tbuckley/cabot-search huggingface dataset:
Epidemiology, treatment modalities and prognostic factors of colon cancer in the central region of Tunisia
Authors: I. Belaid, W. Khechine, A. Saad, A. Fki, H. Makram, A. El Ghali, I. Chabchoub, F. Ezzairi, L. Ben Fatma, S. Ben Ahmed
Journal: Annals of Oncology (2019)
BAD guidelines for SJS/TEN in children and young people, 2018
Authors: T. McPherson, L.S. Exton, S. Biswas, D. Creamer, P. Dziewulski, L. Newell, K.L. Tabor, G.N. Wali, G. Walker, R. Walker, S. Walker, A.E. Young, M.F. Mohd Mustapa, R. Murphy
Journal: British Journal of Dermatology (2019)

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are urgent, serious immune reactions in which there is skin loss and severe ulcers in the mouth, eyes and genital areas. It affects about 5‐6 people per million under 18 years of age in the U.K. each year. It has a mortality of (causes death in) 5‐10% and re‐occurs in up to 18% of survivors. The British Association of Dermatologists led a group of relevant experts to examine the evidence in developing guidelines to aid diagnosis and management of SJS/TEN in children and young people. As with many rare conditions, there are few high‐quality trials comparing one treatment with another. Most of the evidence comes from patient examples reported in the medical literature (i.e. medical journals). The research reveals some important differences between children and adults in terms of the cause and outcomes of SJS/TEN. Infections are a more common cause in children and young people although medication can be the cause in all ages. Children are less likely to die from SJS/TEN than adults. Preventing long‐term complications is of key importance. Management in the early stages should ensure the identification of the cause, stopping any possible medications that might be the cause, and consideration of infection as the trigger. The best evidence for improved outcomes is good supportive care in the right clinical environment. This requires admission to appropriate specialist units with experience in managing skin loss, and a team of hospital specialists who can address all potential clinical complications. Longer‐term management involves supporting patients and their families with any resulting complications including those affecting the eyes, skin, lungs and psychological impact. The guidelines highlight that there is still much that is unknown about the best way to manage this potentially devastating reaction, and identifies the need for better routine data collection, diagnosis and standardised treatment, as well as a multi‐disciplinary (involving different types of healthcare workers) approach to management.
Abstract 1784: High expression of PTK-7 regulates the growth and invasion of triple-negative breast cancer cells
Authors: Lakshmi Reddy Bollu
Journal: Cancer Research (2019)

Abstract Background: Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with poor prognosis. Due to the frequent distant metastasis and lack of successful targeted therapies, the overall survival rate for the patients with TNBC is significantly lower than estrogen receptor positive and HER2 positive breast cancers. To identify potential druggable targets, previously, we performed a gene expression analysis and identified protein kinases that are highly expressed in ER-negative breast cancers. Through these studies, we discovered that the expression of pseudo kinase-7 (PTK-7) is highly elevated in TNBCs and correlated with p53 mutation status and disease progression. We hypothesize that high expression of PTK-7 is required for the growth and invasiveness of TNBC cells. Experimental design and methods: In this study, we analyzed the expression status of PTK-7 in TNBC and the association of PTK-7 expression with p53 status and disease prognosis using publicly available datasets. Protein levels of PTK-7 were determined through western blotting analysis. The association of p53 and PTK-7 expression was determined using Oncomine analysis. Using specific siRNAs against PTK-7, we determined whether PTK-7 is required for the growth of TNBC cells. The role of PTK-7 in migration and invasion of TNBC cells was determined using Boyden trans-well assays. Results: Analysis of publicly available datasets reveals that PTK-7 expression is elevated in TNBCs compared with normal breast and ER-positive breast cancers. High PTK-7 expression was found to be associated with p53 mutations. Knockdown of PTK-7 using siRNA significantly reduced the growth of TNBC cells in vitro. In vitrotrans-well migration and invasion studies also demonstrated that knockdown of PTK-7 significantly reduced the migration and invasion of TNBC cells. In contrast knockdown of PTK-7 did not affect the growth and invasiveness non-TNBC cells. Conclusion: Our results suggest that the expression of PTK-7, a critical regulator of growth and invasion of TNBCs. These results suggest that PTK-7 is a promising target for the treatment of women with TNBC. This work was supported by Susan G Komen Promise Grant (PB), SAB Komen grant (PB) and Young Foundation grant (PB). Citation Format: Lakshmi Reddy Bollu. High expression of PTK-7 regulates the growth and invasion of triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1784.
Abstract 4048: REAlease® technology: Controlled release of antibody-fluorochrome conjugates for maximal flexibility in flow sorting and fluorescence microscopy applications
Authors: Jennifer Pankratz, Sabine Schmachtenberg, Nicole Jansen, Marie Hansen, Susanne Krauthäuser, Ali Kinkhabwala, Karolina Schlegel, Svenja Meiler, Christiane Siewert, Alina Bartholomäus, Dmytro A. Yushchenko, Christian Dose
Journal: Cancer Research (2019)

