tbuckley/cabot-search huggingface dataset:
Is young age a poor prognostic factor in triple-negative breast cancer patients? Analysis of 363 patients from single institution registry.
Authors: Mohamed Salah Fayaz, Gerges Attia Demian, Mustafa El-Sherify, Sadeq Abuzalouf, Thomas George, Suzanne Samir, Heba El-Sayed Eisa, Nashwa Nazmy
Journal: Journal of Clinical Oncology (2013)

e12023 Background: Young age is a known independent poor prognostic factor for breast cancer. Few data exist about validating such prognostic factor in triple negative subtype of breast cancer. In this study, we evaluate the prognostic value of young age presentation in triple negative breast cancer (TNBC) patients who were diagnosed in Kuwait Cancer Control Center. Methods: This is a retrospective analysis of 363 patients diagnosed with TNBC between July 1999 and June 2009. Of these, 27% were diagnosed at or below the age of 40. Chi-square test was used to correlate the age with other prognostic factors. Survival measurements were estimated using Kaplan-Meier analysis. Statistical significance was calculated using the log-rank test. Results: There was no correlation between young age at presentation and other prognostic factors including grade, T stage, lymph node status, lymphovascular invasion, and Ki67 positivity. Similarly, young age was not statistically associated with poorer 5-years overall survival (78% for patients &lt; 40 years compared to 72% for those &gt; 40 years; p = 0.13), disease free survival (66% vs. 61%; p = 0.5) or locoregional recurrence free survival (81% vs. 83%; p = 0.7). Conclusions: Young age does not seem to negatively impact the survival of TNBC patients nor associated with poor prognostic factors in our study population. Further studies are needed to define new prognostic factors, e.g. molecular markers, in this subtype of patients rather than the conventional clinicopathologic prognostic factors.
Pilot study of MAGE-A3 protein vaccination and autologous stem cell transplantation (autoSCT) as consolidation therapy for multiple myeloma (MM).
Authors: Adam D. Cohen, Nikoletta Lendvai, Sacha Gnjatic, Achim A Jungbluth, Linda S. Pan, Stephane V. Bertolini, Ralph Rudolph Venhaus, Rafik Fellague-Chebra, Olivier Gruselle, Hearn J. Cho
Journal: Journal of Clinical Oncology (2012)

TPS8111 Background: MAGE-A3 is a cancer-testis antigen (CT Ag) commonly expressed in MM but not in normal non-gonadal tissues. MAGE-A3 inhibited p53-dependent and independent apoptosis in MM cells (Clin Cancer Res 2011;17:4309), and spontaneous immunity against CT Ags in MM patients was associated with favorable clinical outcomes (Blood 2007;109:1103; Blood 2008;112:3362), making it a rational target for immunotherapy. In this study (NCT01380145), we are examining if a recombinant (rec) MAGE-A3 protein vaccine + adjuvant combined with vaccine-primed peripheral blood lymphocytes (PBL) can safely stimulate antigen-specific immunity in MM patients undergoing autoSCT for consolidation therapy. Methods: Patients meeting the following criteria are eligible: within 12 months of diagnosis; MAGE-A+ MM cells by immunohistochemistry; achieving at least a very good partial response with induction therapy; and meeting institutional criteria for autoSCT. One patient of a planned cohort of sixteen has been enrolled. Six weeks before SCT, subjects will receive their first vaccination (300 μg IM) and three weeks later undergo leukopheresis to collect vaccine-primed PBL. They then undergo stem cell mobilization followed by a standard melphalan-conditioned autoSCT. On day 3 after stem cell infusion, the unmanipulated, primed PBL will be re-infused followed by the second recMAGE-A3 vaccination on day 10. An additional six vaccinations will be administered on days 31, 52, 73, 94, 180, and 270 after autoSCT. The primary objectives are safety and tolerability. The secondary objectives of cellular and humoral immune responses and lymphocyte reconstitution will be assessed by a validated series of quantitative assays using established response criteria (PNAS 2008;105:1650). Success criteria based on immune response have not been specified for this pilot study, though induction of MAGE-A3 immunity in at least 50% of patients would merit consideration for further evaluation of clinical efficacy.
Phase I trial of ADI-peg 20 plus docetaxel (DOC) in patients (pts) with advanced solid tumors.
Authors: Ben Kent Tomlinson, John S. Bomalaski, Monica Diaz, Taiwo Akande, Nichole Mahaffey, Tianhong Li, Mrinal P. Dutia, Karen Kelly, I-Yeh Gong, David R. Gandara, Chong-xian Pan, Primo Lara
Journal: Journal of Clinical Oncology (2013)

