Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.

1997 ◽  
Vol 15 (1) ◽  
pp. 44-51 ◽  
Author(s):  
K Seiter ◽  
E J Feldman ◽  
H D Halicka ◽  
F Traganos ◽  
Z Darzynkiewicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Leukemia ◽  
S Phase ◽  
Low Risk ◽  
Myelogenous Leukemia ◽  
Laboratory Evaluation ◽  
Apoptotic Cells ◽  
High Risk Patients ◽  
Risk Patients

PURPOSE To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients. PATIENTS AND METHODS Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m2/d to 7.75 mg/m2/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m2/d, both for 5 days. Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied. RESULTS Oropharyngeal mucositis was dose-limiting. The MTD of topotecan was 4.75 mg/m2/d for 5 days in high-risk patients and 7.0 mg/m2/d for 5 days in low-risk patients. The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P = .01 and P < .05, respectively). Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of whom 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP). CONCLUSION The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m2/d for high-risk patients and 7.0 mg/m2/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.

Are patients with high-risk polycythemia vera (PV) receiving cytoreductive medications? A retrospective analysis of real-world data.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18031-e18031
Author(s):  
Dilan Paranagama ◽  
Jingbo Yu ◽  
Philomena Colucci ◽  
Kristin Evans ◽  
Machaon Bonafede ◽  
...  
Keyword(s):  
High Risk ◽  
Current Treatment ◽  
Treatment Recommendations ◽  
Low Risk ◽  
Myelogenous Leukemia ◽  
Real World Data ◽  
High Risk Patients ◽  
Risk Patients ◽  
Acute Myelogenous ◽  
History Of

e18031 Background: Risk-adapted therapy in PV is aimed at preventing thrombotic events (TE). Under current treatment recommendations (including European LeukemiaNet), high-risk patients (age ≥ 60 y and/or history of TE) should be managed with cytoreductive medications in addition to phlebotomy and low-dose aspirin. The objective of this study was to describe cytoreductive medication usage in patients with high-risk PV. Methods: Retrospective claims from the Truven Health MarketScan Database were analyzed. Inclusion criteria were ≥ 2 non-diagnostic claims for PV >30 days apart, age ≥ 18 y, continuous enrollment during pre-index (1/1/2012–12/31/2012), and continuous enrollment through or death during the study period (1/1/2013–12/31/2014). Patients with claims for myelodysplastic syndrome, myelofibrosis, acute myelogenous leukemia, or secondary polycythemia were excluded. Descriptive statistics were used. Results: The study included 2856 patients. Mean (SD) age was 62.5 (13.5) y, 65.9% of patients were male, and 63.8% were high-risk. Comorbid conditions of interest were reported more frequently in high-risk patients than low-risk patients: hypertension (65.0% vs 43.1%), diabetes (21.7% vs 10.1%), and congestive heart failure (6.6% vs 0.6%). In low- and high-risk patients, the most commonly used cytoreductive medications were hydroxyurea (93.6%), anagrelide (7.6%), and interferon (2.4%). Low-risk patients received cytoreductive medications less often than high-risk patients (Table). However, only 42% of the high-risk patients received treatment with a cytoreductive medication by the end of the study. Conclusions: Despite higher cardiovascular risk and treatment recommendations, less than half of the high-risk PV patients received cytoreductive medications. Furthermore, less than a third of younger patients with a prior TE received cytoreductive medications. [Table: see text]

scholarly journals Accuracy of upper endoscopies with random biopsies to identify patients with gastric premalignant lesions who can safely be exempt from surveillance

2021 ◽  
Vol 24 (3) ◽  
pp. 680-690
Author(s):  
Michiel C. Mommersteeg ◽  
Stella A. V. Nieuwenburg ◽  
Wouter J. den Hollander ◽  
Lisanne Holster ◽  
Caroline M. den Hoed ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
High Risk ◽  
Low Risk ◽  
Premalignant Lesions ◽  
High Risk Patients ◽  
European Guidelines ◽  
Progression Of Disease ◽  
Risk Patients ◽  
Progression Risk