Abstract Multi-parameter immunofluorescent labeling is the method of choice for the flow-based sorting of targeted cell populations from heterogeneous samples. However, existing antibody-fluorochrome conjugates used for flow sorting limit the types of downstream analyses that can be applied to the isolated cells, as their continued presence on the cells blocks specific cellular epitopes and restricts the choice of downstream fluorescence detection channels. Herein, we present a new type of antibody-fluorochrome conjugates that facilitates a highly specific multi-parameter cell staining for flow sorting as well as subsequent complete release of the conjugate probes from the sample. These new conjugates rely on recombinantly engineered antibody fragments that individually possess low epitope binding affinities. A tailor-made covalent conjugation chemistry allows for their multimerization as well as fluorochrome labeling, generating fluorescent probes comparable to conventional antibody conjugates. Importantly, upon addition of a release reagent, the antibody-fluorophore conjugates can be rapidly released from the cell surface. Accordingly, previously blocked epitopes are free for re-labeling, which provides maximal flexibility for renewed epitope targeting in downstream applications. As many targeted cell populations require multi-parameter detection of several antigens for their isolation, the recombinant engineered antibodies were conjugated with different fluorochromes. The versatility of this technology is presented in multi-parameter panels enabling clear distinction and discrimination of different cell populations of different starting material, e.g. peripheral blood and tumor cells. The applicability of the new REAlease® antibody fluorochrome conjugates is also demonstrated by flow sorting of human naïve regulatory T cells. In addition, we show that the fast and efficient releasability of the new conjugates can serve as an optimal basis for cyclic immunofluorescence microscopy using a new MACSima™ imaging platform, which permits cell analysis with potentially unlimited number of parameters. Citation Format: Jennifer Pankratz, Sabine Schmachtenberg, Nicole Jansen, Marie Hansen, Susanne Krauthäuser, Ali Kinkhabwala, Karolina Schlegel, Svenja Meiler, Christiane Siewert, Alina Bartholomäus, Dmytro A. Yushchenko, Christian Dose. REAlease® technology: Controlled release of antibody-fluorochrome conjugates for maximal flexibility in flow sorting and fluorescence microscopy applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4048.
A retrospective study in the Spanish population with Onco<i>type</i> dx recurrence score (RS) in breast cancer patients with positive and negative-lymph nodes.
Authors: Laura G Estevez, Isabel Calvo, Maria Fernandez Abad, Juan Jose Cruz, Sofia Perea, Ana Suarez, Fernando Lopez Rios, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2013)

