bluuebunny/crossref_metadata_2025_split huggingface dataset:
iStopCancer: A database of 6,016 low pass whole genome sequencing of minimal invasive samples from 21 cancer types of Chinese population.
Authors: Yuan Min , Ziliang Qian , Fang Juemin , Zhu Zhongzheng , Wu Jianguo , Guo Xianling , Liu Weixing , Qian Hong , Xu Qing 
Published: May 2020

7062 Background: Cancer is a group of genetic diseases that result from changes in the genome of cells in the body, leading them to grow uncontrollably. Recent researches suggest Chromosome instability (CIN), which is defined as an increased rate of chromosome gains and losses, manifests as cell-to-cell karyotypic heterogeneity and drives cancer initiation and evolution. Methods: In the past two years, we initiated iStopCancer project, and characterized 4515 ‘best available’ minimal-invasive samples from cancer patients and 1501 plasma samples from non-tumor diseases by using low-pass whole genome sequencing. DNA from ‘best available’ minimal-invasive samples, including peripheral plasma, urines, pancreatic juice, bile and effusions were analyzed by low coverage whole genome sequencing followed by the UCAD Bioinformatics workflow to characterize the CINs. In total, 32T bp nucleotide (coverage =1.7X for each sample) were collected. All the data can be visualized on website: http://www.istopcancer.net/pgweb/cn/istopcancer.jsp . Results: 3748(83%) of tumors present detectable CIN (CIN score>1000) in minimal-invasive samples. The missed cancer patients were majorly from patients with either tumor size less than 2cm or less-aggressive cancers, including thyroid cancer, low-grade urothelial carcinoma, lung cancer in-situ, et al. Of the 1501 non-tumor individuals, 30(2.0%) present detectable CIN (|Z|>=3) at the time of sample collection, 24(80.0%) was diagnosed as tumor patient in 3-6 months follow-up. There were 9 (0.59%) of non-cancer individuals without detectable CIN were also reported as tumor patients during 6-month following up. In summary, the positive and negative prediction value is 80.0% and 99.4% respectively. The false alarms were majorly from patients with EBV activations, which indicates virus may interference chromosome stability and drove virus-associated carcinogenesis. For the patient with repeated detections, plasma cfDNA CIN dynamics predicted clinical responses and disease recurrences. Quick clearance of plasma cfDNA CIN in 2-3 weeks was found in 153 (83.6%) patients. Meanwhile, no quick clearance was found in majority of SDs/PDs (73/88=83.0%). Furthermore, cfDNA CIN predicts clinical response 2-8 weeks ahead of traditional biomarkers (CEA, CA15-3, CA199, AFP et al). Conclusions: Large-scale low coverage whole genome sequencing data provides useful information for cancer detection and managements.
The economic impact of cancer-related premature mortality in Brazil: A human capital approach analysis.
Authors: De Camargo Cancela Marianna , Borges Lopes de Souza Leonardo , Leite Martins Luis Felipe , Souza Dyego , Barchuk Anton , Correa Schilithz Arthur , Hanly Paul , Sharp Linda , Pearce Alison , Soerjomataram Isabelle 
Published: May 2020

7068 Background: One method of calculating indirect costs of cancer is the analysis of productivity loss. Using the human capital approach, we estimate how much cancer-related premature mortality indirectly impacts the economy. Given the diverse causes of cancer death and sociodemographic profiles in Brazil, we estimated lost productivity due to cancer by regions, providing evidence for local decision-makers. Methods: Data of all cancers deaths among working-age people (15-64 years for men and 15-60 for women) occurring in 2016 were extracted from the National Mortality System, by region, sex and age-group. Data on life expectancy, workforce participation, unemployment and wages were extracted from the Brazilian National Institute of Geographics and Statistics. Loss of productivity was calculated as the value of time between death and potential retirement age. Results: In total 536,827 (men) and 407,737 (women) years of potential productive life (YPPLL) were lost in 2016, corresponding to US$ 6,196,682,092 (PPP) for Brazil. The profile of YPPLL by cancer type varied by region. In the affluent South and Southeast regions, the cancers with higher impact in men were lung (12.4% and 9.9% of total YPPLL) and colorectal (9.6% and 10.4% of total YPPLL) while in the less affluent North and Northeast, stomach cancer was responsible for 17% and 12% of YPPLL, respectively. Among women, breast cancer had the highest impact in all regions (21.7%-26.2%), excepting the North, where cervical cancer was responsible for 31.3% of the YPPLL. Nationally, individual YPPLL was higher for testicular cancer in males (31.3 years) and Hodgkin’s disease in females (20.2). In the North and the Northeast, despite lower mortality rates, the economic impact of productivity loss was higher, representing 0.23 and 0.29% of the regional GDP. Conclusions: Our results show the indirect economic impact of premature cancer mortality in Brazil, at a total cost of US$ 6,196,682,092 in 2016, representing 0.2% of the entire country’s GDP. The regional patterns highlight the need for adaption of public policies, typical from a country in transition, with the impact of lifestyle and infection-related cancers simultaneously and differently affecting economically the regions.
