tbuckley/cabot-search huggingface dataset:
Phase 3 PhALLCON study: Ponatinib (PON) versus imatinib (IM) with reduced-intensity chemotherapy (CT) in patients (pts) with newly diagnosed Philadelphia chromosome–positive (Ph+) ALL.
Authors: Elias Jabbour, Giovanni Martinelli, Marco Vignetti, Josep-Maria Ribera, David Gomez-Almaguer, Yosuke Minami, Jing Xu, Shouryadeep Srivastava, Frank Neumann, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2019)

TPS7061 Background: Therapies for adults with newly diagnosed Ph+ ALL are limited and associated with poor outcomes. PON, a potent TKI, is active against native BCR-ABL1 and all identified single resistance mutations, including T315I, which confers resistance to other TKIs (Zhou. Chem Biol Drug Des 2011;77). In the phase 2 PACE study, PON had a 41% major hematologic response rate in heavily pretreated Ph+ ALL, but responses were not durable mainly due to compound mutations (Cortes. Blood 2018;132; Pritchard. Blood 2016;128). As PON suppresses single BCR-ABL1 resistance mutations, resistance in Ph+ ALL is acquired through compound mutations. Decreased likelihood of compound mutations with first-line PON in Ph+ ALL may lead to more durable responses compared with PON in later lines of therapy. In a phase 2 study of PON with CT in newly diagnosed Ph+ ALL, long-term outcomes were improved vs first/second-generation TKIs (Jabbour. Lancet Haematol 2018;5). The PhALLCON trial compares first-line PON vs IM with reduced-intensity CT. Methods: This open-label trial (NCT03589326) is enrolling 230–320 pts (≥18 y) with newly diagnosed Ph+ or BCR-ABL1–positive ALL (p190/p210) and ECOG status ≤2. Pts are randomized 2:1 to PON 30 mg/d or IM 600 mg/d PO with reduced-intensity CT in induction (cycles [C] 1-3), consolidation (C4-9), and maintenance (C10-20). PON dose is reduced to 15 mg once pt achieves minimal residual disease–negative (MRD−) complete remission (CR). After 20C, pts stay on single-agent PON/IM. CNS prophylaxis: 2x/mo in C1-6. Primary endpoint: MRD− (BCR-ABL/ABL1 ≤0.01%) CR (end of induction). Key secondary endpoint: EFS; others in the Table. Subgroup analysis: pts with/without HSCT. Exploratory endpoints include mutation status. Initiated Aug 2018; to include ~110 sites in ≤35 countries. Currently, 5 active sites (4 US, 1 Spain); accrual ongoing. Clinical trial information: NCT03589326. [Table: see text]
Checkpoint inhibitor (CPI) experienced patients (pts) from COSMUS-1: A clinical observational study of talimogene laherparepvec (T-VEC) in United States practice.
Authors: Matthew Perez, Thomas Amatruda, Robert Martin Conry, Charlotte Eielson Ariyan, Anupam M. Desai, John M. Kirkwood, Sheryl Treichel, Rubina Ismail, Leon Raskin
Journal: Journal of Clinical Oncology (2019)

