tbuckley/cabot-search huggingface dataset:
Phase II trial of CPX-351 (cytarabine:daunorubicin) liposome injection in patients with acute myeloid leukemia &gt;60 years of age who have not been treated with intensive chemotherapy.
Authors: Ellen K. Ritchie, Sangmin Lee, Pinkal M. Desai, Jeff Ball, Michael S. Samuel, Tania Curcio, Sumaiya Miah, Gail J. Roboz
Journal: Journal of Clinical Oncology (2019)

7044 Background: This study enrolled older patients without age limitation to intensive chemotherapy with CPX 351 allowing for prior treatment with low intensity regimens for MDS or AML. Methods: 30 patients aged ≥65yrs with diagnosed AML received up to two induction cycles and consolidation cycles of CPX-351 as a first intensive therapy. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day mortality. Secondary efficacy endpoints included response rate and duration, and assessment of the relationship between cognitive function and treatment outcome. Although the primary efficacy endpoint data is pending, these interim results describe promising primary safety and efficacy endpoint results. Of the 30 patients enrolled, 10 patients (33.3%) were ≥75yrs old, 13 patients (43.3%) had had previous hematologic malignancies, 17 patients (56.6%) had adverse ELN risk stratification, and 16 patients (53.3%) had failed to respond to previous non-intensive treatments. In addition, all patients had an average of 2.1 co-morbid medical conditions. Results: 14 patients (47%) achieved best response criteria, with 12 patients (40.0%) achieving complete remission (CR) and 2 patients (6.6%) achieving complete remission with incomplete platelet or neutrophil recovery (CRi). 6 patients (20%) had a morphologic leukemia free state with pancytopenia and 10 patients had persistent disease. 8 patients (26.6%) went to stem cell transplant. 2 patients (6.6%) died within 30-days. Although final analysis on adverse events data is pending, 6 patients (20%) experienced a Grade 2 decrease in left ventricular ejection fraction (LVEF) at the end of first induction. Conclusions: These results suggest that in elderly AML patients regardless of age and prior treatment with non-intensive chemotherapy can be treated safely with CPX 351 with low 30 day mortality. CR in these patients is 40% with 26% going forward to stem cell transplant. Complete data will be assessed for OS and rate of MRD positivity. The relationship of cognitive and social factors to outcome will also be addressed.
Abstract 14674: High Prevalence of Cardiac Involvement in Patients With Myotonic Dystrophy Type 1 - A Cross-Sectional Cohort Study
Authors: Helle Petri, Nanna Witting, Mads K Ersboell, Ahmad Sajadieh, Morten Duno, Susanne Helweg-Larsen, John Vissing, Lars Kober, Henning Bundgaard
Journal: Circulation (2013)

Objectives: To describe cardiac involvement in patients with myotonic dystrophy type 1 (DM1) and the relation to age, gender and neuromuscular involvement in order to optimize recommendations for c...
Should we legalise cannabis?
Authors: Fiona Godlee
Journal: BMJ (2019)

In any public debate there may come a point when the evidence for a shift in direction clearly outweighs that against. Has this point been reached for drug policy reform?

Several UK medical bodies have decided it has. The Royal College of Physicians of London, the Faculty of Public Health, and the Royal Society for Public Health all now support decriminalising non-medical use of drugs such as cannabis, cocaine, and heroin. In this they agree with the World Health Organization and the …
Abstract 4781: Preclinical assessment of efficacy and safety of novel oncolytic adenovirus for therapy of disseminated lung cancer
Authors: Svetlana Atasheva, Jia Yao, Cedrick Young, Nelson C. Di Paolo, Henry Wyche, Dmitry M. Shayakhmetov
Journal: Cancer Research (2019)

