tbuckley/cabot-search huggingface dataset:
Impact of comprehensive genomic profiling (CGP) on physician treatment recommendations in metastatic solid tumor pts who previously failed at least two standard therapies: A prospective study.
Authors: Stuart P. Leitner, Andrew Bennett Brown, Miguel Conde, I. Robert Grossman, Richard Alan Michaelson, Delia Radovich, Michael Scoppetuolo, Jennifer A. Wagmiller, Norma Alonzo Palma, Patricia C. Layton
Journal: Journal of Clinical Oncology (2015)

e22054 Background: Comprehensive genomic profiling (CGP) of routinely fixed tissue from pts with advanced solid tumors can uncover tumor specific gene alterations. Foundation Medicine has developed a CLIA-certified, CAP-accredited test to simultaneously characterize all 4 classes of genomic alterations in 236 (originally 182) cancer genes. Primary study objective was to determine how often physician treatment decisions for pts with advanced cancer would be modified after reviewing results of this test. Methods: This was a prospective, single-center investigator initiated trial in pts with metastatic solid tumors. Pts with disease progression after at least one treatment regimen, determined to be likely to fail current treatment (2ndline or more) within 6 months and an expected survival of ≥ 3 months were eligible. Pts signed protocol informed consent and tumor tissue was sent for CGP. Physicians completed a questionnaire indicating their choice of next appropriate treatment for pts progressing on current therapy while blinded to CGP results. CGP results were then unblinded and final treatment decision was recorded: same treatment or CGP directed decision for new treatment, or clinical trial referral. The switch rate (SR) was calculated as the percentage of treatment decisions changed after unblinding of CGP results. Results: 50 pts were enrolled. 28 pts were evaluable for determination of SR, 22 pts were not unblinded and therefore not evaluable for SR (due to: death n = 5, insufficient sample n = 8, investigator decision n = 5, no further progression of disease n = 3, not progressed or at defined 18 month follow up n = 1). Of evaluable pts, overall median age was (60.5) yrs., female (71%) male (29%). Most frequent tumor types were breast (32%), colon (14%), lung (11%) and uterus (11%). Twelve of 28 evaluable pts had a “switch” (SR = 43%). Seven of 12 pts (58%) had changes in drug treatment, 5 of 12 (42%) were referred to clinical trials. Conclusions: Comprehensive genomic profiling in previously treated patients resulted in frequent changes in MD treatment recommendations including clinical trial referrals in this prospective study.
Giant True Aneurysms of Saphenous Vein Bypass Grafts
Authors: Dieter Ropers, Alexander Kuhlmann, Michael Weyand, Gerhard Faller, Frank A. Flachskampf, Werner G. Daniel, Ulrich Baum, Katharina Anders, Stephan Achenbach, Josef Ludwig, Christoph D. Garlichs
Journal: Circulation (2004)
Optimizing Venous Thromboembolic Prophylaxis
Authors: Matthew J. Martin
Journal: JAMA Surgery (2016)

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High Levels of Periostin in Patients with Multiple Myeloma Correlate with Low Bone Formation, Increased Fracture Rate and Diffuse MRI Pattern; Implications Into the Biology of Myeloma Bone Disease
Authors: Evangelos Terpos, Dimitrios Christoulas, Tina Bagratuni, Athanasios Papatheodorou, Maria Gkotzamanidou, Evangelos Eleutherakis-Papaiakovou, Nikolaos Kanellias, Christina Liakou, Lia A Moulopoulos, Efstathios Kastritis, Meletios A Dimopoulos
Journal: Blood (2012)
Abstract 4830: Preclinical anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) + 5-FU + oxaliplatin in pancreatic cancer
Authors: Daniel F. Gaddy, Helen Lee, Nancy Paz, Shannon C. Leonard, Ashish Kalra, Ninfa L. Straubinger, Robert M. Straubinger, Bryan M. Gillard, Michael T. Moser, Daryl C. Drummond, Stephan G. Klinz, Bart S. Hendriks, Jonathan B. Fitzgerald
Journal: Cancer Research (2016)