142 Background: T-VEC, a modified oncolytic herpes virus, is an intralesional therapy for unresectable advanced melanoma. COSMUS-1, a recently presented observational chart review study from 7 US academic sites, described metastatic melanoma treatment (tx) patterns and safety of T-VEC in the real-world setting (Perez et al, SMR 2018). In this analysis, we evaluated T-VEC use in pts after prior CPI use or with CPI from COSMUS-1. Methods: Of 76 pts treated with T-VEC (first dose 27Nov2015-15Dec2016), 33 pts had received pembrolizumab, nivolumab and/or ipilimumab (ie, CPI) prior to or with T-VEC and were analyzed for demographics, clinicopathologic characteristics, outcomes, and adverse events. Two groups were identified: Group A, CPI then T-VEC only and Group B, CPI with T-VEC. Results: There were 21 pts in A and 12 pts in B; in B, all received TVEC + CPI with (1) prior CPI, n = 5, (2) prior CPI and additional CPI after combination, n = 1, (3) as combination only, n = 4, or (4) as combination followed by CPI only, n = 2. In A and B, respectively, mean age was 72 yrs and 63 yrs; 12 (57%) and 9 (75%) were men; 17 (81%) and 9 (75%) had ECOG 0-1,10 (48%) and 4 (33%) had Stage IIIB-IVM1a, and 11 (52%) and 7 (58%) had Stage IVM1b/c. Two pts (both in B) remained on T-VEC by study end. 21 (100%) pts in A and 10 (83%) pts in B discontinued T-VEC (most common, respectively: 10 pts and 3 pts due to disease progression, 4 pts and 2 pts due to physician decision). 2 pts had no injectable lesions left (in A) and 1 pt (in A) had pathologic complete response (CR). Adverse events of interest were reported in 7 pts (33%) in A and 6 pts (50%) in B; most common events in A and B, respectively, were immune-mediated events (n = 3 and 6) which included flu-like symptoms (fever, chills, rigor; n = 2 and 5) and injection site complications (n = 5 and 2). No herpetic infections were reported in pts. Conclusions: These real-world data suggest that T-VEC is well tolerated and can be administered in pts previously treated with a CPI, both those who switched to T-VEC or those where T-VEC was added on. One pt achieved a pathologic CR.
Alzheimer’s in a dish – induced pluripotent stem cell-based disease modeling
Authors: Sherida de Leeuw, Christian Tackenberg
Journal: Translational Neurodegeneration (2019)

Since the discovery of the induced pluripotent stem cell (iPSC) technique more than a decade ago, extensive progress has been made to develop clinically relevant cell culture systems. Alzheimer's disease (AD) is the most common neurodegenerative disease, accounting for approximately two thirds of all cases of dementia. The massively increasing number of affected individuals explains the major interest of research in this disease as well as the strong need for better understanding of disease mechanisms. IPSC-derived neural cells have been widely used to recapitulating key aspects of AD. In this Review we highlight the progress made in studying AD pathophysiology and address the currently available techniques, such as specific differentiation techniques for AD-relevant cell types as well as 2D and 3D cultures. Finally, we critically discuss the key challenges and future directions of this field and how some of the major limitations of the iPSC technique may be overcome. Stem cell-based disease models have the potential to induce a paradigm shift in biomedical research. In particular, the combination of the iPSC technology with recent advances in gene editing or 3D cell cultures represents a breakthrough for in vitro disease modeling and provides a platform for a better understanding of disease mechanisms in human cells and the discovery of novel therapeutics.
Effect of radiofrequency ablation (RFA) combined with anti-CTLA-4 and anti-PD1 in a preclinical melanoma model.
Authors: Olga L. Franco-Mahecha, Anna Christou, Michal Mauda-Havakuk, Prateek Katti, William F. Pritchard, John W. Karanian, Bradford J. Wood
Journal: Journal of Clinical Oncology (2019)

143 Background: The aim is to characterize the effect of Radiofrequency Ablation (RFA) with anti-CTLA-4 and anti-PD1 checkpoint inhibitors, on tumor growth and immune responses against B16-OVA melanoma tumors implanted in a syngeneic mouse model. Methods: Adult c57BL/6J female mice were distributed among a non-tumor placebo group (n=5) and four experimental tumor groups: no RFA (n=10); RFA alone (n=5); CPI post-RFA (n=5); and CPI pre-and-post-RFA (n=5). On day 0, mice were inoculated SQ with 2.5x10 5 B16-OVA cells. RFA was performed at day 15. Three doses of anti-mouse CTLA-4 and anti-mouse PD-1 (200 µg/dose each, every 24 h) were given IP to the appropriate groups. To evaluate the effect of the therapy on a distant tumor, each tumor group was re-inoculated SQ at day 20 with 2.5x10 5 B16-OVA cells. Serum samples were collected to measure concentration of cytokines. Mice were euthanized at day 36. T-cell and non-T cell fractions were collected from splenocytes for co-culture and evaluation of killing in vitro. Results: Mice that received RFA alone or RFA plus CPI showed significantly smaller primary tumors and minimal growth of secondary tumors compared to untreated mice, suggesting that these therapies may have an abscopal effect. Based on the cytokine profile in serum, mice treated with CPI pre-and-post-RFA showed balanced and sustained concentrations of IFNγ and IL-2 (T cell activation) and controlled inflammatory responses. In vitro experiments showed that T cells from mice treated with CPI pre-and-post-RFA produced significantly more IFNγ when co-cultured with B16-OVA cells. However, these T cells did not demonstrate a high killing activity on the tumor cells. The killing capacity of T cells from mice treated with RFA alone or with CPI pre-and-post-RFA increased significantly when the non-T cell fraction (dendritic cells, macrophages, NK cells, and B cells) was added to the co-culture. Conclusions: RFA therapy combined with CPI given to mice bearing B16-OVA tumors may induce systemic immune responses capable of improving control of distant tumor growth. In culture, primed T cells are not able to kill B16-OVA by themselves, but the addition of the non-T cell fraction may improve T cell killing capacity.
Campath activity in tumor bearing mice involves both ADCC and CDC effector functions
Authors: William Siders, Jacqueline Shields, Yanping Hu, Carrie Garron, Michael LaMorte, Qun Zhou, Bruce Roberts, Johanne Kaplan
Journal: Cancer Research (2007)