Abstract The majority of lung cancer patients do not respond to current immune-oncology drugs due to low PD1 and PD-L1 expression on immune and cancer cells. Oncolytic viruses are being actively explored as an alternate modality for cancer therapy due to their natural ability to kill infected cells through viral replication. In this study, we analyzed the anti-tumor efficacy and safety profile of AVID-317 oncolytic virus in pre-clinical mouse models of disseminated lung cancer. AVID-317 is a novel oncolytic adenovirus possessing a set of mutations in the virus capsid, which ablate virus interactions with cellular b3 integrins on macrophages and hepatic cells, resulting in virus de-targeting from the liver after intravenous administration. In vitro studies demonstrated that 70% of tested human non-small cell lung cancer (NSCLC)-derived cell lines (N=16) are sensitive to AVID-317 infection, and 85% of AVID-317-sensitive NSCLC lines express no or low PD-L1. Intravenous injection of control parental human adenovirus type 5 (HAdv5) at a dose of 1e11 v.p. per mouse into wild-type mice resulted in release of pro-inflammatory cytokines IL-1b, IL-6, IL-16, and G-CSF into the bloodstream at 6 hours post virus administration. Furthermore, this dose of HAdv5 was lethal due to severe hepatotoxicity within 48 h post virus injection. In contrast, intravenous administration of AVID-317 in the range of doses up to 1e12 v. p. per mouse resulted in no detectible IL-6 and significantly reduced IL-1b, IL-16, G-CSF amounts in the blood. Importantly, AVID-317 administration did not result in mortality. Next, we grafted PD-L1-low human adenocarcinoma A549-Luc-C8 cells into lungs of NCr nude mice to establish an orthotopic model of disseminated lung cancer. When tumor burden reached between 2xe6 to 8e6 RLU, mice were enrolled in four cohorts and treated with AVID-317 at doses of 5e10, 1e11, or 3e11 v.p. per mouse or administered with saline only (control group; N=&amp;gt;10 in each cohort). Mice were euthanized upon detection of 20% weight loss compared to baseline. The median survival in saline-treated group was 57 days post treatment. However, median survival has not be reached for AVID-317-treated groups for the duration of the study (80 days). Taken together, our study demonstrates feasibility of using AVID-317 oncolytic adenovirus for systemic therapy of disseminated lung cancer and its greatly improved safety profile observed upon intravenous virus delivery. Citation Format: Svetlana Atasheva, Jia Yao, Cedrick Young, Nelson C. Di Paolo, Henry Wyche, Dmitry M. Shayakhmetov. Preclinical assessment of efficacy and safety of novel oncolytic adenovirus for therapy of disseminated lung cancer [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 4781.
Effect of adjuvant chemoradiotherapy on survival in primary small cell carcinoma of esophagus (SCCE) patients: An analysis of multicenter clinical outcomes.
Authors: Bingwen Zou, Li Tao, Zhou Qiang, Ma Dai Yuan, Yongshun Chen, Conghua Xie, Wenhui Li, You Lu, Yong Xu
Journal: Journal of Clinical Oncology (2013)

e15125 Background: To retrospectively evaluate the therapy pattern and survival in patients with dissection of primary SCCE. Methods: This study included 119 patients from seven centers in Middle and Western China who underwent radical section of SCCE. Forty six of them were treated with postoperative chemoradiotherapy (POCRT), and 73 of them with postoperative chemotherapy (POCT) alone. The median radiation dose to clinical target volume (CTV) was 50 Gy (varying between 44 and 52 Gy), while the cycles of platinum-based chemotherapy ranged from two to eight with a median of four. Results: The 5-year OS and DFS were 14.5% and 11.7% of all patients, respectively. The median OS and DFS of all patients were 17.0(95%CI: 13.2-20.8) and 10.0(95%CI: 7.3-12.3) months, respectively. The 5-year OS and DFS were 22.0% and 20.0%, respectively, in the POCRT group, and 9.3% and 6.4%, respectively, in the POCT group (P=0.003 for OS and P=0.007 for DFS). There was significant difference in LRFS, favoring the POCRT group (5-year LRFS 74.3% vs. 42.0%, P=0.010), while the 5-year DRFS was 34.1% for the POCRT group comparing to 15.5% for the POCT group (P=0.039).In a multivariate analysis, treatment with more than four cycles of chemotherapy was associated with significantly better OS (HR=0.553, 95% CI, 0.347 to 0.881, P=0.0128) and DFS (HR=0.594, 95% CI, 0.386 to 0.914, P=0.0177). Tumor size less than 3cm was a poor prognostic factor for both overall survival and disease-free survival. Conclusions: Compared with chemotherapy alone, adjuvant treatment with both radiotherapy and chemotherapy improves survival in patients with completely resected SCCE. Future study of treatment modality with radiotherapy and chemotherapy is warranted.
Abstract 16590: Underuse of Oral Anticoagulation, High Use of Aspirin and Worse Clinical Outcomes in Patients With Type 2 Diabetes and Atrial Fibrillation: Insights From the TECOS Trial
Authors: Patricia Guimaraes, Renato D Lopes, Susanna R Stevens, Jennifer B Green, Darren K McGuire, Rury R Holman, Eric D Peterson
Journal: Circulation (2017)

