tbuckley/cabot-search huggingface dataset:
Abstract 4737: New platinum (Pt)-based anticancer agents, bearing a PtN2SO coordination core, for treating advanced melanoma
Authors: Kenneth K.W. To, Peace Chong, Steve C.F. Au-Yeung.
Journal: Cancer Research (2016)

Abstract The aim of this project is to demonstrate the potential utility of a new series of platinum (Pt) compounds having a PtN2SO coordination core in treating advanced melanoma. There is currently an unsatisfied medical need for a more effective treatment of advanced melanoma, which is notorious for its prominent resistance to conventional chemotherapeutic drugs due to elevated DNA repair capacity and dysregulation of cancer apoptotic pathways. Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key component in combination chemotherapy. They bind to DNA and form mainly the DNA-Pt bifunctional crosslink, subsequently leading to apoptosis to mediate cell death. A series of new Pt(II) compounds possessing a bidentate ligand modified from oxaliplatin has been synthesized, with one of the oxygen ligating atom substituted for a sulfur atom (resulting in a PtN2SO coordination core structure). This novel design is to minimize competition from protein and other bionucleophiles for the Pt drug but maximize drug-DNA interaction. We hypothesize that the unique features of the new PtN2SO compounds may make them good candidates for treating advanced melanoma by (i) overcoming DNA repair-mediated drug resistance; and (ii) generating excess reactive oxygen species (ROS) to selectively trigger apoptosis in melanoma cells. The new compounds were found to be more cytotoxic than cisplatin in a panel of human and mouse melanoma cell lines. Importantly, the new compounds were also found to be minimally affected by Pt resistance, which is presumably caused by the formation of unique DNA-Pt monoadduct and reduced DNA repair. DNA-platination study in melanoma cell lines revealed that the new PtN2SO compounds are able to form more DNA-Pt adducts and there was less repair than treatment with cisplatin. The new compounds were also found to cause a greater induction of the MAPKs (p38, JNK and ERK) than cisplatin to mediate apoptosis. On the other hand, at equipotent concentration, some of the new Pt compounds were found to generate more ROS than cisplatin as indicated by a general fluorescent dye-based oxidative stress indicator. Interestingly, the cytotoxicity of the new compounds were blocked to a greater extent than cisplatin by ROS scavengers, suggesting a more prominent role played by ROS in mediating the cytotoxicity of the new compounds. Our study thus advocates further investigation of the new PtN2SO compounds in treating advanced melanoma. Citation Format: Kenneth K.W. To, Peace Chong, Steve C.F. Au-Yeung. New platinum (Pt)-based anticancer agents, bearing a PtN2SO coordination core, for treating advanced melanoma. [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 4737.
Abstract 4974: Using serological proteomics analysis to identify anti-nucleophosmin 1 autoantibody in sera from prostate cancer patients as potential diagnositic and prognostic biomarker
Authors: jitian li, Liping Dai, Ningjing Lei, Mengtao Xing, Carlos A. Casiano, Jianying Zhang
Journal: Cancer Research (2016)

Abstract Prostate specific antigen (PSA) level test in blood has been widely implemented for the early detection and prediction of prostate cancer (PCa). However, lack of specificity led to overdiagnosis, following by unnecessary biopsies and overtreatment. Therefore, novel serological biomarkers are urgently needed to complement PSA by enhancing its sensitivity and specificity in the diagnosis of PCa. Autoantibodies against intracellular tumor associated antigens (TAAs) are commonly found in various types of human cancers. Their utility in providing insights into tumor biology and as potential cancer biomarkers is well documented. Previous studies have demonstrated that sera from patients with PCa contain autoantibodies that react with TAAs. In this study, we identified and characterized nucleophosmin 1 (NPM1) with 33 kDa molecular weight as an autoantigen by using serological proteomics analysis (SERPA) approach. In the further validation study, it was observed that the level of anti-NPM1 in sera from patients with PCa was significantly higher than that from benign prostatic hyperplasia (BPH) and healthy individuals and receiver operating characteristic (ROC) curve analysis showed high diagnostic value for PCa (area under the curve (AUC):0.805). Interestingly, when considering anti-NPM1 combined with PSA level in sera from PCa patients at the early stage as well as BPH, 100% PCa patients could be identified correctly, while 69.2% patients with BPH who has elevated PSA level were found anti-NPM1 negative. The data suggested that anti-NPM1 can elicit humoral immune response in PCa and might be a potential biomarker for the immunodiagnosis of PCa, and it would be a supplementary of PSA examination to distinguish PCa from BPH. Key words: prostate cancer; nucleophosmin 1 (NPM1); tumor-associated antigens (TAAs); autoantibodies; serological proteomics analysis (SERPA) Citation Format: jitian li, Liping Dai, Ningjing Lei, Mengtao Xing, Carlos A. Casiano, Jianying Zhang. Using serological proteomics analysis to identify anti-nucleophosmin 1 autoantibody in sera from prostate cancer patients as potential diagnositic and prognostic biomarker. [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 4974.
Donor-Derived T-Cell Large Granular Lymphocytic Leukemia in a Patient With Peripheral T-Cell Lymphoma
Authors: Juliana E. Hidalgo Lopez, Mariko Yabe, Adrian A. Carballo-Zarate, Sa A. Wang, Jeffrey L. Jorgensen, Sairah Ahmed, John Lee, Shaoying Li, Ellen Schlette, Timothy McDonnell, Roberto N. Miranda, L. Jeffrey Medeiros, Carlos E. Bueso-Ramos, C. Cameron Yin
Journal: Journal of the National Comprehensive Cancer Network (2016)