Abstract Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.

scholarly journals A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

2021 ◽  
Vol 22 (3) ◽  
pp. 1075
Author(s):  
Luca Bedon ◽  
Michele Dal Bo ◽  
Monica Mossenta ◽  
Davide Busato ◽  
Giuseppe Toffoli ◽  
...  
Keyword(s):  
Machine Learning ◽  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Progression Free Survival ◽  
Low Risk ◽  
Functional Enrichment ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Of Progression ◽  
Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

scholarly journals Does socioeconomic status make a difference? A register-based study on the extent to which cardiovascular screening in patients with inflammatory arthritis leads to recommended follow-up in general practice

RMD Open ◽  
2020 ◽  
Vol 6 (2) ◽  
pp. e000940
Author(s):  
Anette Hvenegaard Kjeldgaard ◽  
Kim Hørslev-Petersen ◽  
Sonja Wehberg ◽  
Jens Soendergaard ◽  
Jette Primdahl
Keyword(s):  
Blood Pressure ◽  
Socioeconomic Status ◽  
High Risk ◽  
Secondary Care ◽  
Inflammatory Arthritis ◽  
Low Risk ◽  
Risk Screening ◽  
High Risk Patients ◽  
Eular Recommendations ◽  
Risk Patients

ObjectiveTo investigate to what extent patients with inflammatory arthritis (IA) follow recommendations given in a secondary care nurse-led cardiovascular (CV) risk screening consultation to consult their general practitioner (GP) to reduce their CV risk and whether their socioeconomic status (SES) affects adherence.MethodsAdults with IA who had participated in a secondary care screening consultation from July 2012 to July 2015, based on the EULAR recommendations, were identified. Patients were considered to have high CV risk if they had risk Systematic COronary Risk Evaluation (SCORE) ≥5%, according to the European SCORE model or systolic blood pressure ≥145 mmHg, total cholesterol ≥8 mmol/L, LDL cholesterol ≥5 mmol/L, HbA1c ≥42 mmol/mol or fasting glucose ≥6 mmol/L. The primary outcome was a consultation with their GP and at least one action focusing on CV risk factors within 6 weeks after the screening consultation.ResultsThe study comprised 1265 patients, aged 18–85 years. Of these, 336/447 (75%) of the high-risk patients and 580/819 (71%) of the low-risk patients had a GP consultation. 127/336 (38%) of high-risk patients and 160/580 (28%) of low-risk patients received relevant actions related to their CV risk, for example, blood pressure home measurement or prescription for statins, antihypertensives or antidiabetics. Education ≥10 years increased the odds for non-adherence (OR 0.58, 95% CI 0.0.37 to 0.92, p=0.02).Conclusions75% of the high-risk patients consulted their GP after the secondary care CV risk screening, and 38% of these received an action relevant for their CV risk. Higher education decreased adherence.