3547  Campath (Alemtuzumab) is a recombinant humanized IgG1 monoclonal antibody directed against the cell surface glycoprotein CD52 which is expressed on the surface of normal and malignant B and T lymphocytes as well as on NK cells, monocytes, and macrophages. Currently, Campath is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). We have previously demonstrated that, in vitro, Campath is able to induce killing of CD52+ tumor cells through both ADCC and CDC associated mechanisms. However, the mechanism(s) by which Campath depletes malignant lymphocytes in vivo is not clearly defined. To evaluate the activity of Campath in vivo, xenograft tumor studies were first performed to determine whether treatment with the antibody could affect the growth of subcutaneous tumors. SCID mice were injected with a lethal dose of tumorigenic CHO cells engineered to express human CD52. Mice were then treated twice weekly with either Campath or a control antibody. Treatment with either vehicle or the control antibody had no significant impact on the progression of the tumors. In contrast, administration of Campath resulted in the dose dependent inhibition of tumor growth and increased survival. Following i.v. administration in tumor bearing animals, Campath, quickly localized to the tumor and remained present for several days based on in vivo imaging analysis. To determine whether Campath activity was associated with ADCC or CDC in vivo, NK cells or complement were selectively depleted using anti-asialo GM1 treatment or cobra venom factor, respectively. Results indicated that, under the conditions tested, inactivation of either arm alone did not significantly inhibit the protective activity of Campath. A deglycosylated form of Campath was generated that did not exhibit either ADCC or CDC effector function in vitro but bound to CD52 positive cells to the same extent as unmodified Campath. Compared to unmodified Campath, the deglycosylated antibody lost all anti-tumor activity and did not provide any survival advantage over treatment with vehicle alone. These data suggest that, in this model, the anti-tumor protection provided by Campath is not strictly dependent on ADCC or CDC alone but is severely compromised when both mechanisms are inactivated.
Abstract 17223: Compositional Lipoprotein Changes With Omega-3 Carboxylic Acids in Patients With Hypertriglyceridemia Paired With Low HDL-C: A Substudy From the ESPRIT Trial
Authors: Michael H Davidson, Jan Oscarsson, Mats Kvarnström, Larrye Loss, Torbjörn Lundström
Journal: Circulation (2015)

Introduction: STRENGTH (NCT02104817) is a 13,000-patient cardiovascular (CV) outcomes trial testing the hypothesis that high-CV-risk patients on statins with hypertriglyceridemia paired with low levels of high-density lipoprotein cholesterol (HDL-C) will have a reduction in incidence of major adverse CV events with omega-3 carboxylic acids (OM3-CA) 4 g/day compared with corn oil control. At present, the triglyceride (TG)-lowering mechanisms by which OM3-CA therapy may reduce CV risk are uncertain. Methods: In the ESPRIT trial (NCT01408303), patients (n=277) on statins who had fasting TG ≥200 mg/dL and &lt;500 mg/dL and HDL-C &lt;40 mg/dL for men and &lt;45 mg/dL for women (also STRENGTH inclusion criteria) received either OM3-CA 4 g/day or olive oil (OO) 4 g/day for 6 weeks. The primary efficacy end point was percentage change in non-HDL-C from baseline to 6 weeks. We evaluated the lipoprotein compositional changes associated with non-HDL-C reduction. Results: Least-squares mean difference in HDL2:HDL3 ratio increased by 12% (p=0.004), while apolipoprotein (Apo)B100, ApoB48 and PCSK9 were not significantly affected. The sum of the change in the highly atherogenic subfractions, very-low-density lipoprotein cholesterol (VLDL-C) + small LDL-C + remnant lipoprotein-C, was strongly correlated with TG reduction (0.732; p&lt;0.001) and percentage change in plasma eicosapentaenoic acid + docosahexaenoic acid + docosapentaenoic acid (–0.281; p&lt;0.001). Conclusions: Compared with OO, OM3-CA 4 g/day significantly lowers non-HDL-C in patients with hypertriglyceridemia and low HDL-C by lowering VLDL-C, small LDL-C and remnant lipoprotein-C. Large LDL-C is raised without modifying ApoB100, ApoB48 or PCSK9 levels. STRENGTH will determine whether these lipoprotein compositional changes in this high-risk population will result in a CV benefit.
Association between proton pump inhibitors therapy and fracture risk in patients with rheumatoid arthritis
Authors: Shih-Wei Lai, Yu-Hung Kuo, Kuan-Fu Liao
Journal: Annals of the Rheumatic Diseases (2019)