2569 Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3+3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were &gt;18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ≥ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.
Bioresorbable photonic devices for the spectroscopic characterization of physiological status and neural activity
Authors: Wubin Bai, Jiho Shin, Ruxing Fu, Irawati Kandela, Di Lu, Xiaoyue Ni, Yoonseok Park, Zhonghe Liu, Tao Hang, Di Wu, Yonghao Liu, Chad R. Haney, Iwona Stepien, Quansan Yang, Jie Zhao, Khizar Rehan Nandoliya, Hao Zhang, Xing Sheng, Lan Yin, Keith MacRenaris, Anlil Brikha, Fraser Aird, Maryam Pezhouh, Jessica Hornick, Weidong Zhou, John A. Rogers
Journal: Nature Biomedical Engineering (2019)
Phase II study of sorafenib mesylate (So) in patients (pts) with evolutive and advanced epithelioid hemangioendothelioma (EHE) or hemangiopericytoma/solitary fibrous tumor (SFT).
Authors: Christine Chevreau, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui Nguyen, Emmanuelle Bompas, Nicolas Isambert, Loic Chaigneau, Jacques-Olivier Bay, Olivier Collard, Ewa Cottura, Julien Domont, Jean-Yves Blay, Charles Fournier, Stephanie Clisant, Eric Gauthier, Nicolas Penel
Journal: Journal of Clinical Oncology (2012)

10020 Background: There is no standard of care for both rare sarcomas. Regarding, the important vascularization of EHE and SFT, we explored the activity/toxicity of So in pts with these sarcomas. Methods: We conducted a multicenter one-step phase II trial of So (800 mg/d). The primary endpoint was the 9-months progression-free rate (9-PFR). According to EORTC criteria, So is considered as promising drug if 6-PFR≥14%. All pts have had documented progressive disease at entry. Results: 20 pts (15 EHE &amp; 5 SFT) were enrolled from June 2009 to February 2011 in the 8 participating institutions. 12 men and 8 women. Median age was 57. The most common primaries were superficial trunk (8 cases) and liver (4 cases). PS were 0 in 10 cases, 1 in 7 cases and 2 in 3 cases. 16 pts had metastasic disease , especially in lung (15), liver (6) and bone (4). Eight pts received prior chemotherapy (Doxorubicin : n= 8 cases and taxane : n =3). The median So treatment duration was 124 days. 9 pts experienced grade-3 toxicities; the most frequent grade-3 toxic events were hand foot syndrome (5 pts), myalgia (1), stomatitis (1), anorexia (1), diarrhea (1) and arterial hypertension (1).Because of this toxicity, treatment discontinuation was necessary in 6 cases and dose reduction was necessary in 5 pts. The 9-PFR was 6/18 (33.3% [11.5-55.1]). The 2, 4 and 6 PFR were 15/18 (83.3%), 8/18 (44.4%) and 7/18 (38.8) respectively We observed 2 partial responses lasting 2 and 9 months in 2 pts with EHE. Analysis of the predictive value of circulating pre-angiogenetic biomarkers is ongoing. Conclusions: According to the STBSG-EORTC criteria (3-PFR≥40% &amp; 6-PFR≥14%), So is a promising drug for EHE and SFT pts. Further trials is needed, especially a discontinuation randomized trial.
Interneuron Types as Attractors and Controllers
Authors: Gord Fishell, Adam Kepecs
Journal: Annual Review of Neuroscience (2019)

Cortical interneurons display striking differences in shape, physiology, and other attributes, challenging us to appropriately classify them. We previously suggested that interneuron types should be defined by their role in cortical processing. Here, we revisit the question of how to codify their diversity based upon their division of labor and function as controllers of cortical information flow. We suggest that developmental trajectories provide a guide for appreciating interneuron diversity and argue that subtype identity is generated using a configurational (rather than combinatorial) code of transcription factors that produce attractor states in the underlying gene regulatory network. We present our updated three-stage model for interneuron specification: an initial cardinal step, allocating interneurons into a few major classes, followed by definitive refinement, creating subclasses upon settling within the cortex, and lastly, state determination, reflecting the incorporation of interneurons into functional circuit ensembles. We close by discussing findings indicating that major interneuron classes are both evolutionarily ancient and conserved. We propose that the complexity of cortical circuits is generated by phylogenetically old interneuron types, complemented by an evolutionary increase in principal neuron diversity. This suggests that a natural neurobiological definition of interneuron types might be derived from a match between their developmental origin and computational function.
<i>In Vitro</i>, <i>In Vivo</i>, and Parallel Phase I Evidence Support the Safety and Activity of Duvelisib, a PI3K-δ,γ Inhibitor, in Combination with Romidepsin or Bortezomib in Relapsed/Refractory T-Cell Lymphoma
Authors: Alison J. Moskowitz, Raphael Koch, Neha Mehta-Shah, Patricia Myskowski, Meenal Kheterpal, Ahmet Dogan, Theresa Davey, Natasha Galasso, Marzouk Evan, Monica Shah, Nivetha Ganesan, Lakeisha Lubin, Youn H. Kim, Michael Khodadoust, Timothy Almazan, Julia Dai, Eric D. Jacobsen, David M. Weinstock, Steven M. Horwitz
Journal: Blood (2017)
Single-agent pemetrexed in patients with advanced and metastatic hepatoma
Authors: A. Cohn, J. W. Myers, S. Mamus, C. Deur, S. Nicol, K. E. Hood, M. M. Khan, D. Ilegbodu, L. Asmar
Journal: Journal of Clinical Oncology (2006)