Post-traumatic stress symptoms in hematopoietic stem cell transplant (HCT) recipients.
Authors: Griffith Sarah , Fenech Alyssa L. , Nelson Ashley , Greer Joseph A. , Temel Jennifer S. , El-Jawahri Areej 
Published: May 2020

7505 Background: Patients admitted for HCT, an intensive and potentially curative therapy for hematologic malignancies, experience a prolonged, isolating hospitalization and endure substantial physical and psychological symptom burden. However, data are limited regarding long-term post-traumatic stress (PTSD) in HCT survivors and its risk factors. Methods: We conducted a secondary analysis examining longitudinal data from 250 patients who underwent autologous and allogenic HCT. We used the Post-Traumatic Stress Checklist (PTSD-CL) to assess for PTSD symptoms at six months post-HCT. We used the Functional Assessment of Cancer Therapy—Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale to assess quality of life (QOL), depression, and anxiety symptoms at the time of admission for HCT, at week-2 during hospitalization, and at six months post-HCT. We used multivariate regression models to assess factors associated with PTSD symptoms, modeling QOL, depression, and anxiety symptoms separately given their collinearity. Results: The mean age was 56.3 (SD = 13.3). The rate of clinically significant PTSD symptoms at six months post-HCT was 18.9% and these patients experienced hypervigilance (92.3%), avoidance (92.3%), and intrusion (76.9%) symptoms. Among patients without clinically significant PTSD symptoms, 24.5% and 13.7% had clinically significant hypervigilance and avoidance symptoms, respectively. Lower QOL at time of HCT admission (B = -0.04, P = 0.004), and being single (B = -3.35, P = 0.027) were associated with higher PTSD symptoms at six months post-HCT. Higher anxiety at time of HCT admission (B = 1.34, P < 0.001), change in anxiety during HCT hospitalization (B = 0.59, P = 0.006), and being single (B = -3.50, P = 0.017), were associated with higher PTSD symptoms at six months. In a separate model, younger age (B = -0.13, P = 0.017), being single (B = -3.58, P = 0.018), and higher baseline depression symptoms were also associated with higher PTSD symptoms at six months (B = 0.97, P < 0.001). Conclusions: Approximately one fifth of patients undergoing HCT experienced clinically significant PTSD symptoms at six months post-transplant. Patients’ baseline QOL and psychological symptoms emerged as important predictors of their risk for PTSD at six months post-HCT. Thus, interventions to prevent and treat PTSD symptoms in HCT recipients are clearly warranted.
Ten-day decitabine with venetoclax (DEC10-VEN) in AML and high-risk (HR) MDS.
