis in vivo. Using cultured human pancreatic cancer cell lines, we found that in a dose- and time-dependent fashion Dex inhibited cytokine (IFN-γ/LPS, IL-4, and IL-17)-mediated up-regulation of Duox2 and VEGF-A expression in several human pancreatic cancer cell lines, including BxPC-3, ASPC-1, and CFPAC-1. The effects of Dex were abolished by pre-treatment with the Dex antagonist RU-486. As expected, we did not observe anti-proliferative effects of Dex on PDAC cells in vitro. However, Dex strongly repressed Duox2 mRNA and protein expression as well as the growth of xenografts initiated from BxPC-3 cells; in contrast, for the MIA-Paca line that is unresponsive to cytokines in culture, Dex produced no effect on Duox2 expression and tumor growth when these cells were grown as xenografts. Examination of the human Duox2 promotor in silico revealed a putative negative glucocorticoid receptor (GR) binding element. Western analysis, using nuclear extracts from pancreatic cancer cells treated with Dex, revealed that both activated glucocorticoid receptor and certain co-repressors, such as NCOR-1/2 and histone deacetylases (HDAC1, 2, and 3) exist in human pancreatic cancer cell nuclei. Our ongoing experiments are focused on understanding the molecular mechanism of Dex-mediated Duox2 repression both in vitro and in vivo. In summary, these studies suggest that cytokine-related oxidant stress, generated by Duox2, could play a role in the progression of pancreatic cancer. Citation Format: Yongzhong Wu, Smitha Antony, Jennifer L. Meitzler, Jiamo Lu, Agnes Juhasz, Guojian Jiang, Krishnendu Roy, James H. Doroshow. Dexamethasone suppresses cytokine-induced dual oxidase 2 (Duox2) and VEGF-A expression in human pancreatic cancer cells in vitro and pancreatic cancer growth in xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1456.
In the Novel Agents Era, Is the International Staging System Still Has the Prognostic Value in Patients with Renal Impairment?
Authors: Sung-Hoon Jung, Hee Kyung Kim, Seok Jin Kim, Seung-Shin Lee, Jae-Sook Ahn, Yeo-Kyeoung Kim, Deok-Hwan Yang, Hyeoung-Joon Kim, Je-Jung Lee, Kihyun Kim
Journal: Blood (2015)
Abstract 1265: Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia
Authors: Fatma Eryildiz, Jeffrey W. Tyner
Journal: Cancer Research (2016)

Abstract The undesirable outcomes of classical chemotherapy approaches in the treatment of cancer pathogenesis has directed scientists to find more targeted and less toxic therapies. Numerous studies of targeted therapies in cancer have demonstrated that finding target genes that are responsible for cancer pathogenesis can lead to novel targeted cancer therapies. Among these studies, tyrosine kinases have been prominent as effective gene targets. We have employed this approach to study the hematologic malignancy, Acute Myeloid Leukemia (AML). In this study, we aimed to understand how human tyrosine kinase members, as functional drivers of leukemogenesis, promote tumor progression by activating downstream molecules. For this purpose, an RNAi assisted silencing assay was designed in which every individual tyrosine kinase member was silenced and impact on primary AML cell viability was assessed. Bioinformatic interpretation of the data revealed that TYRO3 is one of the genes showing significant sensitivity to silencing in 7.64% of AML cases tested (n = 484). This data is compatible with previous studies showing aberrant expression of TAM family member tyrosine kinases in several human cancers. In addition, immunoblotting was performed to assess TYRO3 protein expression in several AML cell lines. Several AML lines demonstrated higher expression levels of TYRO3. In a strong correlation with this finding, TYRO3 siRNA was able to partially silence the TYRO3 expression especially in those cell lines that have higher expression levels of TYRO3 and due to this silencing we observed decreased cell viability relative to non-specific siRNA suggesting that high expression of TYRO3 provides a cell survival advantage in AML. Even though signaling pathways of other TAM family members and their interactions are described in detail, TYRO3 downstream signaling pathway still remains quite undetermined which makes it an intriguing player in cell survival. There are not many small molecules designed to inhibit TAM tyrosine kinases, but our study shows that successful targeted inhibition of this family of receptor tyrosine kinases may represent a promising avenue to provide opportunities to improve therapeutic approaches for patients with AML. [1] Druker, Brian J. “Imatinib as a paradigm of targeted therapies.” Advances in cancer research 91 (2004): 1-30. Citation Format: Fatma Eryildiz, Jeffrey W. Tyner. Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1265.
High Similarity between Distantly Related Species of a Plant SINE Family Is Consistent with a Scenario of Vertical Transmission without Horizontal Transfers
Authors: Jeffrey A. Fawcett, Hideki Innan
Journal: Molecular Biology and Evolution (2016)