Introduction: While type 2 diabetes (T2D) is a known risk factor for adverse cardiovascular clinical outcomes in those with atrial fibrillation (AF), little is known about the real world use of ant...
Abstract 1781: Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation
Authors: Yong Feng, Francis Hornicek, Zhenfeng Duan
Journal: Cancer Research (2019)

Abstract Aberrant expression and activation of cyclin-dependent protein kinase (CDK) is a hallmark of cancer. CDK11 is a protein kinase in the CDK family and plays a crucial role in cancer cell growth and proliferation. However, the molecular mechanisms of CDK11 in osteosarcoma and CDK11 transcriptional regulated genes are largely unknown. In this study, we performed global transcriptional analysis using gene array technology to investigate the transcriptional role of CDK11 in osteosarcoma. The promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay were used to identify direct transcriptional target of CDK11. Clinical significance relevance and function of CBFβ were further accessed in osteosarcoma tissue microarray and in osteosarcoma cell lines. We identified a transcriptional role of protein-DNA interaction for CDK11p110, but not CDK11p58, in the regulation of core-binding factor subunit beta (CBFβ) expression in osteosarcoma cells. The CBFβ promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay confirmed that CBFβ is a direct transcriptional target of CDK11. High expression of CBFβ is associated with poor outcome in osteosarcoma patients. Expression of CBFβ contributes to the proliferation and metastatic behavior of osteosarcoma cells. These data establish CBFβas a mediator of CDK11p110dependent oncogenesis and suggest that targeting the CDK11-CBFβ pathway may be a promising therapeutic strategy for osteosarcoma treatment. Citation Format: Yong Feng, Francis Hornicek, Zhenfeng Duan. Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation [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 1781.
The law on compulsory vaccination in Italy: an update 2 years after the introduction
Authors: Fortunato D’Ancona, Claudio D’Amario, Francesco Maraglino, Giovanni Rezza, Stefania Iannazzo
Journal: Eurosurveillance (2019)

Italy introduced a national law extending the number of compulsory vaccines from four to 10 in July 2017. The implementation placed a further burden on immunisation centres as they were required to cover the increased demand of vaccination by the parents of unvaccinated children. Vaccine coverage (VC) estimated 6 months and 1 year later, at 24 and 30 months (same birth cohort), had increased for all vaccines. At 24 months of age, measles VC increased from 87.3% in 2016 to 91.8% in 2017 and 94.1% at 30 months of age as at June 2018. In six of 21 regions and autonomous provinces, VC for measles was &gt;95%. Despite the implementation of this law, vaccine hesitancy is still a problem in Italy and the political and social debate on mandatory vaccination is ongoing. Regardless of the policy to be adopted in the future, strategies to maintain high vaccination rates and the related herd immunity should be considered, including adequate communication to the population and the implementation of electronic immunisation registries.
Abstract 818: Changes in tumor suppressor methylation in SKBR3 cells during treatment with Olaparib or Doxorubicin
Authors: Zuzana Sichmanova, Asta Ottesen, Per Eystein Lonning, Elisabet Ognedal Berge, Stian Knappskog
Journal: Cancer Research (2019)