e11531 Background: The international guidelines include the use of Oncotype DX as a predictor of chemotherapy (CT) benefit in hormonal sensitive breast cancer patients (pts) with node negative and node positive (1-3 positive nodes) disease.The aim of this study was to assess the distribution of the RS in breast cancer pts regardless lymph nodes status, and the association with treatment recommendations. Methods: Retrospectivedata from 131 pts with invasive breast cancer for which the OncotypeDX Assay had been ordered, and pathology data were available. Estrogen (ER) and progesterone (PR) receptor was assessed by IHC (cut-off 10% nuclear staining). Ki67 by IHC [high (≥14%) and low (&lt; 14%)]. Positive-lymph nodes pts was classified as isolated tumoral cells (ITC), micrometastasis (MIC) and macrometasis (MAC). Results: Median age: 51 (range: 35-78); premenopausal status: 74 pts (56%). Median tumor size: 1.5 cm (0.3- 6); Median Ki 67 index: 15 (3-63); Median ER: 93 (35-100) and PR: 85(0-100). 42 pts (32%) had positive-lymph nodes: 6 ITC (14%), 14 MIC (33%) and 22 MAC (52%). RS was low in 82 (63%) cases, intermediate 39 (30%), and high 10 (7%). RS according to nodal status was: positive nodes, 31 pts (74%) low RS, 10 pts (24%) intermediate and 1 pts (2%) high; negative nodes: 50 pts (57%) low RS, 26 (29%) intermediate and 12 pts (14%) high RS. ER and Ki67 was similar between both lymph-nodes groups whereas a higher PR expression (median 90) was seen in positive-lymph nodes vs 76 in negative nodes. First recommendation in positive-lymph nodes: hormonotherapy (HT) 33%, CT 55% and 12% no defined (ND); after RS, HT 83% and CT 17% (p=0.021). Negative nodes first recommendation: HT 68%, CT 23% and ND 14%; after RS, HT 68% and CT 32%. Conclusions: Although based on a small case series, the results show that a substantial number (73%) pts with positive-lymph nodes have low RS, indicating minimal if any benefit from adjuvant CT. The proportion of patients with low scores is higher than in the validation studies and selection bias can’t be excluded. The wide range of RS in both negative and positive-lymph nodes breast cancer confirm the important role of Oncotype DX in treatment decision- making.
Abstract CT062: A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma
Authors: Adilia Hormigo, Alex Rubinsteyn, Julia Kodysh, Ana Blazquez, Nina Bhardwaj
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) like other cancers generates mutation-derived tumor antigens (MTA) arising from somatic mutations such as insertions, deletions, nucleotide substitutions and gene fusions. These mutations can be recognized by the immune system, providing a specific target for antitumor therapy. The use of TTFields, a modality that utilizes low intensity electric fields that disrupt cell division, increases progression-free survival and overall survival in newly diagnosed GBM. Among several mechanisms of action, TTFields potentially induces an immunogenic cell death. Therefore, we combined this modality treatment with the standard of care of adjuvant Temozolomide chemotherapy and a personalized vaccine for newly diagnosed GBM in a single-arm, open label clinical trial. Phase Ia tests the safety and immunogenicity of MTA-vaccine and phase Ib tests the safety and immunogenicity of the vaccine in conjunction with the TTFields. RNA and DNA are extracted from tumor specimens and blood, and whole-exome sequencing and mRNASeq is performed. HLA typing is obtained for each patient. MTA are identified using a computational pipeline for prediction and ranking according to both HLA binding affinity and expression. A maximum of 10 peptides is selected for the synthesis of each patient vaccine. Patients receive 14 doses of the MTA-vaccine in combination with 14 doses of poly-ICLC, the vaccine adjuvant. We have found mutation-derived tumor antigens in all patients included in phase Ia despite a low mutational load in GBM patients. The patients that took part in phase Ia have received multiple vaccinations spanning over 6 months of treatment. The vaccine has been well tolerated without serious adverse events. Quantitative and qualitative changes in epitope-specific circulating T-cell response is currently being evaluated. Citation Format: Adilia Hormigo, Alex Rubinsteyn, Julia Kodysh, Ana Blazquez, Nina Bhardwaj. A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT062.
ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research
Authors: C. Marchiò, M. Scaltriti, M. Ladanyi, A.J. Iafrate, F. Bibeau, M. Dietel, J.F. Hechtman, T. Troiani, F. López-Rios, J.-Y. Douillard, F. Andrè, J.S. Reis-Filho
Journal: Annals of Oncology (2019)
Weak and Winded
Authors: Ikjae Lee, Jeremey B. Walker, Kenkichi Nozaki, Lisa L. Willett
Journal: New England Journal of Medicine (2019)