Many transposable element (TE) families show surprisingly high levels of similarity between distantly related species. This high similarity, coupled with a "patchy" phylogenetic distribution, has often been attributed to frequent horizontal transfers of TEs between species, even though the mechanistic basis tends to be speculative. Here, we studied the evolution of the Au SINE (Short INterspersed Element) family, in which high similarity between distantly related plant species has been reported. We were able to identify several copies present in orthologous regions of various species, including species that diverged ∼90 Ma, thereby confirming the presence of Au SINE at multiple evolutionary time points. We also found that the Au SINE has been degenerating and is en route to disappearing in many species, indicating that the loss of Au SINE is common. Our results suggest that the evolution of the Au SINE can be readily explained by a scenario of vertical transmission without having to invoke hypothetical scenarios of rampant horizontal transfers. The Au SINE was likely present in the common ancestor of all angiosperms and was retained in some lineages while lost from others. The high level of conservation is probably because the sequences were important for ensuring their transpositional activity. This model of TE evolution should provide a basic framework for understanding the evolution of TEs in general.
Abstract 3316: The effects of dopamine receptor 2 on breast cancer tumor initiating cells
Authors: Matthew Tegowski, Charlene Santos, Albert Baldwin
Journal: Cancer Research (2016)

Abstract Despite advances in early detection and treatment of breast cancers, metastatic disease remains a significant problem and a large cause of mortality in the US. Although tumors are characterized as a mass of uncontrolled cell division, it is thought that only small populations of cells, known as tumor initiating cells (TICs), are primarily responsible for metastasis. TICs are less differentiated than most tumor cells and many TICs show an epithelial-to-mesenchymal transition (EMT). Recently, the FDA-approved drug thioridazine, a dopamine receptor 2 (DRD2) antagonist, has been shown to inhibit pluripotency gene expression only in transformed stem cells. To test whether DRD2 can regulate TICs in breast cancer cells, two main assays were performed. The tumorsphere assay is used to measure TIC activity within a population of cells in vitro. In this assay, single cells are cultured in suspension, in the absence of serum. Cells must escape anoikis and grow without cell-cell contacts or the assortment of factors contained in serum. However, the gold standard in vivo assay to measure tumor initiation is the transplantation assay at limiting dilutions. Cells are injected into immunocompromised mice in decreasing numbers and the number of tumors each population of cells is capable of forming is measured. In this study the tumorsphere assay and transplantation assay both show that DRD2 supports TICs in breast cancers. Interestingly, our data suggest that DRD2 regulates TICs and cellular differentiation through the activity of the STAT3 transcription factor. Activation of STAT3 has been shown to induce gene expression changes that support TICs and upregulate the pluripotency factor OCT4. STAT3 activity can also induce EMT and resistance to some therapeutics. By inducing the expression of its own activator, IL-6, STAT3 can initiate a feed forward loop to maintain continual expression to promote TICs, EMT, and drug resistance. Halting the continual activation of STAT3 in these cells should be an important objective. Our data supports the concept that DRD2 may represent a new, and druggable target for therapies to decrease metastasis and/or recurrence by interfering with STAT3 and inhibiting TIC-like activities. Citation Format: Matthew Tegowski, Charlene Santos, Albert Baldwin. The effects of dopamine receptor 2 on breast cancer tumor initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3316.
Safe and Effective Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) and Low Baseline Platelet Counts with Belinostat
Authors: Kerry J. Savage, Steven M. Horwitz, Pier Luigi Zinzani, Achiel Van Hoof, Sarit E. Assouline, Gajanan Bhat, Mi Rim Choi, Lee F Allen, Dina Ben-Yehuda, Wojciech Jurczak, Tamas Masszi, Andrei R. Shustov
Journal: Blood (2014)
Abstract 4896: A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flow cytometry using cryopreserved human peripheral blood mononuclear cells
Authors: Shigehisa Kitano, Makiko Yamashita, Hiroaki Aikawa, Aya Kuchiba, Mitsuhiro Hayashi, Noboru Yamamoto, Kenji Tamura, Akinobu Hamada
Journal: Cancer Research (2016)