Proton pump inhibitors are commonly prescribed for the treatment of acid-related gastrointestinal diseases. The association between proton pump inhibitors therapy and other subsequent comorbidities has been extensively explored.1 Recently, a cohort study in USA conducted by Ozen et al published in the Annals of the Rheumatic Diseases reported that proton pump inhibitors therapy was not associated with increased fracture risk in patients with rheumatoid arthritis (HR=0.92; 95% CI 0.80 to 1.06).2 Ozen et al ’s study is an important one and deserves a practical value. Some points not shown in the original article are shared with the readers. First, in order to test …
Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome
Authors: Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey W. Taub, John D. Crispino, Mitchell J. Weiss, Yasuhide Hayashi, Takashi Taga, Etsuro Ito, Seishi Ogawa, Dirk Reinhardt, Marie-Laure Yaspo, Peter J. Campbell, Irene Roberts, Stefan N. Constantinescu, Paresh Vyas, Dirk Heckl, Jan-Henning Klusmann
Journal: Cancer Cell (2019)
Long-term Weight Loss Maintenance in the Continuation of a Randomized Diabetes Prevention Translational Study: The Healthy Living Partnerships to Prevent Diabetes (HELP PD) Continuation Trial
Authors: Mara Z. Vitolins, Caroline S. Blackwell, Jeffrey A. Katula, Scott P. Isom, L. Douglas Case
Journal: Diabetes Care (2019)

HELP PD was a clinical trial of 301 adults with prediabetes. Participants were randomized to enhanced usual care (EUC) or to a lifestyle weight loss (LWL) intervention led by community health workers that consisted of a 6-month intensive phase (phase 1) and 18 months of maintenance (phase 2). At 24 months, participants were asked to enroll in phase 3 to assess whether continued group maintenance (GM) sessions would maintain improvements realized in phases 1 and 2 compared with self-directed maintenance (SM) or EUC.
The Prognostic Role of Late Gadolinium Enhancement in Aortic Stenosis
Authors: Christos A. Papanastasiou, Damianos G. Kokkinidis, Polydoros N. Kampaktsis, Iosif Bikakis, Daniela K. Cunha, Evangelos K. Oikonomou, John P. Greenwood, Mario J. Garcia, Theodoros D. Karamitsos
Journal: JACC. Cardiovascular imaging (2019)
Association of Mirabegron With the Risk of Arrhythmia in Adult Patients 66 Years or Older—A Population-Based Cohort Study
Authors: Mina Tadrous, Rano Matta, Simon Greaves, Sender Herschorn, Muhammad M. Mamdani, David N. Juurlink, Tara Gomes
Journal: JAMA Internal Medicine (2019)