scholarly journals Changes in patient activation following cardiac rehabilitation using the Active+me digital healthcare platform during the COVID-19 pandemic: a cohort evaluation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Gabbi Frith ◽  
Kathryn Carver ◽  
Sarah Curry ◽  
Alan Darby ◽  
Anna Sydes ◽  
...  
Keyword(s):  
Blood Pressure ◽  
High Risk ◽  
Cardiac Rehabilitation ◽  
Group Analysis ◽  
Patient Activation ◽  
Low Risk ◽  
Smart Device ◽  
Face To Face ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background Restrictions on face-to-face contact, due to COVID-19, led to a rapid adoption of technology to remotely deliver cardiac rehabilitation (CR). Some technologies, including Active+me, were used without knowing their benefits. We assessed changes in patient activation measure (PAM) in patients participating in routine CR, using Active+me. We also investigated changes in PAM among low, moderate, and high risk patients, changes in cardiovascular risk factors, and explored patient and healthcare professional experiences of using Active+me. Methods Patients received standard CR education and an exercise prescription. Active+me was used to monitor patient health, progress towards goals, and provide additional lifestyle support. Patients accessed Active+me through a smart-device application which synchronised to telemetry enabled scales, blood pressure monitors, pulse oximeter, and activity trackers. Changes in PAM score following CR were calculated. Sub-group analysis was conducted on patients at high, moderate, and low risk of exercise induced cardiovascular events. Qualitative interviews explored the acceptability of Active+me. Results Forty-six patients were recruited (Age: 60.4 ± 10.9 years; BMI: 27.9 ± 5.0 kg.m2; 78.3% male). PAM scores increased from 65.5 (range: 51.0 to 100.0) to 70.2 (range: 40.7 to 100.0; P = 0.039). PAM scores of high risk patients increased from 61.9 (range: 53.0 to 91.0) to 75.0 (range: 58.1 to 100.0; P = 0.044). The PAM scores of moderate and low risk patients did not change. Resting systolic blood pressure decreased from 125 mmHg (95% CI: 120 to 130 mmHg) to 119 mmHg (95% CI: 115 to 122 mmHg; P = 0.023) and waist circumference measurements decreased from 92.8 cm (95% CI: 82.6 to 102.9 cm) to 85.3 cm (95% CI 79.1 to 96.2 cm; P = 0.026). Self-reported physical activity levels increased from 1557.5 MET-minutes (range: 245.0 to 5355.0 MET-minutes) to 3363.2 MET-minutes (range: 105.0 to 12,360.0 MET-minutes; P < 0.001). Active+me was acceptable to patients and healthcare professionals. Conclusion Participation in standard CR, with Active+me, is associated with increased patient skill, knowledge, and confidence to manage their condition. Active+me may be an appropriate platform to support CR delivery when patients cannot be seen face-to-face. Trial registration As this was not a clinical trial, the study was not registered in a trial registry.

scholarly journals Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2139-2149 ◽  
Author(s):  
JH Antin ◽  
BE Bierer ◽  
BR Smith ◽  
J Ferrara ◽  
EC Guinan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Hematologic Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Risk Patients ◽  
Risk Patients

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti- CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC- mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC- mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

P3609Temporal trends of the management and outcomes of patients after myocardial infarction according to the risk for recurrent cardiovascular events

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Grinberg ◽  
T Bental ◽  
Y Hammer ◽  
A R Assali ◽  
H Vaknin-Assa ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Risk ◽  
Cardiovascular Events ◽  
Risk Group ◽  
Temporal Trends ◽  
High Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background Following Myocardial Infarction (MI), patients are at increased risk for recurrent cardiovascular events, particularly during the immediate period. Yet some patients are at higher risk than others, owing to their clinical characteristics and comorbidities, these high-risk patients are less often treated with guideline-recommended therapies. Aim To examine temporal trends in treatment and outcomes of patients with MI according to the TIMI risk score for secondary prevention (TRS2°P), a recently validated risk stratification tool. Methods A retrospective cohort study of patients with an acute MI, who underwent percutaneous coronary intervention and were discharged alive between 2004–2016. Temporal trends were examined in the early (2004–2010) and late (2011–2016) time-periods. Patients were stratified by the TRS2°P to a low (≤1), intermediate (2) or high-risk group (≥3). Clinical outcomes included 30-day MACE (death, MI, target vessel revascularization, coronary artery bypass grafting, unstable angina or stroke) and 1-year mortality. Results Among 4921 patients, 31% were low-risk, 27% intermediate-risk and 42% high-risk. Compared to low and intermediate-risk patients, high-risk patients were older, more commonly female, and had more comorbidities such as hypertension, diabetes, peripheral vascular disease, and chronic kidney disease. They presented more often with non ST elevation MI and 3-vessel disease. High-risk patients were less likely to receive drug eluting stents and potent anti-platelet drugs, among other guideline-recommended therapies. Evidently, they experienced higher 30-day MACE (8.1% vs. 3.9% and 2.1% in intermediate and low-risk, respectively, P<0.001) and 1-year mortality (10.4% vs. 3.9% and 1.1% in intermediate and low-risk, respectively, P<0.001). During time, comparing the early to the late-period, the use of potent antiplatelets and statins increased among the entire cohort (P<0.001). However, only the high-risk group demonstrated a significantly lower 30-day MACE (P=0.001). During time, there were no differences in 1-year mortality rate among all risk categories. Temporal trends in 30-day MACE by TRS2°P Conclusion Despite a better application of guideline-recommended therapies, high-risk patients after MI are still relatively undertreated. Nevertheless, they demonstrated the most notable improvement in outcomes over time.