T-cell large granular lymphocytic (T-LGL) leukemia after hematopoietic stem cell transplantation (SCT) is rare and its natural history and clinical outcome have not been well described. We report the clinical, morphologic, immunophenotypic, and molecular features of a case of donor-derived T-LGL leukemia in a 16-year-old man who received allogeneic SCT for peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). The patient presented with persistent neutropenia and splenomegaly 9 months after SCT when the chimerism study showed a 100% donor pattern. A splenectomy revealed T-LGL leukemia. Flow cytometric analysis showed an aberrant T-cell population positive for CD3, CD5 (dim, subset), CD7, CD8, CD16 (subset), CD57, CD94 (dim, partial), and T-cell receptor (TCR) αβ, and negative for CD4, CD26, CD56, and TCRγδ. Molecular studies showed monoclonal TCRβ and TCRγ gene rearrangements. Both the immunophenotype and molecular profile of the T-LGL leukemia were different from the pre-SCT PTCL. Sequencing analysis for STAT3 exon 21 did not reveal any mutation in both pre-SCT and post-SCT specimens. The patient did not receive any treatment for T-LGL leukemia; however, his count progressively increased after splenectomy, despite the presence of persistent T-LGL leukemia in the bone marrow. There was no evidence of recurrent PTCL. We propose an algorithm to diagnose this rare post-SCT neoplasm.
NPM1 Minimal Residual Disease As Prognostic and Predictive Factor in Young Adults with Acute Myeloid Leukemia: a Study By the French ALFA Group
Authors: Marie Balsat, Aline Renneville, Xavier Thomas, Alice Marceau, Stéphane De Botton, Olivier Nibourel, Emmanuel Raffoux, Céline Rodriguez, Jean-Michel Cayuela, Sandrine Hayette, Christine Terré, Karine Celli-Lebras, Hervé Dombret, Claude Preudhomme, Nicolas Boissel
Journal: Blood (2015)
Abstract 123: Multiplatform molecular profiling of invasive lobular breast cancer
Authors: Raquel A. Nunes, David Arguello, Zoran Gatalica, Sandeep Reddy, Sandra M. Swain
Journal: Cancer Research (2016)