preceding persons' first intramuscular B 12 injection, 25.5% (n = 37 487) had a normal B 12 level, whereas 38.2% (n = 56 128) did not have a B 12 level documented.Findings were similar over a 24-month look-back period (data not shown).Only 43.1% (n = 24 175) of the 56 128 people without a B 12 level documented in the year preceding their first B 12 prescription had ever had one measured.This was performed a mean (SD) 1033.5 (488.1)days prior to their first prescription (range, 366-2801 days).Only 35.3% (n = 8539) of these 24 175 persons had marginally deficient B 12 levels.The estimated annual cost of inappropriate B 12 prescribing was $45.6 million, assuming a 64% inappropriate prescription rate.Finally, only 1.7% (n = 2498) of persons prescribed intramuscular B 12 demonstrated any deficiency with a malabsorptive indication.Discussion | Most parenteral B 12 in Ontario was prescribed to persons without evidence of deficiency in the year preceding their first B 12 prescription.Potential drivers of this include patient demands and poor physician awareness of the evidence informing B 12 supplementation. 3,4It is also questionable whether parenteral supplementation is required over oral supplementation because oral B 12 raises B 12 serum levels and improves sequelae of deficiency as well as, if not better than, intramuscular B 12 , even for pernicious anemia. 1 Plausible reasons why physicians prefer parenteral B 12 include low quality of evidence supporting oral B 12 , society guidelines recommending intramuscular B 12 for all patients, poor physician understanding of how to prescribe oral B 12 , and physician misperception that patients prefer parenteral over oral B 12 . 1,3,5,6 Our study's limitations include only looking 2 years before a person's first documented prescription; using this abridged period might have misclassified persons undergoing treatment for chronic B 12 deficiency, and so with normal B 12 levels, as receiving inappropriate supplementation.We were also unable to access information on oral B 12 , and could not understand why B 12 was prescribed without laboratory evidence of deficiency.Further studies should examine this issue, to inform quality improvement initiatives aimed at reducing this unnecessary care.
The parent-offspring microbiome and neurobehavioral development
Authors: Jeffrey R. Alberts, Christopher Harshaw, Gregory E. Demas, Cara L. Wellman, Ardythe L. Morrow
Journal: Behavioral and Brain Sciences (2019)

Abstract We identify the significance and typical requirements of developmental analyses of the microbiome-gut-brain (MGB) in parents, offspring, and parent-offspring relations, which have particular importance for neurobehavioral outcomes in mammalian species, including humans. We call for a focus on behavioral measures of social-emotional function. Methodological approaches to interpreting relations between the microbiota and behavior are discussed.
Association between immunoglobulin isotypes and cytogenetic risk groups in multiple myeloma.
Authors: Ramya Muddasani, Angela Ramdhanny, Gabriel Lutz, Meredith Akerman, Albert Ho, Jaime Andres Suarez, Marc Justin Braunstein
Journal: Journal of Clinical Oncology (2019)

e19510 Background: Cytogenetic abnormalities (CA) carry prognostic significance in MM. Immunoglobulin isotypes also predict disease behavior, with non-IgG subtypes historically being associated with poorer outcomes. We hypothesized that MM non-IgG isotype and higher risk CA are associated with greater degree of marrow infiltration (BM%) and presence of end organ damage at presentation. Methods: 552 MM patients were retrospectively analyzed using a multi-institution repository of BM%, isotype, and CA risk groups stratified by mSMART criteria. A subset of 110 patients were used to assess clinical comparisons and associations between CA, isotype, and end organ damage using the chi-square or Fisher’s exact test for categorical variables and the Mann-Whitney test to compare between groups for continuous variables. Results: There was a higher BM% seen in the intermediate risk group compared to standard risk group (50% vs 20%, p &lt; 0.04). A lower BM% was seen in the IgG subtype compared to other isotypes (27% vs 45%, p &lt; 0.02). CA including del(13q), del(16q), dup(1p), dup(1q), t(4;14), t(11;14), and trisomy 11 were associated with a higher BM%. When comparing isotypes to CA risk groups, IgA isotype was associated with greater risk, including del(13q) and del(16q). IgG isotype was associated with trisomy 11, while light chain MM correlated with higher risk CA including del(17p), and dup(1q). Lytic lesions on presentation were more frequent in patients with trisomy 11 and less frequently in IgA MM. Anemia presented more in IgA MM, and renal failure in patients with t(14;16). Conclusions: Lower BM% was found in IgG isotype MM, which correlated with standard risk CA, whereas light chain MM was associated with higher risk CA; this risk group being more likely to present with renal failure. Unexpectedly, lytic lesions on presentation correlated with non-IgA isotype and better risk CA. Further studies are needed to confirm these findings prospectively to determine if they can predict end organ damage in patients with specific isotypes or CA groups.