Abstract For predicting the clinical efficacy of antibody-dependent cellular cytotoxicity (ADCC) -dependent antibody therapy, analyzing the cytotoxic functions of effector cells such as NK cells against target cancer cells is thought to be necessary. The 51Cr release assay has long been the most widely used method for quantification of ADCC activity. However, the reproducibilities of these release assays are not adequate, and they do not allow evaluation of the lysis susceptibilities of distinct cell types within the target cell population. In this study, we established a novel method for evaluating cytotoxicity, which involves the detection and quantification of dead target cells using flowcytometry. CFSE (carboxyfluorescein succinimidyl ester) was used as a dye to specifically stain and thereby label the target cell population, allowing living and dead cells, as well as also target and effector cells, to be quantitatively distinguished. Furthermore, with our new approach, ADCC activity was more reproducibly, sensitively, and specifically detectable in not only freshly isolated but also in frozen human peripheral blood mononuclear cells (PBMCs) compared to the calcein-AM release assay. This assay, validated herein, is expected to be a standard assay to evaluate ADCC activity and finally contribute clinical development of ADCC dependent-antibody therapies. Citation Format: Shigehisa Kitano, Makiko Yamashita, Hiroaki Aikawa, Aya Kuchiba, Mitsuhiro Hayashi, Noboru Yamamoto, Kenji Tamura, Akinobu Hamada. A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flow cytometry using cryopreserved human peripheral blood mononuclear cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4896.
Abstract 2121: Src mediates acquired resistance to ALK inhibitor in ALK-rearranged non-small cell lung cancers
Authors: Ryohei Yoshida, Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Osaki
Journal: Cancer Research (2016)

Abstract ALK tyrosine kinase inhibitors (TKIs) play a significant role in the treatment of ALK-rearranged non-small cell lung cancer patients.After the significant initial response to ALK-TKIs, the emergence of acquired resistance ultimately occur for all patients. Understanding the origin of resistance mechanisms within a patient is crucial to guide treatment and developing drugs/combinations to circumvent resistance. There are reported that some of the tyrosine kinases are involving by bypassing ALK signaling, but comprehensive identification of proteins that are significant for acquired resistance in ALK-TKIs is still required. Quantitative proteomic analysis provides a powerful approach in screening for alterations in protein levels. An analysis of the differential proteins expression between original cancer cell and acquired resistance cell would be useful for identification of proteins drug resistance. To investigate the changes of chaperon holding proteins, ALK rearranged-cell line H3122 were used. ALK-TKI Alectinib resistant cell lines were established by exposing increased dose of alectinib to ALK rearranged H3122 cell line (AFR). Luminespib (AUY922, Novartis Pharm.) was used as HSP90 inhibitor and Saracatinib (Selleck Chemicals.) was used as Src inhibitor in this study. We used iTRAQ (isobaric tags for relative and absolute quantitation) technology using nano-LC-MS/MS analysis, to identify alterations in H3122 protein levels of pre/post HSP90 inhibitor treatment. For further analysis, protein expression was measured by western blot. To assess the cancer cell growth inhibition for ALK and/or Src inhibitors, we used colony formation assay. Our results revealed that Crk-Src related proteins were overexpressed in ALK TKI resistance cells and had a significant protein expression changes after HSP90 inhibitor treatment. To address the impact of overcoming resistance by blocking Crk-Src pathway, Drugs/combinations with ALK inhibitor and/or Src inhibitors showed that significant treatment effect in vitro and in vivo study using tumor-bearing mouse model. Conclusion Src is one of the significant signaling pathways in the ALK-rearranged NSCLCs resistant to ALK-TKIs including alectinib, and inhibiting Src signaling could be a potential target for ALK-rearranged NSCLC after ALK-TKI resistance. Citation Format: Ryohei Yoshida, Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Osaki. Src mediates acquired resistance to ALK inhibitor in ALK-rearranged non-small cell lung cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2121.
Abstract 882: TMPRSS2-ERG drives global mistargeting of mammalian SWI/SNF (BAF) complexes in prostate cancer
Authors: Gabriel J. Sandoval, John L. Pulice, David Y. Takeda, Monica A. Schenone, Marius Pop, Gaylor Boulay, Miguel N. Rivera, Lucienne Ronco, William C. Hahn, Cigall Kadoch
Journal: Cancer Research (2016)