Abstract Introduction: Invasive lobular breast cancer (ILC) is the second most common subtype of invasive breast cancer accounting for 10% of breast cancer diagnosis. ILC has particular histological and clinical characteristics and a distinct response to therapy. Characterizing the molecular alterations in ILC may lead to an improved understanding of its biology and provide new therapeutic options. The purpose of this study is to describe the molecular profile of ILC and compare it to the one of invasive ductal cancer (IDC). Methods: Three-hundred and thirty nine pure ILC specimens profiled from January 2012 - November 2015 were evaluated (Caris Life Sciences, Phoenix, AZ). Multiplatform profiling consisted of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or FISH), and protein expression (immunohistochemistry [IHC]). Molecular characteristics of estrogen receptor (ER) positive and human epidermal growth receptor factor 2 (HER2) negative pure ILC (n = 236) and IDC (n = 286) were compared. Results: By IHC, ER expression was present in 87.7% (277/316), progesterone receptor in 59.6% (198/313), HER2 in 3.5% (11/313), androgen receptor in 87% (262/301), PD-L1 in 8.1% (12/148) and PTEN in 63.3% (198/313). Amplifications were detected in MYC (7.7%, 2/26), EGFR (8.3%, 2/24), ERBB2 (4.5%, 13/290) and TOP2A (1.3%, 3/236). Mutations were detected in AKT1 (4.7%, 9/191), ATM (3.7%, 7/190), BRCA1 (4.2%, 4/96), BRCA2 (9.5%, 9/95), ERBB2 (7.5%, 14/186), PIK3CA (54.5%, 103/189), PTEN (7.9%, 15/189), and TP53 (13.4%, 25/186). A comparison of ER-positive/HER2-negative invasive lobular and ductal carcinomas revealed significant differences in AR expression (89.7% vs 79.6%, p = 0.0022), and mutations in CDH1 (10.1% vs 0.0%, p = 0.0001), ERBB2 (8.2% vs 2.1%, p = 0.0079), and TP53 (10.3% vs 31.8%, 0.0001). Conclusions: Multiplatform testing of this large series of ILC reveals recurrent alterations and a distinct molecular profile when compared to IDC. These support the definition of ILC as biologically distinct entity. High AR expression and high rates of dysregulation along the PIK3CA/AKT/mTOR pathway are consistent with recent reports in the literature. Citation Format: Raquel A. Nunes, David Arguello, Zoran Gatalica, Sandeep Reddy, Sandra M. Swain. Multiplatform molecular profiling of invasive lobular breast 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 123.
Complex lung function in severe asthma: seeing is believing
Authors: Gregory G. King, Cindy Thamrin
Journal: European Respiratory Journal (2016)

Difficult-to-treat or severe asthma remains a common problem and a challenge for healthcare providers. It affects up to 10% of asthmatic individuals, who continue to suffer high disease burden and healthcare costs [1]. This clinical problem still exists despite many advances in the understanding of the underlying basis of asthma and improved management strategies, which include targeted anti-inflammatory therapy with monoclonal antibodies. Research effort continues, with exploration of different aspects of pathophysiology such as genomics, proteomics, inflammation, airway remodelling and airway smooth muscle abnormalities. In this context, the examination of complex lung function at the whole-organ level becomes increasingly important. There have been many technical advances in functional imaging and in complex measures of lung function that can now be used to explore the pathophysiology of asthma at the whole-organ level, and which can be more directly related to clinical manifestations of disease such as symptoms and airway hyperresponsiveness. Techniques to partition airway dysfunction could improve understanding of severe asthma <http://ow.ly/N7zD301wFn6>
Abstract 638: Clinical characteristics of breast cancer xenograft models
Authors: Wendie D. den Brok, Stephen Chia, Cherie Bates, Steve Kalloger, Samuel Aparicio, Mar Mar, Karen Gelmon, Peter Eirew
Journal: Cancer Research (2016)