A 22-year-old woman with a history of sickle cell disease and migraine headaches presented with weakness that had caused her to fall on the day of admission. She reported gradual progression of weakness during the previous 6 months, which had led in the previous few weeks to difficulty standing, climbing steps, and lifting her child.
Alcohol Consumption And Cardiovascular Mortality In Hypertensive Patients
Authors: Maciej K. Malinski, Howard D. Sesso, Francisco Lopez-Jimenez, Julie E. Buring, J. Michael Gaziano
Journal: Circulation (2001)

P83 Background: Alcohol drinking is associated with a dose-dependent increase in blood pressure, and JNC VI advises limiting alcohol consumption in patients with hypertension. Data are sparse on relationship between alcohol consumption and mortality in hypertensive patients. We therefore assessed whether alcohol consumption is associated with decrease in total, and cardiovascular mortality among subjects with hypertension. Methods: From the enrollment cohort of 89,251 men from the Physicians’ Health Study who provided self-reported information on alcohol intake and were free of myocardial infarction, stroke, cancer or liver disease at baseline, we identified a group of 14,125 persons with a history of current or past treatment for hypertension. Results: During 75,710 person-years of follow up, there were 1,018 deaths including 579 from cardiovascular disease and 224 from cancer. In multivariate analyses that controlled for several potential confounders, moderate alcohol intake was associated with significant decrease in cardiovascular mortality (P&lt;0.001 for linear trend). Compared with non-drinking men, those who drank 1 to 3 drinks per month had a RR for cardiovascular mortality of 0.86 (CI 0.63-1.18, P=0.35); for 1 to 6 drinks per week, the RR was 0.64 (CI 0.51-0.81, P&lt;0.001); for &gt;= 1 drink per day the RR was 0.57 (CI 0.44-0.72, P&lt;0.001). RR values for all-cause mortality in the same groups were respectively 0.89 (CI 0.70-1.15, P=0.38); 0.73 (CI 0.60-0.88, P=0.001); and 0.73 (CI 0.61-0.89, P=0.0014)(P=0.0025 for linear trend). On the other hand, we found no significant association between moderate alcohol consumption and cancer mortality (P=0.68 for linear trend). Conclusion: These results suggest that light to moderate alcohol consumption is associated with a significant reduction in cardiovascular and all-cause mortality in patients with hypertension.
Abstract 15894: Metallic Bodies in the MRI Environment; Effect of the Magnetic Field on Loops, Stimulators and Retained Pacemaker/ICD Leads
Authors: Robert W Biederman, Loretta Gevenosky, Prabhakaran Gopalakrishnan, Ronald Williams, Richard Lombardi, Moneal Shah, Christopher Bonnet, Mark Doyle
Journal: Circulation (2017)

Background: Performance of MRI is infrequently conducted on patients with metallic devices/objects within the body. Recent work has suggested with an appropriate protocol, pacemakers/ICD's may on o...
Abstract 170: Loss of the ubiquitin-specific peptidase 18 (USP18) reduces lung cancer metastasis
Authors: Zibo Chen, Lin Zheng, Yulong Chen, Masanori Kawakami, Lisa Mustachio, Jason Roszik, Xin Liu, Jonathan Kurie, Xi Liu, Ethan Dmitrovsky
Journal: Cancer Research (2019)