Abstract Nanoliposomal irinotecan (Nal-IRI, MM-398) recently gained approval in combination with 5-fluorouracil/leucovorin (5-FU/LV) in post-gemcitabine metastatic pancreatic cancer based on results of the Phase 3 NAPOLI-1 trial. Nal-IRI, in combination with 5-FU/LV, improved overall survival in gemcitabine-refractory metastatic PDAC relative to 5-FU/LV alone with a well-defined and manageable toxicity profile in pretreated patients. FOLFIRINOX (5-FU/LV, irinotecan and oxaliplatin) is a chemotherapy regimen active in first-line metastatic PDAC. Herein, we evaluate the preclinical anti-tumor activity of a nal-IRI + 5-FU + oxaliplatin regimen relative to the FOLFIRINOX regimen. Using pancreatic cancer cell lines, we demonstrate enhanced cell death when nal-IRI treatment is simulated using prolonged exposure of SN-38 (the active metabolite of irinotecan) in combination with 5-FU and oxaliplatin. In cell line-derived and patient-derived xenograft models of pancreatic cancer we demonstrate improved anti-tumor activity of nal-IRI relative to exposure-matched doses of unencapsulated irinotecan. Further, nal-IRI consistently improved tumor growth inhibition and survival relative to unencapsulated irinotecan in preclinical models, both as a monotherapy and in combination with 5-FU and oxaliplatin. The addition of nal-IRI to 5-FU and/or oxaliplatin did not exacerbate the baseline toxicities of these agents, including weight loss and neutropenia, and tolerability could be further improved by delaying the administration of oxaliplatin to 1 day post-MM-398. These findings illustrate the therapeutic potential of nal-IRI in combination with 5-FU/LV and oxaliplatin and support an ongoing Phase 2 trial (NCT02551991) of this triplet regimen in first-line PDAC. Citation Format: Daniel F. Gaddy, Helen Lee, Nancy Paz, Shannon C. Leonard, Ashish Kalra, Ninfa L. Straubinger, Robert M. Straubinger, Bryan M. Gillard, Michael T. Moser, Daryl C. Drummond, Stephan G. Klinz, Bart S. Hendriks, Jonathan B. Fitzgerald. Preclinical anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) + 5-FU + oxaliplatin in pancreatic 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 4830.
Abstract 1865: Areca nut-induced JNK/ATF2/Jun axis regulates TGF-beta signaling contributing to pre-cancerous oral submucous fibrosis
Authors: Ila Pant, Paturu Kondaiah
Journal: Cancer Research (2016)

Abstract Oral Submucous Fibrosis (OSF) is an inflammatory, pre-cancerous condition of the oral submucosa. It affects individuals with prolonged areca nut chewing habit and therefore areca nut is regarded as the etiological agent for OSF manifestation. Transforming Growth Factor beta is an established promoter of cancer and fibrosis. Up-regulation of TGF-β and its target genes has also been reported in OSF. However, the underlying mechanism for the regulation of TGF-β by areca nut has not been elucidated. The present study demonstrates that TGF-β pathway is activated in epithelial cells after two hour exposure to areca nut extract. Areca nut increases TGF-β transcript as well as protein and thereby the downstream canonical Smad2/3 signaling. Pre-treatment with various pathway inhibitors showed JNK pathway activation as a pre-requisite to TGF-β pathway activation by areca nut. Areca nut activated JNK pathway within half an hour of treatment and this was reversed by atropine treatment suggesting involvement of muscarinic acid receptor signaling. Second messengers upstream to JNK activation and regulated by areca nut were calcium/CAMKII and reactive oxygen species. Further, areca nut treatment resulted in JNK dependent phosphorylation of ATF2 and c-Jun transcription factors. These were found to bind TGF-β promoter, as revealed by chromatin immunoprecipitation experiments. Expectedly, knockdown of these transcription factors abrogated areca nut induced TGF-β pathway activation. Based on the data obtained a model is proposed to elucidate activation of TGF-β pathway by areca nut extract involving activation of JNK and ATF2, c-Jun resulting in the over expression of TGF-β in epithelial cells which may contribute to the manifestation of OSF. Thus, this study highlights ATF2/c-Jun as the critical nodes for therapeutic intervention to prevent TGF-β over production in OSF. Funding by DST and CSIR is acknowledged. Citation Format: Ila Pant, Paturu Kondaiah. Areca nut-induced JNK/ATF2/Jun axis regulates TGF-beta signaling contributing to pre-cancerous oral submucous fibrosis. [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 1865.
Abstract 827: Polyphenon E treatment affects p73 mRNA levels
Authors: L. Michael Carastro, Ricardo A. Cordova, Christopher D. Cole, Jong Y. Park
Journal: Cancer Research (2016)