14064 Background: The incidence of hepatoma is rising in the United States, primarily due to the increase in the prevalence of hepatitis C. Surgical treatments are rarely an option for patients with advanced hepatoma, and while chemotherapy, particularly with doxorubicin-based regimens, has marginally prolonged survival, response rates have been poor with the burden of high toxicity. Pemetrexed, a folate antimetabolite, has demonstrated activity in hepatoma cell lines with a manageable toxicity profile, making it a potentially useful agent in hepatocellular carcinoma. Methods: A multicenter, Phase II study was conducted to assess the response rate and evaluate the toxicity profile of single-agent pemetrexed (ALIMTA) in first-line patients with advanced or metastatic hepatoma. Pemetrexed 600 mg/m 2 IV was administered on Day 1 of each 21-day cycle until disease progression (PD). Patients were premedicated with dexamethasone 4 mg PO BID and received daily folic acid 350–1000 μg PO and Vitamin B 12 1000 μg IM every 9 weeks. Results: This nonrandomized study employed Simon’s 2-stage design. There were 21 eligible patients enrolled in the first stage, and all 21 patients were enrolled within 4 months of trial opening. Median age was 72 years (range, 44–88), and most patients were white (62%) and male (81%). Ten percent (10%) had an ECOG PS of 2, 48% Stage IV disease, 52% prior surgery, and 33% tumors of unknown histological grade. The plan was to stop accrual if ≤2 responders were observed among the 21 patients. Of the 21 patients, 3 had SD, 2 had early toxicities (renal/liver failure, sepsis), 15 progressed, and 1 was noncompliant. The trial was closed due to lack of response. The most common Grade 3 hematological toxicities were neutropenia 6/21 (28.6%) and thrombocytopenia 3/21 (14.3%). One patient experienced both Grade 3 nausea and vomiting. There were no Grade 4 toxicities. There were 10 on-study deaths: 9 PD and 1 liver failure. None of the deaths were drug-related. The median actual survival was 2.5 months (range, &lt;1–8). Conclusions: While pemetrexed was well tolerated in this patient population, it was not active. Most adverse events were related to disease state, not study treatment. Supported by Eli Lilly and Company, Indianapolis, IN [Table: see text]
Abstract 4126: Inferring target occupancy from fitting nonlinear-PK data with mechanistic PKRO model for Pembrolizumab
Authors: Fei Hua, Lin Lin, Lore Gruenbaum, Bjorn L. Millard, John M. Burke, Joshua F. Apgar
Journal: Cancer Research (2019)