Study on Methylation of p15INK4B Gene and Its Mechanisms in Patients with Myelodysplastic Syndrome and Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3441-3441
Author(s):  
Hongyan Tong ◽  
Maofang Ling ◽  
Jie Jin
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Low Risk ◽  
Blast Phase ◽  
Genetic Event

Abstract The expression and methylation of p15INK4B gene and the expression of DNA methyltransferase genes (DNMTs) in the mononuclear cells (MNCs) from bone marrow of 54 cases with hematopoietic malignances were detected by using RT-PCR, Western blot, and methylation-specific PCR. Of the 54 patients, 10 cases were low-risk MDS, 10 cases were high-risk MDS, 10 cases were acute myeloid leukemia (AML), 10 cases were acute lymphocytic leukemia (ALL), 10 cases were chronic myeloid leukemia in chronic phase (CML-CP), and 4 cases were CML in blast phase (CML-BP). 10 normal persons were studied as nective controls. The results showed that the incidence of p15INK4B methylation in cells of high-risk MDS was higher than that in low-risk MDS (6/10 VS 1/10, P=0.003), and the p15INK4B methylation was found to be associated with the down-regulation of the expressions of p15INK4B gene on both mRNA (r=−0.734, p<0.001) and protein (r=−0.664, p=0.001)levels, which indicated that the silencing of p15INK4B gene was in conjunction with hypermethylation in MDS. The expressions of p15INK4B on mRNA level and protein levels were almost detected in the MNCs from bone marrow of normal persons without the p15INK4B methylation. We also found the expression of DNMT3A and DNMT3B in high-risk MDS (densitometry readings respectively: 0.624±0.146, 0.577±0.344) were higher than in low-risk MDS (densitometry readings respectively: 0.487±0.300, 0.338±0.290) (P<0.05). The expression of DNMT1 was higher in the groups of low-risk MDS, high-risk MDS, AL and CML-CP( densitometry readings respectively: 0.487±0.218, 0.697±0.243, 0.706±0.463 and 0.867±0.375) than in normal control (densitometry reading: 0.181±0.312)(P<0.05, figure listed bellow), which indicated that up-regulated DNMTS might contribute to the hypermethylation of p15INK4B, and the higher expressions of de novo methyltransferases DNMT3A and DNMT3B may be related to the disease progression of MDS. The methylation of p15INK4B was also detected in 9/20 of AL cases accompanied by over-expressions of DNMT1, DNMT3A, and DNMT3B (densitometry readings respectively: 0.706±0.463, 1.066±0.547, and 0.530±0.428). The methylation of p15INK4B was detected in 1 of 10 cases of CML-CP patients, but all be detected in 4 case of CML-BP patients. These results indicated that the hypermethylation of p15INK4B gene may be one of the most common genetic event in pathogenesis of high-risk MDS, acute leukemia, and blast phase of CML. Furthermore, DNMT3A and DNMT3B were substantially over-expressed in the bone marrow cells of these patients. which might play an important role in the transformation from MDS to acute leukemia. Figure Figure

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