Authors: Maiti Abhishek , Dinardo Courtney Denton , Pemmaraju Naveen , Kadia Tapan M. , Rausch Caitlin R , Naqvi Kiran , Daver Naval Guastad , Borthakur Gautam , Ohanian Maro , Issa Ghayas C. , Alvarado Yesid , Short Nicholas James , Andreeff Michael , Jabbour Elias , Pierce Sherry A. , Ravandi Farhad , Garcia-Manero Guillermo , Welch John Sutton , Kantarjian Hagop M. , Konopleva Marina ,   Department of Leukemia, MD Anderson Cancer Center
Published: May 2020

7519 Background: VEN-based low intensity regimens have shown promise in older pts with newly diagnosed (ND) AML. We hypothesized that adding VEN to 10-day (d) DEC may improve outcomes in AML and HR MDS. Methods: Pts received VEN 400 mg daily or equivalent with DEC 20 mg/m2 for 10d every 4-8 weeks for induction and DEC 5d with VEN for consolidation after CR/CRi. If cycle 1 day 21 bone marrow showed ≤5% blasts, VEN was held to enable count recovery. VEN duration could be further reduced for myelosuppression. FLT3 and IDH inhibitors were allowed for applicable pts. All pts received tumor lysis syndrome (TLS) prophylaxis. Primary objective was overall response rate (ORR). Secondary objectives were safety and overall survival (OS). Data cut-off date was February 6, 2020. Results: Between January 2018 and December 2019 we enrolled 184 pts with ND AML (>60 yrs), untreated secondary AML (sAML), treated sAML, relapsed/refractory (R/R) AML and HR MDS (Table). 58% pts were ≥70 yrs, 30% pts had ECOG PS ≥2, 67% pts had ELN adverse risk AML. Previously treated pts (n=96) had received a median of 1 prior therapy (range 1-8) including HMA (62), intensive chemotherapy (49) and stem cell transplantation (SCT, 27). 30d mortality was 3.3% and 60d mortality was 7.6%. 30d mortality in ND AML was 1.4%. Most common G3/4 adverse events were infections with G3/4 neutropenia (46%), febrile neutropenia (28%), infections with ANC ≥1x109/L (6%) and TLS (3%). Outcomes are shown in Table. 25 pts (14%) proceeded to SCT including treatment naive AML (ND+ untreated sAML, 12), previously treated AML (treated sAML + R/R, 11) and HR MDS (2). 100d post-SCT mortality was 4%. Median OS in treatment naïve AML pts undergoing SCT was not reached (1yr OS 100%) and for previously treated AML pts was 22.1 months (mo). After a median follow up of 15 mos, 25% PTS continue therapy. Additional analyses by molecular subgroups will be presented. Conclusions: DEC10-VEN is safe and highly effective in ND AML and can serve as an effective bridge to SCT in previously treated pts. Trial continues to accrue (NCT03404193). Clinical trial information: NCT03404193 . [Table: see text]
Stability of rare TP53 co-mutations in AML patients.
Authors: Bloom Kenneth Joel , Idica Adam , Smart Dave , Allen Wendy , Scanlon Enya , Clark Jordan 
Published: May 2020

7528 Background: Acute Myeloid Leukemia (AML) is a devastating disease with poor overall survival. Access to precision medicines, is revolutionizing AML care and is driving an increase in Next Generation Sequencing (NGS) utilization to determine the genomic profile of patients with AML. Advanced analysis into the interplay between mutational status for multiple genes is granting access to new targeted and precision medicine treatment options with improved outcomes. Methods: Rate of NGS adoption and TP53 mutation status were determined for a cohort of 984 AML patients tested by NGS from the Diaceutics Diagnostic Index between 2017 and 2019. Mutation rate of other genes on the same NGS panel used to determine if TP53 status was determined and compared using the z-score test for two population proportions. The stability of TP53 and co-mutation status at time of diagnosis and relapse/refractory was also analyzed. Results: We have seen a 2-fold increase in the average routine clinical practice uptake of NGS in a representative real-world patient cohort (Q3 2017, n = 144; Q3 2019, n = 290). In a cohort of 984 AML patients tested by NGS 151 (15.3%) had a TP53 mutation (Exon 4-9). Of those that had a TP53 mutation, significant negative associations were observed with mutations in seven other genes (ASXL1 p = 0.00308, CEBPA p = 0.0027, FLT3 p < 0.00001, IDH1 p = 0.04338, NRAS p = 0.0012, RUNX1 p = 0.01878 and TET2 p = 0.0251). There were no statistically significant differences in TP53 mutation and other gene mutation rates between diagnosis and relapse/refractory timepoints. Conclusions: This data suggests that TP53 and other gene co-mutants may act in similar activation pathways resulting in rare detection. One possibility is that double mutants result in synthetic lethality leading to a low clonal population. Second, when co-mutated clones escape immune surveillance and regulation, it results in particularly aggressive leukemias with lower overall survival. The stability of TP53 and co-mutation is relatively stable, which has implications for testing algorithms and clinical utility as a marker of MRD. Although a clinical trial may be difficult due to low numbers of patients, a TP53 antagonist and targeted therapy may be a valuable treatment option in rare cases where co-mutation does exist. [Table: see text]
Molecular dissection of normal karyotype acute myeloid leukemia.