Abstract Purpose: Pembrolizumab (Pembro), an anti-PD-1 antibody, has been approved for several cancer indications at 200 mg or 2 mg/kg IV every 3 weeks (Q3W). Understanding the percent target receptor occupancy (RO) for PD-1 at this approved dose can help with dose selection for other anti-PD-1 drugs in development. However, RO can be challenging to determine through direct experimental measurements. A mechanistic PKRO model was developed to fit to Pembro phase 1 PK data and was then used to predict RO at 2 mg/kg IV dosing Q3W. Methods: A mechanistic PKRO model describes linear clearance of Pembro, tissue distribution of Pembro, binding to PD-1, binding to soluble PD-1 (sPD-1) and clearance of drug-PD-1 complex, clearance of drug-sPD-1 complex as well as drug distribution to tumor and binding to PD-1 in the tumor compartment. Binding between Pembro and PD-1 was fixed to 29 pM (Pembro BLA, Pharmacology Review) and half-life of internalization of drug-PD-1 complex was set to 2 hours. Results: Since a wide range of sPD-1 concentration has been reported, different sPD-1 concentration was used to fit to the PK data. The model predicted PD-1 expression level in circulation to be approximately 10.8 pM with no soluble PD-1. In the presence of soluble PD-1, PD-1 expression is predicted to be higher to capture the non-linear PK. The model was then used to predict RO at 2 mg/kg IV dosing Q3W and &amp;gt; 98% RO was predicted in the tumor compartment with a range of sPD-1 concentrations from 0 to 3000 pg/mL tested. The impact of Kd and drug-PD-1 turnover rate on predicted RO was explored. When either of the parameters was varied by 10-fold higher or lower from its nominal value, the model still predicted greater than 90% RO at 2 mg/kg dose. Conclusion: A mechanistic PKRO model was built to capture Pembro phase I PK data and then predicted near complete PD-1 target receptor occupancy at the approved dose. This approach with expanded model scope has the potential to be used to inform dose selection for other anti-PD-1, or I/O therapeutics, as a single therapy or in combination. Citation Format: Fei Hua, Lin Lin, Lore Gruenbaum, Bjorn L. Millard, John M. Burke, Joshua F. Apgar. Inferring target occupancy from fitting nonlinear-PK data with mechanistic PKRO model for Pembrolizumab [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 4126.
Surgical resection of liver metastases and survival outcomes in real-life for metastatic colorectal cancer (mCRC) patients treated in front-line with cetuximab (CTX): The EREBUS cohort.
Authors: Denis Michel Smith, Antonio Sa Cunha, Magali Rouyer, Pernelle Noize, Jeremy Jove, Emmanuelle Bignon, Alise Le Monies, Emmanuel Mitry, Eric Francois, Annie Fourrier-Réglat
Journal: Journal of Clinical Oncology (2013)

e14514 Background: CTX has demonstrated improved survival outcomes and resection rate in unresectable mCRC patients (pts) but little data is available from real-life use. Methods: EREBUS is a French multicentre (n=65) cohort that included pts with unresectable mCRC and wt KRAS initiating 1 st -line CTX in 2009 and 2010, and followed 12 months. An expert committee validated baseline resectability and resection results. Resection rates and survival outcomes were described according to metastases site: liver-only, liver-not exclusively, other. Results: 389 pts were included: 37.8% liver-only metastases, 38.3% liver-not exclusively, 23.9% other. Baseline characteristics of the cohort: median age 64 yrs, 67.4% male, 77.9% ECOG=0-1, 55.5% primary tumor resection, 53% single metastatic site. Combined chemotherapy regimen were with irinotecan (56.6%) or oxaliplatin (38.2%). Median duration of CTX use was 4.8 months. 97 pts (24.9%, 95%CI: 20.6-29.2) had metastases resection; rates for liver-only: 36.7% (28.9-44.5), liver-not exclusively: 20.8% (14.3-27.3), other: 12.9% (6.9-21.5). Among them, 51.5% had radical resection with R0+/-radiofrequency (liver-only: 61.1% and liver-not exclusively: 32.3%), 11.3% R1+/-radiofrequency (liver-only: 16.7% and liver-not exclusively: 3.2%) and 9.4% missing metastases, 27.3%R2. 52.6% had post-operative complications (20.6% infection, 8.2% thromboembolic event, 8.2% other cardiovascular event, 3.1% death). Median PFS for the cohort was 9.7 months (8.6-10.5). In multivariate Cox analysis progression was independently associated with metastases site, liver-only: HR=1.93 (1.36-2.74), liver-not exclusively: HR=1.46 (1.06-2.02). The 1-yr OS probability was 71.3% (66.4-75.6) without any site difference. In Cox analysis, death was less likely in responders with or without metastases surgery: HR=0.26 (0.08-0.90) and HR=0.37 (0.21-0.63). Conclusions: This cohort shows that 1 st -line CTX in wt KRAS mCRC allows a high proportion of metastases resection, particularly in liver-only. It also provides data on rarely studied mCRC pts (liver-not exclusively and other metastases).
Creation and characterization of a novel human PDGFRA D842V-mutant GIST cell line.
Authors: Lillian Rose Klug, Gleb Abalakov, Diana Griffith, Ajia Town, Arin McKinley, Susanne Grunewald, Sebastian Bauer, Lori Rink, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2019)