Abstract DNA methylation is an epigenetic mechanism that can alter gene expression without modifying the DNA sequence. Reactivation of tumor suppressor genes that have been epigenetically silenced in cancer could be a potential therapeutic approach. In this study, we performed long-term treatment of the breast cancer cell line SKBR3, with Olaparib or Doxorubicin in order to assess the methylation status of tumor suppressor genes, after the cell cultures had become resistant to these drugs. Using bisulphite conversion and massive parallel sequencing we examined CpG islands in promoter regions of 283 tumor suppressor genes at several time points under the two treatment regiments. Methylation analysis was carried out for each sample using our in-house bioinformatic pipeline established in collaboration with Roche and publicly available tools. We assessed differentially methylated CpG’s for each drug, compared to control samples treated with dimethyl sulfoxide (DMSO) using the R package methylKit. Gene ontology and pathway analysis revealed hypermethylation in genes belonging to homologous recombination pathway and hypomethylation in genes responding to cellular stress and protein kinase signaling in Olaparib-treated samples. In Doxorubicin-treated samples, we identified genes involved in inter-strand cross-link repair to be hypomethylated, while other genes associated with more general cellular response to DNA damage were hypermethylated. While in Olaparib-treated samples, differential methylation seemed to be reversible and dependent on the dosage of Olaparib, methylation patterns in Doxorubicin-treated samples appeared to change in an incremental manner, as a function of exposure time to the drug. Citation Format: Zuzana Sichmanova, Asta Ottesen, Per Eystein Lonning, Elisabet Ognedal Berge, Stian Knappskog. Changes in tumor suppressor methylation in SKBR3 cells during treatment with Olaparib or Doxorubicin [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 818.
Polatuzumab vedotin (Pola) + obinutuzumab (G) and lenalidomide (Len) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL): Interim analysis of a phase Ib/II trial.
Authors: Catherine Diefenbach, Brad Kahl, Lalita Banerjee, Andrew McMillan, Radhakrishnan Ramchandren, Fiona Miall, Javier Briones, Raul Cordoba, Eva González Barca, Carlos Panizo, Jamie Hirata, Naomi Chang, Lisa Musick, Pau Abrisqueta Costa
Journal: Journal of Clinical Oncology (2019)

7505 Background: Pola-G-Len may enhance anti-tumor immune response in R/R FL. We report a pre-planned interim analysis of the safety/efficacy of induction and maintenance with Pola-G-Len in pts with R/R FL in a phase Ib/II study. Methods: Pts received induction treatment with 6x 28-D cycles of: G 1000mg IV (C1: D1, D8, D15; C2–6: D1); Pola 1.4mg/kg or 1.8mg/kg (dose escalation [DE]) or RP2D (expansion) IV (D1); and Len 10–20mg (DE) or RP2D (expansion) PO (D1–21). Pts with CR/PR/SD at the end of induction (EOI) received G 1000mg (D1 every 2mo, for 24mo), and Len (10mg, D1–21 monthly, 12mo). Primary endpoints: C1 DLTs, safety/tolerability, CR rate at EOI (modified Lugano criteria). Results: At the interim data cut-off (7/6/2018), 52 pts were enrolled: 9 discontinued the study (adverse events [AE], n=3; death due to PD, n=4; pt withdrawal, n=1; other, n=1). Median pt age was 62 (range 32–87) years; 58% FLIPI 3–5; 79% ≥2 prior therapy lines; 50% refractory to last treatment. Grade ≥3 AEs were experienced by 75% of pts: neutropenia (46%), thrombocytopenia (17%), anemia (12%) and infections (12%) were most common. AEs leading to Len dose reduction/interruption occurred in 31%/52% of pts. One Grade 5 AE was reported (septic shock after PD in pt receiving subsequent therapy). RP2D: Pola 1.4mg/kg + Len 20mg. Preliminary efficacy data suggest high activity (Table). Median PFS not reached (median follow-up duration 8.95mo; efficacy-evaluable population [EEP]). Conclusions: The safety profile of Pola-G-Len is consistent with known profiles of the individual drugs. Response rates at EOI with Pola-G-Len are promising, with high CR compared with available R/R FL treatments. Responses at EOI (EEP; RP2D; N=18). Clinical trial information: NCT02600897. [Table: see text]
Discrepancy of blast percentage between the bone marrow aspirate and biopsy and its impact on survival outcomes in patients with myelodysplastic syndromes excess blast (MDS-EB).
Authors: Meera Yogarajah, Phuong L. Nguyen, Rong He, Hassan Alkhateeb, Mithun Vinod Shah, Mrinal Mahesh Patnaik, Naseema Gangat, William J. Hogan, Ayalew Tefferi, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2019)