Abstract Metastasis is a major cause of cancer-related mortality. Yet, current antineoplastic strategies do not effectively repress metastasis. Thus, there is a pressing need to explore targets that can reduce metastasis, especially in lung cancer that is the most common cause of cancer mortality. Our prior work reported that expression of the ubiquitin-specific peptidase 18 (USP18) was augmented in diverse cancers (including lung cancers) and USP18 knock-down suppressed in vitro and in vivo growth of murine and human lung cancers. This deubiquitinase stabilizes target proteins by removing interferon-stimulated gene 15 (ISG15) from substrate proteins. We explored here whether engineered loss of USP18 decreased lung cancer metastasis. Stable USP18 knockdown was independently achieved in human (A549 and H1299) and murine (344SQ and KC2) lung cancer cells by use of small hairpin RNAs (shRNAs). Notably, knockdown of USP18 expression reduced lung cancer cellular proliferation, migration and invasion versus control shRNA transfectants (p &amp;lt; 0.001). Lung cancer cells selected for high metastatic potential (344SQ and KC2) were independently injected via tail vein or subcutaneously to establish metastatic mouse models. USP18 knockdown statistically-significantly decreased lung cancer metastases as compared to control shRNA transfectants. To elucidate engaged mechanisms, Reverse Phase Protein Array (RPPA) analysis was performed to interrogate over 300 growth-regulatory proteins in human (A549 and H1299) and murine (344SQ and KC2) lung cancer cells having engineered USP18 knockdown. Results were compared to control shRNA transfectants. Ingenuity pathway analysis highlighted fatty acid synthase (FASN) as a potential USP18 target that regulated lung cancer metastasis. Independent immunoblot analysis confirmed FASN expression was reduced in cancers once USP18 knockdown was achieved. Functional validation of FASN in lung metastasis is underway. These and other findings that will be presented provide a strong rationale for targeting the deubiquitinase USP18 to reduce lung cancer metastasis and combat lung cancers. Citation Format: Zibo Chen, Lin Zheng, Yulong Chen, Masanori Kawakami, Lisa Mustachio, Jason Roszik, Xin Liu, Jonathan Kurie, Xi Liu, Ethan Dmitrovsky. Loss of the ubiquitin-specific peptidase 18 (USP18) reduces lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 170.
Abstract 2199: BOS172738: A novel highly potent and selective RET kinase inhibitor in Phase 1 clinical development
Authors: Mitchell Keegan, Keith Wilcoxen, Peter T. Ho
Journal: Cancer Research (2019)

Abstract Background: RET gene alterations including point mutations and gene fusions have been detected in multiple cancers, including colorectal cancer, NSCLC and various thyroid cancers. RET fusion events involve the kinesin family member 5B (KIF5B-RET), as well as a number of other fusion partners such as CCDC6, TRIM33, and NCOA, and are considered to be the driver mutations in NSCLC and other tumors harboring RET fusions. Selective inhibitors of RET kinase recently has been associated with durable objective responses in patients with RET gene-altered NSCLC and papillary thyroid carcinoma. BOS172738 (formerly DS-5010) is an orally available small-molecule RET kinase inhibitor that has previously been shown to have potent in vitro RET inhibitor activity and in vivo potency against transfected allograft and xenograft models. In this study, we discuss additional in vitro characterization and in vivo efficacy in patient derived xenograft (PDX) models driven by RET fusions and emergent resistant mutations. Results: An expanded kinase profile was conducted with BOS172738 against over 450 kinases, and demonstrated exquisite potency for RET and RET mutations with Kd values ≤ 1 nM for RETwt, RET(M918T), RET(V804L) and RET(V804M). BOS172738 also demonstrated high selectivity over KDR (&amp;gt;300 fold). To confirm this selectivity in vitro, BOS172738 was compared to ponatinib, a multikinase inhibitor with potent activity against both KDR and RET. While BOS172738 demonstrated similar potency to ponatinib (IC50 0.5 µM vs. 0.3 µM) in inhibiting the in vitro proliferation of a NCO4-RET human CRC cell line (CR1520), it resulted in significantly less anti-proliferative activity in HUVEC normal endothelial cells (IC50 2.9 µM vs 0.2 µM). BOS172738 was also evaluated in a number of PDX models of RET fusion cancers, including three CRC PDX models (CR2518:CCDC6-RET, CR1520: NCOA4-RET and CR2545: CCDC6-RET with a V804M mutation) and one NSCLC PDX model (CTG-0838:KIF5B-RET). In all cases tested, BOS172738 demonstrated potent and durable tumor regression at doses of 30 mg/kg, with tumor growth inhibition at lower doses. BOS172738 also demonstrated potent tumor regression on larger, established tumors (&amp;gt;1000 mm3). Conclusion: These results support that BOS172738 is a potent and selective RET kinase inhibitor, with strong antitumor activity against a range of RET fusion proteins, as well as resistant RET active site mutations. BOS172738 is currently being evaluated in a Phase 1 clinical study. Citation Format: Mitchell Keegan, Keith Wilcoxen, Peter T. Ho. BOS172738: A novel highly potent and selective RET kinase inhibitor in Phase 1 clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2199.