Abstract Prostate cancer (PCa) is the most common malignancy among men in the USA. Polyphenon E (PolyE) is a standardized blend of polyphenols found in green tea extract, which has been shown to have chemoprevention value in PCa models, but the molecular mechanism(s) have not been elucidated. The p73 gene is a member of the p53 tumor suppressor family. A p73 dinucleotide polymorphism (DNP) (rs1801173) is a G4C14-to-A4T14 linked pair of transitions located in exon 2 and lies between the P1 and P2 gene promoters. The P1 and P2 p73 gene promoters are the transcription initiation sites for mRNAs encoding TAp73 and deltaNp73 (DNp73) isoforms, respectively. These p73 mRNA isoforms, TAp73 and áNp73, encode protein isoforms which differ in their N-termini. TAp73 isoforms include the full-length N-terminal sequence and are transcriptionally active. áNp73 isoforms lack the N-terminal trans-activation domain and are dominate negative. Recently, we reported the p73 DNP allele was associated with (1) decreased risk [OR = 0.55, 95%CI = 0.31-0.99] for aggressive PCa and (2) increased TAp73/DNp73 protein isoform ratios in ten human cancer cell lines. We hypothesize that exposure to PolyE induces changes in TAp73/DNp73 mRNA isoform ratios. Our goal for this study is to assess the effect of PolyE on total p73 mRNA levels and TAp73/DNp73 mRNA isoform ratios using two human PCa cell lines with different p73 DNP genotypes: DU145 (wild-type) and PC-3 (heterozygous). Cultured cells were treated with PolyE (100 or 200 mg/L). Cellular RNA was isolated, converted to cDNA and used in TaqMan RT-PCR assays to detect total p73, TAp73 or DNp73 isoform mRNAs. Our data from PolyE treatments of both DU145 and PC-3 cells are consistent with increased p73 mRNA levels (2.05 and 1.60 fold, respectively) and higher TAp73/DNp73 mRNA ratios (1.13 and 1.29 fold, respectively) at the low Poly E level (100 mg/L). At the high PolyE level (200 mg/L), the TAp73/DNp73 mRNA ratios significantly decreased for both DU145 and PC-3 (0.54 and 0.49 respectively). However, the overall p73 mRNA levels was not changed in DU145 (0.91 fold), but increased in PC-3 (1.60 fold) as compared with level in negative control at the high Poly E concentration. Therefore, in this exploratory study, PolyE treatment of the two PCa cell lines tested using a more moderate concentration of 100 mg/L results in higher overall p73 levels and increased TAp73/DNp73 mRNA ratios. This data could provide a potential molecular rationale for the observation that Poly E treatments provide chemopreventative impact against PCa. Citation Format: L. Michael Carastro, Ricardo A. Cordova, Christopher D. Cole, Jong Y. Park. Polyphenon E treatment affects p73 mRNA levels. [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 827.
Abstract 1406: Analysis of immune responses as a consequence of androgen deprivation therapy in patients with biochemical progression of prostate cancer
Authors: Caroline Jochems, Ravi A. Madan, Romaine I. Fernando, James L. Gulley, Kwong Y. Tsang, Jeffrey Schlom
Journal: Cancer Research (2016)