Abstract Purpose: We have expertise in breast cancer xenograft models and have previously published data on clonal dynamics. Our aim was to explore clinical characteristics of those patients (pts) whose breast cancer tumours engrafted versus those that did not. Methods: Tissue from pts enrolled in a locally advanced/metastatic (MBC) study and a breast tumour tissue repository between Sept. 2008 and July 2014 underwent xenografting using NodScid/IL2rgKO (NSG) mice. Xenografts were passaged when tumour volume reached 1 cm3. Mice were sacrificed if no engraftment by 12 months (mos). Pt charts were reviewed to determine biomarker status (hormone receptor [HR], HER2), grade, LVI, time free from disease/progression, and pathologic complete response (pCR) for pts receiving neoadjuvant therapy. Results: A total of 64 pts had known xenograft status: 32 engrafters, 32 non-engrafters. Biomarker status did not predict likelihood of engraftment (p = .0695) and is shown in Table 1 along with site/timing of biopsy for tissue engraftment within biomarker groups. When HER2+ cases are excluded from analysis, the HR-/HER2- phenotype yields a 72% probability of engraftment compared to 39% for the HR+/HER2- group (p = .0418). For engrafters, 22/32 (68%) of pts had or went on to have relapsed or de novo MBC. For non-engrafters, 7/32 (22%) had or went on to have relapsed disease (p = .0004). Grade and LVI did not predict engraftment (p = .1806 and p = .8657 respectively). No grade 1 tumours engrafted (n = 3). There were 25 pts who received neoadjuvant chemotherapy: 14 engrafters, 11 non-engrafters. None of the engrafters achieved a pCR; 3 non-engrafters achieved a pCR. Median time to engraftment was 5 mos for pts with relapsed/advanced disease vs 9.8 mos for pts who did not relapse however, treatment was variable. Conclusion: This preliminary study highlights potential differences in clinical characteristics of engrafters vs non-engrafters in breast cancer xenograft models and warrants further exploration. (Funded by CBCRA, BCCF) TABLE 1.Biomarker status, tissue site/type in attempted xenografts.Engrafter (N = 32) N, (%)Non-engrafter (N = 32) N, (%)HR+/HER2-14 (44)22 (69)Tissue from:Primary tumour419Recurrence23Advanced dz on therapy80HR-/HER2-13 (40)5 (16)Tissue from:Primary tumour114Recurrence21Advanced dz on therapy00HER2+/HR+0 (0)2 (9)Tissue from:Primary tumour02Recurrence00Advanced dz on therapy00HER2+/HR-5 (16)3 (9)Tissue from:Primary tumour42Recurrence01Advanced dz on therapy10 Citation Format: Wendie D. den Brok, Stephen Chia, Cherie Bates, Steve Kalloger, Samuel Aparicio, Mar Mar, Karen Gelmon, Peter Eirew. Clinical characteristics of breast cancer xenograft models. [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 638.
Patterns of opioid use in sickle cell disease
Authors: Jin Han, Santosh L. Saraf, Xu Zhang, Michel Gowhari, Robert E. Molokie, Joharah Hassan, Chaher Alhandalous, Shivi Jain, Jewel Younge, Taimur Abbasi, Roberto F. Machado, Victor R. Gordeuk
Journal: American Journal of Hematology (2016)

Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States, but comprehensive data regarding the long-term use of opioids in this patient population is lacking. The pain medication prescription records from a cohort of 203 SCD patients were analyzed. Twenty-five percent were not prescribed opioid medications while 47% took only short-acting opioids, 1% took only long-acting opioids, and 27% took a combination of short-acting and long-acting opioids. The median (interquartile range) daily opioid dose was 6.1 mg (1.7-26.3 mg) of oral morphine equivalents, which is lower than the published opioid use among patients with other pain syndromes. The dose of opioids correlated with the number of admissions due to vaso-occlusive crisis (VOC) (r = 0.53, P < 0.001). When the patients were grouped into quartiles based on daily dose opioid use, a logistic regression model showed that history of avascular necrosis (AVN) (OR: 2.87, 95% CI: 1.37-6.02, P = 0.005), 25-OHD levels (OR: 0.59, 95% CI: 0.38-0.93, P = 0.024) and total bilirubin concentration (OR: 0.64, 95% CI: 0.42-0.99, P = 0.043) were independently associated with opioid use quartiles. In conclusion, doses and types of opioid medications used by adult SCD patients vary widely. Our findings implicate AVN and lower vitamin D levels as factors associated with higher opioid use. They also suggest an association of higher bilirubin levels, possibly suggesting higher hemolytic rate, with lower opioid use. Am. J. Hematol. 91:1102-1106, 2016. © 2016 Wiley Periodicals, Inc.
Analytical Performance of Nanostring's Companion Diagnostic (CDx) Lymphoma Subtyping Test (LST) with Diffuse Large B-Cell Lymphoma Core Needle Biopsy Samples
Authors: James Storhoff, Brett Wallden, Rita M. Braziel, Catherine Thieblemont, Tressa Hood, Harini Ravi, Shannon Dennis, Naeem Dowidar, Patrick Danaher, Jennifer Dunlap, Josette Briere, Eric de Kerviler, Sean Ferree
Journal: Blood (2015)
Comparison of innovative estimation of efficacy to standard using the ACCENT database.
Authors: J. W. Chapman, C. O'Callaghan, N. Hu, K. Ding, G. A. Yothers, P. J. Catalano, Q. Shi, R. G. Gray, M. J. O'Connell, D. J. Sargent
Journal: Journal of Clinical Oncology (2011)