Authors: Shreve Jacob Tyler , Meggendorfer Manja , Mukherjee Sudipto , Walter Wencke , Hutter Stephan , Makhoul Ahed , Kerr Cassandra M. , Radakovich Nathan , Awada Hassan , Nagata Yasunobu , Guan Yihong , Kuzmanovic Teodora , Hasipek Metis , Jha Babal , Maciejewski Jaroslaw P. , Haferlach Claudia , Sekeres Mikkael A. , Haferlach Torsten , Nazha Aziz 
Published: May 2020

7534 Background: Conventional cytogenetics remain one of the most important prognostic factors in acute myeloid leukemia (AML), though 50-60% of patients (pts) have normal karyotype (NK), conventionally classified as intermediate-risk, and have very heterogeneous outcomes. A fraction of mutations such as NPM1, FLT3-ITD, and CEBPa can improve risk stratification for some pts but underestimate the molecular complexity and interactions between these genes and others. Methods: Genomic and clinical data of 2,793 primary AML (pAML) pts were analyzed. A panel of 35 genes that are commonly mutated in AML and myeloid malignancies and have shown to impact OS was included. Correlation of each mutation with others and their impact on OS were evaluated. OS was calculated from the date of diagnosis to date of death or last follow-up. Results: Of 2,793 pts with pAML, 1,352 (48%) had NK and were included in the final analysis. The median age was 55 years (range, 18-93). The median number of mutations/sample was 3 (range, 0-7). The most commonly mutated genes were: NPM1 (49%), DNMT3A (37%), FLT3-ITD (24%), CEBPa (19%), TET2 (17%), IDH2 (17%), and RUNX1 (15%). In univariate Cox regression analysis, mutations in NPM1 (HR 0.81, p =0.008), and CEBPa (single mutant, HR 0.8, double mutant, HR 0.69, p< 0.001, respectively) were associated with longer OS, while mutations in DNMT3a (HR 1.26, p =0.003), FLT3-ITD (HR 1.49, p< 0.001), TET2 (HR 1.26, p =0.02), RUNX1 (HR 1.36, p =0.003), SRSF2 (HR 1.58, p <0.001), IDH1 (HR 1.29, p <0.001), and ASXL1 (HR 1.89, p <0.001) were associated with shorter OS. A total of 67% of pts had NPM1, DNMT3A, and FLT3-ITD mutated alone or in combination with each other. The median OS for pts with NMP1Mut/ DNMT3AWT/FLT3-ITDWT was 99.1 months(m), NMP1Mut/DNMT3AMut /FLT3-ITDWT 54.8m, NMP1Mu t/DNMT3AWT/FLT3-ITDMut 42.3m, NMP1Mut/DNMT3AMut/FLT3-ITDMut 13.4m, NMP1WT/DNMT3AMut/FLT3-ITDMut 13.1m, and NMP1WT/DNMT3AWT/FLT3-ITDWT (triple negative) 32.7m. The median OS for pts with 0-2 mutations/sample was 59.3m, compared to 34.1m for pts with 3-4 mutations, and 16.1m for pts with > 5 mutations ( p< 0.001). Conclusions: We propose a simplified and robust approach to risk stratify AML pts with NK based on the mutational status of NPM1, DNMT3A, FLT3-ITD (alone or in combination with each other), CEBPa, and the number of mutations/sample.
Characterization of clinical pharmacokinetics and exposure-response relationships of AMG 330, a bispecific CD33 T-cell engager antibody construct, in patients with relapsed/refractory AML.