7053 Background: The revised International Prognostic Scoring System (IPSS-R) aids in prognosticating MDS. The percentage (%) of blasts in the bone marrow is one of the major determinants of the scoring system. The aspirate blast % is utilized as the standard of care, but there could be discrepancies in the blast % reported by the aspirate and the biopsy. We aim to study the possible use of bone marrow biopsy blasts in MDS-EB in calculating IPSS-R. Methods: The MDS database was reviewed for cases of MDS-EB after due IRB approval. We calculated IPSS-R scores based on the aspirate blast % (IPSS-R Asp ) and biopsy blast % (IPSS-R Bx ). The biopsy blast % was reported morphologically or by the CD34 stain. Whenever a range was reported the highest value was utilized as the blast %. Suboptimal aspirates were excluded from the study. The overall survival (OS) was determined by IPSS-R Asp , IPSS-R Bx and IPSS-R highest blast (IPSS-R Hi ). OS estimates were calculated by Kaplan-Meier curves and log-rank testing using JMP v.13. Uno’s concordance statistic was used to compare all 3 risk scoring systems. Results: Of 1322 patients, 431 (33%) cases were identified with MDS-EB; out of which 173 cases had both blasts reported in the biopsy and the aspirate. Out of 173 cases, 35 (20%) had MDS-EB1, and 61 (35%) had MDS EB-2 based on both biopsy and aspirate (concordant cases). Seventy seven (45%) patients changed from EB-1 to EB2 or vice versa based on the biopsy blast (44/77 (57%) cases were upstaged). The OS outcomes based on the IPSS-R Bx biopsy showed a clear and meaningful separation with median OS decreasing with increased risk but IPSS-R Asp and IPSS-R Hi did not (Table). We compared the 3 models for observed OS differences using the Uno model and there was no statistically significant difference. Conclusions: IPSS-R Bx (but not IPSS-R Asp and IPSS-R Hi ) identified prognostic groups for OS with median OS decreasing with increased risk. The small sample size may have led to an insignificant effect on model power by Uno model. This finding needs to be validated by other centers. [Table: see text]
Abstract 233: Bispecific HER2 ADC: Making more potent HER2 ADC by improving target internalization
Authors: Andres Perez Bay, Anuj Kalsy, Shiwani Tiwari, Bo Luan, Art Kunz, Zhaoyuan Chen, Li Zhang, Terra Potocky, Thomas Nittoli, Gavin Thurston, Christopher Daly, Julian Andreev
Journal: Cancer Research (2019)

Abstract Trastuzumab-emtansine (T-DM1) targets the well-characterized breast cancer oncogene HER2, and has shown success in the clinic, but tumors expressing intermediate levels of HER2 remain resistant to T-DM1 therapy, apparently due to insufficient lysosomal trafficking of T-DM1. Here, we engineered bispecific HER2-DM1 conjugates that bridge HER2 with the rapidly internalizing receptor APLP2. The high affinity arm of HER2xAPLP2 bispecific antibodies mediates surface binding to HER2+ tumor cells (but not to HER2- normal cells). After binding to HER2, the low affinity APLP2 arm promotes antibody internalization and lysosomal degradation. The strength of the APLP2 arm allows for modulation of the degree of internalization, degradation and killing. In in vitro killing assays, HER2xAPLP2-DM1 were significantly more potent than T-DM1 in cell lines expressing high (IHC3+) and intermediate (IHC 2+) levels of HER2, albeit induced little or no killing in cell lines expressing low HER2 levels (IHC 1+). Monovalent APLP2-ADCs induced little or no killing in all cell lines tested. Selected HER2xAPLP2-DM1 conjugates had acceptable PK profile in APLP2 humanized mice while significantly outperforming T-DM1 in inhibiting growth of IHC2+ tumor xenografts. These data pave the way to generate clinical candidate ADCs that will improve on T-DM1. In addition, our study opens up a possibility to exploit internalizing proteins such as APLP2 in combination with bispecific antibodies to enhance efficacy of ADCs. Citation Format: Andres Perez Bay, Anuj Kalsy, Shiwani Tiwari, Bo Luan, Art Kunz, Zhaoyuan Chen, Li Zhang, Terra Potocky, Thomas Nittoli, Gavin Thurston, Christopher Daly, Julian Andreev. Bispecific HER2 ADC: Making more potent HER2 ADC by improving target internalization [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 233.