Abstract We evaluated the immune responses in 28 patients enrolled in a phase II trial at the National Cancer Institute (NCI). The aim was to investigate the effects of 3 months of androgen deprivation therapy (ADT) with goserelin on the immune responses in patients with biochemical progression of prostate cancer following local definitive therapy. PBMC and sera were collected before treatment and after 3 months. We performed flow cytometry to evaluate the frequencies of subsets of CD4+ and CD8+ T-cells, regulatory T-cells (CD4+ CD25hi CD127− FoxP3+), MDSCs and CD4 and CD8 recent thymic emigrants. CD4 T-cell proliferation and NK-cell lytic activity were evaluated. Serum samples were analyzed for cytokines, sCD27 and sCD40L. The baseline characteristics were: median age 64 years, testosterone 361 ng/dl, PSA 2.2 ng/ml, PSA-doubling time 7.0 months, and Gleason score 7. After 3 months of ADT we found no significant changes in NK-cell function or frequencies of NK subsets. CD4+ T-cell proliferation decreased slightly. The number of CD4+ effector memory T-cells decreased, but other CD4 subsets were unchanged. The frequencies of CD4 and CD8 recent thymic emigrants did not change. Regulatory T-cells (including the CTLA4+ subset), and the effector:Treg ratio did not change. In contrast, the frequency of granulocytic MDSC decreased (P&amp;lt;0.01). There was an increase in the sCD27:sCD40L ratio (P = 0.012), due to decreased sCD40L. There was a decrease in the serum levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, GM-CSF and IFNγ. There were no changes in the serum levels of TNFα or CXCL2 after therapy. In conclusion, three months of ADT with goserelin did not alter the immune response in a way that would decrease the likelihood of successful immunotherapy after this treatment. The decreased MDSC and the increased sCD27:sCD40L ratio could indicate a more favorable immune environment. Citation Format: Caroline Jochems, Ravi A. Madan, Romaine I. Fernando, James L. Gulley, Kwong Y. Tsang, Jeffrey Schlom. Analysis of immune responses as a consequence of androgen deprivation therapy in patients with biochemical progression of 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 1406.
Abstract 1900: MiR-222 accelerates the progression of inflammatory breast cancer by targeting tumor suppressor gene p27kip1 (CDKN1B)
Authors: Joshua Were Ogony, Erin Hayes, Jennifer Knapp, Joan Lewis-Wambi
Journal: Cancer Research (2016)

Abstract MicroRNAs (miRNAs) are small non-coding RNAs about 18-22 nucleotides in length, whose main role is to regulate gene expression by altering mRNA stability and translation. MicroRNAs have been shown to play a role in many types of cancer, including breast cancer by targeting tumor suppressor genes such as p53, p27, PTEN, BRCA1, BRCA2 and many others. The goal of this study was to investigate the role of miRNAs in inflammatory breast cancer (IBC). IBC is the most aggressive and metastatic form of breast cancer, that is characterized by very rapid progression, poor prognosis, with a 5 year survival outcome of 30-40%. The mechanism that underlies the rapid progression of IBC is currently under intense investigation, and novel approaches are needed to better understand this disease. To understand the role that microRNAs might play in IBC, we conducted next generation sequencing of the miRNAs from two IBC cell line, SUM149 which is a triple negative IBC (ER-, PR-, HER2-), and SUM190 which is HER2 overexpressing, but ER and PR negative (ER-, PR-, HER2+). We found that 463 miRNAs were differentially expressed in the two cell lines, with 243 miRNAs being overexpressed in SUM149 compared to SUM190, while 220 miRNAs were overexpressed in SUM190. Notably, our qPCR analysis confirmed the raw read counts, showing that miR-155, miR-221, and miR-222 were overexpressed in SUM149 as compared to SUM190 cells by 15, 10, and 3 fold respectively. Furthermore, the inhibition of miR-222 in SUM149 resulted in significant reduction in cell proliferation, tumorsphere formation, and migration in these cells as compared to SUM190 cells. Our flow cytometry data showed that there was cell cycle arrest at the G1 phase in SUM149 cells due to miR-222 inhibition, while SUM190 cells showed little or no change. Additionally, Western blot and immunofluorescence analyses showed that the protein levels of p27, which is one of the targets of miR-222, significantly increased in SUM149 cells, but not in SUM190 cells when miR-222 inhibitor was used in these cells. These results suggest that miR-222 may accelerate the progression of some IBCs by targeting tumor suppressor genes, resulting in rapid cell proliferation, and may be a potential therapeutic target for triple negative inflammatory breast cancers. Citation Format: Joshua Were Ogony, Erin Hayes, Jennifer Knapp, Joan Lewis-Wambi. MiR-222 accelerates the progression of inflammatory breast cancer by targeting tumor suppressor gene p27kip1 (CDKN1B). [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 1900.
Abstract 3384: IGFBP5-derived peptide as a novel angiogenesis inhibitor for treatment of ovarian cancer
Authors: Jeong-Won Lee, Jae Ryoung Hwang, Young-Jae Cho, Yoo-Young Lee, Chel Hun Choi, Duk-Soo Bae, Byoung-Gie Kim
Journal: Cancer Research (2016)