Authors: Agarwal Suresh K , Bhagwat Sharvari , Mehta Khamir , Hindoyan Antreas , Stein Anthony Selwyn , Ravandi Farhad , Subklewe Marion , Walter Roland B. , Jongen-Lavrencic Mojca , Ossenkoppele Gert J. , Paschka Peter , Khaldoyanidi Sophia , Dutta Sandeep , Upreti Vijay V. 
Published: May 2020

7536 Background: AMG 330 binds both CD33 and CD3 and redirects T cells toward CD33+ cells leading to T-cell‒mediated cytotoxicity against AML blasts. An ongoing open label phase I dose-escalation study (NCT02520427) has shown preliminary activity and acceptable safety in relapsed or refractory (R/R) acute myeloid leukemia (AML) patients (pts) (Ravandi et al. ASH 2018). Pharmacokinetics and exposure-response (E-R) relationships of AMG 330 were characterized in this trial. Methods: A continuous IV infusion of AMG 330 was evaluated at escalating target doses (range from 0.5 to 720 μg/day) using a 3+3 design with pts receiving step dose/s prior to reaching target doses of ≥ 30 μg/day. Population pharmacokinetics (popPK) using non-linear mixed effects modeling and E-R analyses were conducted to characterize relationships between AMG 330 exposure (steady-state concentration [Css]) at target dose, the baseline tumor burden, clinical response per revised IWG criteria and incidence of cytokine release syndrome (CRS). Results: As of Dec 10, 2019, 55 patients (males, 56.4%; median age, 58.0 [18.0–80.0] years) were enrolled in 16 cohorts. AMG 330 PK was best described by a one-compartment linear PK model. Dose dependent increases were observed in AMG 330 Css exposures. Responders typically showed higher AMG 330 Css than non-responders. Preliminary exploratory analysis indicated that higher AMG 330 exposures, lower baseline leukemic burden in bone marrow and CD33+ AML cells in peripheral blood, and higher baseline Effector:Target cell ratio may be associated with clinical response. Additionally, a positive relationship was observed for AMG 330 exposures and baseline leukemic burden (p < 0.05) with probability of CRS occurrence and severity. Based on the model, at a baseline leukemic burden of 20%, a 240 µg/day target dose is predicted to result in a 28% and 4% probability of developing CRS of grade ≥ 2 and ≥ 3, respectively. Conclusions: Clinical pharmacokinetic profile and E-R relationships of AMG 330 were characterized to identify optimal AMG 330 dosing regimens that minimize the risk for CRS in ongoing and planned clinical investigations. Clinical trial information: NCT02520427 .
Incidence of large granular lymphocytosis (LGL) in patients with late cytopenias after allogeneic blood or marrow transplantation (AlloBMT).
Authors: Messmer Marcus , Wake Laura , Tsai Hua-Ling , Jones Richard J. , Varadhan Ravi , Wagner-Johnston Nina D. 