3616 Background: The ACCENT database contains individual patient data from over 32,000 patients enrolled onto 18 international clinical trials. Based on recent breast cancer literature, we hypothesized that there could be substantive differences in apparent efficacy estimates using a log-normal (L-N) survival model rather than with standard Kaplan-Meier (K-M) or Cox model methods. While both Cox and L-N survival analyses offer greater specification by individual patient characteristics, the L-N model may more robustly estimate survival under model misspecification. Methods: We compared DFS (N=1540) and OS (N=1545) K-M survival estimates for males with stage III disease who were aged 60-65 and received 1) 5FU+LV+/−LEV or 2) other systemic therapy. Cox and L-N modeling with 9,961 patients for DFS and 9,981 patients for OS was for males (all ages: estimation at 60, 62, and 65 yr) with stage II or III disease (estimation for stage III) by the same therapies. Comparisons were at 3, 5, and 8 yr. Results: There was evidence that the Cox assumption of proportional hazards was violated, and of minor departures from a L-N distribution in the tails of the DFS and OS distributions. Absolute differences between Cox and L-N estimates varied by endpoint and time of assessment: DFS at 3 yr 3.3-4.2%, at 5 yr 1.4-2.7%, and at 8 yr 0.1-1.8%; OS at 3 yr 0.7-1.3%, at 5 yr 1.6%-2.3%, and at 8 yr 0.1-0.8%. While K-M and Cox estimates were generally more similar, than K-M and L-N, this would in part be attributable to the step-wise adjustments at events for K-M and Cox, rather than smooth modeling with the L-N. The need of the Cox model for a baseline hazard function is a disadvantage for extrapolation, compared with the L-N. Conclusions: Even with reasonably large population subgroups, there were substantive differences in apparent survival (3.3-4.2%) between Cox and L-N model types, particularly for 3-yr DFS. Smaller differences (0.1-0.8%) between the methods were observed near the truncation of follow-up at 8 yr. The magnitude of differences in survival estimates with a L-N versus a Cox model were large enough to be clinically relevant and warrant further consideration as we evaluate new therapies and prognostic/predictive factors.
Discovery and Validation of a Novel Class of Small Molecule Inhibitors of the CDC7 Kinase: Modulation of Tumor Cell Growth in Vitro and In Vivo.
Authors: Mark G. Frattini, David Shum, Kristen M O'Dwyer, Renier J. Brentjens, Peter Maslak, Mark Heaney, Joseph G Jurcic, Hakim Djaballah, Thomas J Kelly
Journal: Blood (2009)
Phase II study of fixed dose-rate gemcitabine plus S-1 as second-line treatment in advanced biliary tract cancer.
Authors: Satoshi Kobayashi, Kazuya Sugimori, Chigusa Morizane, Yasushi Kojima, Makoto Ueno, Manabu Morimoto, Shinichi Ohkawa
Journal: Journal of Clinical Oncology (2016)

301 Background: Cisplatin plus gemcitabine (GC) is considered as standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). However, no standard therapy is established for second-line setting. Some clinical studies showed that gemcitabine was more effective if administered by the fixed dose rate method, and S-1 had anti-tumor effect as second-line chemotherapy for BTC. We evaluated the efficacy and safety of combination therapy of fixed dose-rate gemcitabine and S-1 after failure of GC or gemcitabine alone. Methods: This study was a single arm phase II study, and primary endpoint was response rate (RR) with MinMax two stage design to test the hypothesis that RR was more than 7%. Number of patients needed was 35 with a power of 90% and two-sided α value of 0.05. Patients received gemcitabine (1,000 mg/m 2 , div, over 100 minutes, day 1) and S-1 (40 mg/m 2 twice daily, oral, day 1-7), every two weeks until disease progression or intolerable adverse events. Results: Forty patients were enrolled from July, 2011 to Nov., 2014. Of 23 patients in the first stage, two patients showed response and proceeded to the second stage. Overall response rate was 7.5%. Overall survival, progression-free survival and disease control rate were 7.7 months, 2.6 months, and 47.5%, respectively. Common adverse events were anemia (97.2%), thrombocytopenia (66.7%), leukopenia (47.2%), neutropenia (41.7%), anorexia (39.0%) and fatigue (37.8%). Grade 3–4 adverse events were leukopenia (19.5%), neutropenia (19.5%), anemia (14.6%), thrombocytopenia (7.3%) and anorexia (4.8%). Biliary tract infection led to death in two patients; however, these were reported as not related to this study treatment. Conclusions: Fixed dose-rate gemcitabine plus S-1 was tolerable as second-line settings in BTC; however, its activity was modest for patients refractory to the standard gemcitabine. Clinical trial information: UMIN000005918 Clinical trial information: UMIN000005918.