Abstract Insulin-like growth factor-binding protein 5 (IGFBP5) plays a role in cell growth, differentiation, and apoptosis. We found that IGFBP5 was markedly downregulated in ovarian cancer tissue, and that its overexpression in cancer cells induced cell death. In this study, we undertook to evaluate the functional significance of each region of IGFBP5 as a tumor suppressor of ovarian cancer. We found that the C-terminal region of IGFBP5 inhibited tumor growth in a 2774 cell xenograft mouse model, and that expression of VEGF, IL-6, and TNF-α were inhibited in 2774 cells stably expressing the C-terminus of IGFBP5. In order to evaluate its effects on tumor suppression, a peptide derived from the C-terminus of IGFBP5 (BP5-C) was synthesized. As a control, a peptide mutated in the IGF-binding site of BP5-C (BP5-Cmut), as well as peptides derived from the IGFBP2 C-terminus and heparin-binding site were also synthesized. Of these peptides, BP5-C and BP5-Cmut inhibited VEGF expression and NF-kB activity. Furthermore, BP5-C inhibited angiogenesis in an in vitro and an ex vivo system, consisting of HUVEC tube formation and rat aortic ring blood vessel sprouting, respectively. The in vivo effect of BP5-C on tumor growth was studied using i.p. injection of ovarian cancer 2774 cells into mice, as well as with a patient-derived xenograft mouse model. BP5-C peptide significantly inhibited tumor growth, angiogenesis, and VEGF expression in both xenograft models. These results suggest that the C-terminus of IGFBP5 exerts an anti-cancer activity by inhibiting angiogenesis via downregulation of VEGF in an IGF-independent manner, and may be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer. Citation Format: Jeong-Won Lee, Jae Ryoung Hwang, Young-Jae Cho, Yoo-Young Lee, Chel Hun Choi, Duk-Soo Bae, Byoung-Gie Kim. IGFBP5-derived peptide as a novel angiogenesis inhibitor for treatment of ovarian 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 3384.
Hyperhydration alone in children with acute lymphoblastic leukemia (ALL) at very low risk for developing tumor lysis syndrome (TLS).
Authors: Katie Therese Carlberg, James Henry Feusner
Journal: Journal of Clinical Oncology (2016)

e22012 Background: TLS is considered an oncologic emergency and occurs when large numbers of malignant cells die and release massive amounts of certain intracellular contents (especially potassium and phosphorus). Guidelines for the prevention and management of TLS typically involve some combination of hydration, alkalinization, and hypouricemic agents. There is however a lack of published data addressing the best management for patients with ALL who are at very low risk of developing TLS. Methods: We reviewed the records of all patients diagnosed with ALL at our institution over the past five years to identify those managed without either allopurinol or Rasburicase. Data were collected that were required to establish either laboratory or clinical TLS (serum levels of potassium, phosphorus, uric acid, calcium, creatinine, and evidence of cardiac arrhythmia, seizure, or death) per the 2010 Cairo-Bishop definition [Br J Haematol, 149 (2010)]. We reviewed lab values from three days prior to seven days following the start of systemic therapy. Results: One hundred eighty children have been diagnosed with ALL, ten of whom met our inclusion criteria. Five were hyperhydrated and alkalinized while the other five received hyperhydration alone. None of them received allopurinol or Rasburicase. All ten were diagnosed with B-Lymphoblastic Leukemia. All but one were considered standard risk; the tenth was assigned high risk because of age. None of the ten patients developed either lab or clinical TLS. In fact only two of the 371 labs for the key components of the TLS (potassium, phosphorus, uric acid, creatinine) were even abnormal, given the patients’ age. Conclusions: These results support the hypothesis that there is a population of children with ALL for whom hyperhydration alone is sufficient and appropriate treatment for the prevention of TLS. When we project characteristics common to our ten patients (WBC < 50, age between 1 and 18, without hyperuricemia at presentation) onto our most recently diagnosed leukemic patient population, we estimate that over 50% of them (30 of 56) may have successfully been managed in this way. We recommend a prospective trial to confirm our hypothesis.