e22512 Background: Activating PDGFRA mutations are seen in about 10% of gastrointestinal stromal tumors (GIST). Of these, the majority are one specific PDGFRA mutation, D842V, which confers resistance to all clinically approved tyrosine kinase inhibitors (TKI). Much has been learned about the mechanism by which TKIs work in GIST using cell lines derived from human GIST that bear activating KIT mutations. However, despite enormous effort to develop cell lines derived from human tumors over the past 15 years, there are currently no human cell models of PDGFRA D842V GIST. With the development of potent PDGFRA D842V TKI, such as crenolanib, avapritinib, and DCC2618 it is of interest to understand how these drugs affect PDGFRA-mutant GIST biology. Methods: We sought to convert the KIT-driven GIST-T1 cell line to be PDGFRA-driven by transduction with PDGFRA D842V. Endogenous KIT expression was knocked-out using CRISPR Cas9. Knockout was verified at protein and DNA levels. Clonal KIT knockout cell lines were tested for sensitivity to KIT and PDGFRA TKI both in vitro and in vivo models. Kinase dependence was determined by measuring the effect on viability after KIT and/or PDGFRA knockdown by siRNA. Results: GIST-T1 cells transduced with PDGFRA D842V display highly phosphorylated PDGFRA, imatinib resistance, and PDGFRA dependence. Cell lines that express both endogenous mutant KIT and exogenous PDGFRA D842V maintain some dependence on KIT, but less so than the parental KIT-driven GIST-T1 cell line. Complete knockout of KIT protein expression was achieved in GIST-T1 D842V cells using CRISPR-Cas9. GIST-T1 D842V KIT ko cell lines demonstrate sensitivity to TKI avapritinib, crenolanib, and DCC2618. Xenografts were established using GIST-T1 D842V KIT ko cell lines and are sensitive to avapritinib in vivo. Conclusions: The GIST-T1 D842V KIT ko cell line demonstrates ability to switch kinase allegiance resulting in PDGFRA-dependence and KIT-independence. This GIST-T1 D842V KIT ko cell line represents a novel model of PDGFRA-mutant GIST and can be used to understand the unique biological aspects of these tumors, particularly the response to new potent PDGFRA kinase inhibitors such as avapritinib which will have immense clinical relevance.
Unmutated IGHV and Double Negative CD38/CD49d Predict Good Prognosis and Long Treatment Free Survival (TFS) in Chronic Lymphocytic Leukaemia; Regardless of Genetic Mutations
Authors: Saad Ahmed, John Quinn, Mark Catherwood, Patrick Thornton, Stephen Bergin, Paul Kennedy, Sally Elsir, Bryan Hennessy, Philip Murphy
Journal: Blood (2017)
Considerable international variation exists in blood pressure control and antihypertensive prescription patterns in chronic kidney disease
Authors: Natalia Alencar de Pinho, Adeera Levin, Masafumi Fukagawa, Wendy E. Hoy, Roberto Pecoits-Filho, Helmut Reichel, Bruce Robinson, Chagriya Kitiyakara, Jinwei Wang, Kai-Uwe Eckardt, Vivekanand Jha, Kook-Hwan Oh, Laura Sola, Susanne Eder, Martin de Borst, Maarten Taal, Harold I. Feldman, Bénédicte Stengel, Adeera Levin, Ognjenka Djurdjev, Mila Tang, Masafumi Fukagawa, Naohiki Fujii, Shoichi Maruyama, Takahiro Imaizumi, Wendy E. Hoy, Jianzhen Zhang, Zaimin Wang, Helen G. Healy, Natalia Alencar de Pinho, Bénédicte Stengel, Ziad A. Massy, Christian Combe, Maurice Laville, Roberto Pecoits Filho, Antonio Lopes, Helmut Reichel, Bruce Robinson, Ronald Pisoni, Brian Bieber, Charlotte Tu, Chagriya Kitiyakara, Pornpen Sangthawan, Warangkana Pichaiwong, Pinkaew Klyprayong, Harold I. Feldman, Paula Orlandi, Raymond Townsend, Alan Go, Jinwei Wang, Luxia Zhang, Kai-Uwe Eckardt, Vivekanand Jha, Vivek Kumar, Ashok Kumar Yadav, Seema Baid-Agrawal, Kook-Hwan Oh, Curie Ahn, Dong Wan Chae, Seung Hyeok Han, Laura Sola, Pablo G. Rios, Liliana Gadola, Veronica Lamadrid, Susanne Eder, Johannes Leierer, Julia Kerschbaum, Martin H. de Borst, Frans J. Van Ittersum, Jan A. Van den Brand, Maarten A. De Jong, Maarten W. Taal, Adam Shardlow
Journal: Kidney International (2019)