Abstract Prostate cancer remains one of the leading causes of cancer-related death in men. Chromosomal rearrangements resulting in the fusion of the androgen regulated gene TMPRSS2 and the ETS-family transcription factor ERG occur in over 50% of all prostate cancer cases. Recent studies enabled by genome-wide methodologies have implicated altered epigenomic landscapes and changes in DNA accessibility as major contributors to ERG-driven oncogenesis, however the precise mechanism underlying the ERG transcriptional signature has to date remained unclear. Here we performed the first endogenous purification and SILAC-mass spectrometric analysis of ERG in TMPRSS2-ERG prostate cancer cells. Remarkably, we demonstrate that ERG directly interacts with the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which was recently shown to be mutated in &amp;gt;20% of human malignancies. ERG co-localizes with BAF complexes genome-wide, resulting in specific ERG-dependent BAF complex targeting to sites enriched in known ERG, FOXA1, and HOXB13 motifs; additionally, loss of ERG in TMPRSS2-ERG driven cell lines results in dramatic retargeting of BAF complexes away from ERG-dependent sites, to sites enriched in known AR and CTCF motifs. Importantly, ERG-driven BAF complex retargeting contributes to activation of TMPRSS2-ERG prostate cancer gene expression signatures. We map the ERG-BAF interaction to a specific region within the ERG amino acid sequence and find that this region is required to bind BAF complexes. These studies reveal a novel, unexpected mechanism of action of ERG-driven oncogenesis and offers new strategies for therapeutic intervention. Citation Format: Gabriel J. Sandoval, John L. Pulice, David Y. Takeda, Monica A. Schenone, Marius Pop, Gaylor Boulay, Miguel N. Rivera, Lucienne Ronco, William C. Hahn, Cigall Kadoch. TMPRSS2-ERG drives global mistargeting of mammalian SWI/SNF (BAF) complexes in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 882.
Phase II study of preoperative helical tomotherapy with a simultaneous integrated boost for rectal cancer.
Authors: G. Storme, B. Engels, H. Everaert, K. Tournel, A. Hoorens, A. Sermeus, D. Verellen, M. De Ridder
Journal: Journal of Clinical Oncology (2010)

e14014 Background: Preoperative chemoradiotherapy is standard of care for locally advanced rectal cancer. However, adding concomitant chemotherapy to preoperative radiotherapy does not improve survival or the incidence of distant metastasis, and is associated with considerable grade 3+ toxic effects. The aim of this study is to explore the efficacy and toxicity profile of helical tomotherapy in the preoperative treatment of rectal cancer. Methods: This interim analysis reports the first 106 patients. A dose of 46 Gy, in daily fractions of 2 Gy, was delivered to the presacral space and the perineum if an abdominoperineal resection was deemed necessary. No concomitant chemotherapy was administered, but the dose of radiation was increased by a simultaneous integrated boost to 55.2 Gy, when the circumferential resection margin (CRM) was less than 2 mm. The response was determined by measuring the metabolic tumor volume prior to and five weeks after the end of radiotherapy by FDG-PET. Results: 54 patients presented with a T2 or good T3 tumor (CRM ≥ 2 mm) and entered the no boost group, 52 patients presented with a bad T3 (CRM < 2 mm) or T4 tumor on MRI and entered the boost group. One patient, in the no-boost group, developed grade 3 enteritis. No other grade 3+ acute toxicities were observed. 16, 12, 28 and 1 patient developed acute grade 2 gastrointestinal, urinary, dermatologic and gynecologic toxic effects respectively. The mean decrease in metabolic volume was 61 ± 30% in the no boost group, compared to 76 ± 27% in the boost group (p = 0.04). With a median follow-up of 25 months, 1 locoregional relapse was observed. Conclusions: Helical tomotherapy reduces acute toxicity in preoperative radiotherapy of rectal cancer. A simultaneous integrated radiation boost increases the metabolic response, without excessive toxicity. A multicentric randomized noninferiority multicenter trial that compares this approach to preoperative chemoradiotherapy is being initiated. No significant financial relationships to disclose.