Published: May 2020

7544 Background: LGL - often called LGL leukemia - is a clonal disorder of T or NK cells often associated with cytopenias, autoimmunity, splenomegaly, and B symptoms. There are a limited number of studies of benign LGL expansion after alloBMT, some suggesting an association with improved transplant-related outcomes. In contrast, clinically significant LGL leukemia after alloBMT is only described in case reports. Methods: We cross referenced all patients receiving an alloBMT at Johns Hopkins since 2010 with patients who were evaluated for LGL expansion by peripheral blood (PB) flow cytometry (FC) since 2012. Results: There were 1930 alloBMTs from 1/1/10 to 7/1/19. PB FC for suspected LGL was sent on 153 unique patients after alloBMT, usually in the setting of cytopenias (97%). Median age was 59. 69 (45%) had LGL expansion (LGL+) at a median 194 days after alloBMT. Among LGL+, 53 (77%) had an absolute neutrophil count (ANC) < 1500. The majority of the alloBMTs were non-myeloablative (NMA) (97%), related (88%), and haploidentical (89%), consistent with our center’s characteristics. Graft vs host disease (GVHD) prophylaxis was post-transplant cyclophosphamide (PTCy), mycophenolate mofetil, and tacrolimus or sirolimus. 64 (93%) cases were T cell LGL (T-LGL) and 5 were NK cell. Of those with T-LGL, 43 were assessed for T cell receptor clonality. 21% were clonal, 53% oligoclonal, 5% polyclonal, and 21% indeterminate. There were no significant demographic or transplant-related differences between LGL+ and LGL- in our 153 patient cohort. LGL+ were more likely to have had CMV viremia (75% vs 26%, p < 0.0001), but not acute or chronic GVHD. LGL+ had higher lymphocyte counts (1520/cu mm vs 495, p < 0.0001) and a trend toward more neutropenia (77% vs 63%, p = 0.07). There were no differences in overall survival, relapse, or non-relapse mortality. 29 (42%) of LGL+ received immunosuppressive therapy (IST) for cytopenias. First line treatment was corticosteroids for 24 (83%). 65% had normalization of ANC with first line treatment, compared to improvements in anemia in 15% and thrombocytopenia in 36%. 34% of those treated required ≥2 lines of treatment. Conclusions: In contrast to prior studies, where LGL after alloBMT was asymptomatic and associated with improved transplant outcomes, we identified a high rate of LGL with cytopenias and no improvement in transplant outcomes. Neutropenia was common in LGL+ and usually improved with IST.
Bosutinib in patients with chronic phase chronic myeloid leukemia intolerant to prior tyrosine kinase inhibitors: Analyses from the BYOND study.
Authors: Saussele Susanne , Gambacorti-Passerini Carlo , García Gutierrez Valentin , Abboud Camille N. , Purcell Simon , Viqueira Andrea , Leip Eric , Ernst Thomas , Giles Frank , Hochhaus Andreas 
Published: May 2020

7551 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and in newly diagnosed pts in chronic phase (CP). Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). We report findings in pts intolerant to all prior TKIs. Data are reported ≥1 y after the last enrolled pt (~85% TKI-intolerant pts had ≥2 y follow-up). Results: Of 163 pts who received BOS, 156 had Ph+ CP CML. 73 pts entered the study due to intolerance; 29, 26 and 18 had 1 (CP2L), 2 (CP3L) and 3 (CP4L) prior TKIs, respectively. After a median follow-up of 30.4 mo, median treatment duration across all 3 cohorts (CP2L, CP3L, CP4L, respectively) was 25.3 mo (29.2, 24.6, 17.6) and median dose intensity was 292.0 mg/d (304.5, 284.8, 272.1). Across CP CML cohorts (CP2L, CP3L, CP4L, respectively), 84.9% of patients (82.8%, 88.5%, 83.3%) had ≥1 dose reduction and 83.6% (79.3%, 84.6%, 88.9%) had ≥1 dose interruption due to adverse events (AEs). At the data cutoff, 53.4% (CP2L 65.5%, CP3L 42.3%, CP4L 50.0%) were still receiving BOS. The most common reason for discontinuation was AEs (28.8%). The most common ( > 40%) treatment-emergent AEs (TEAEs) were diarrhea (87.7%) and nausea (43.8%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.4%), increased alanine aminotransferase (19.2%) and increased lipase (12.3%). Most pts with a valid baseline assessment achieved major molecular responses (MMR) across therapy lines (Table). Deaths occurred in 4 pts (CP2L 1, CP3L 3, CP4L 0); none were related to BOS or CML. Overall survival rate (95% CI) at 2 y in TKI-intolerant pts was 97.2% (89.2–99.3); rates were 96.4% (77.2–99.5), 96.0% (74.8–99.4) and 100% (100–100) in CP2L, CP3L and CP4L pts, respectively. Conclusions: A long duration of treatment and high response rate were observed in TKI-intolerant pts treated with BOS. Despite being intolerant to all prior therapies, ≥50% of pts in the overall intolerant cohort remained on BOS treatment at the data cutoff and > 80% achieved/maintained MMR. These results further support BOS use in pts with Ph+ CP CML and intolerance to all prior TKIs. Clinical trial information: NCT02228382 . [Table: see text]