Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in phase I trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14032-e14032
Author(s):  
Shigehiro Koganemaru ◽  
Yasutoshi Kuboki ◽  
Kohei Shitara ◽  
Shogo Nomura ◽  
Kenichi Harano ◽  
...  
Keyword(s):  
Risk Assessment ◽  
High Risk ◽  
Phase I ◽  
Cox Regression ◽  
Risk Group ◽  
Risk Index ◽  
Antibody Therapy ◽  
Phase I Trials ◽  
Intermediate Risk ◽  
Serious Adverse Events

e14032 Background: Although patients (pts) in phase I trials may have expectations about their chance to benefit, they sometimes experience serious adverse events (SAEs). These events impact on their quality of life negatively as well as their clinical management and survival, if once occurred, regardless of timing of occurrence or relation to study drugs. Therefore, paying close attention for pts who are more likely to experience SAEs may be required; however, little is known about which clinical features are related to SAEs in phase I trials. The aim of this study is to construct a risk index for SAEs prediction. Methods: We collected medical records of 418 pts with solid tumor who participated in phase I trials for the first time and were treated at our hospital from January 2011 to December 2015. The time to first SAE (TTS), defined as the time from registration to first SAE, was analyzed. Stepwise Cox regression model was applied to screen out the factors to build a risk index. Internal validation was performed using a bootstrap procedure. Results: Four hundred and seven pts were analyzed for building a risk index. Median age was 63 years (range 22-81). Predominant primary tumor site was gastrointestinal cancer (65.1%), followed by lung cancer (8.4%) and genitourinary cancer (5.7%). A total of 251 pts (61.7%) were treated with small molecule compounds, while 136 pts (33.4%) were treated with antibody therapy including immune therapy. A total of 101 pts (24.8%) experienced SAEs included 18 events related to study drugs. Four independent risk factors (use of antibody therapy, 60 < age < 70, higher serum albumin concentration and lower serum alkaline phosphatase concentration), identified by stepwise Cox regression model, were combined into simple ternary risk index that stratified pts into low- (n = 93), intermediate- (n = 175) and high-risk group (n = 139). Hazard ratios for high-risk and intermediate-risk relative to low-risk group and their 95% confidence intervals were 5.25 (2.64-10.42; high-risk) and 2.00 (0.99-4.07; intermediate-risk). Conclusions: Risk assessment based on the risk index for SAEs may be useful for patient management in phase I trials. Further research is needed to validate this risk index.

scholarly journals Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in Phase I trials

2017 ◽  
Vol 28 ◽  
pp. ix108
Author(s):  
Sigehiro Koganemaru ◽  
Yasutoshi Kuboki ◽  
Kohei Shitara ◽  
Shogo Nomura ◽  
Hideaki Takahashi ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Adverse Events ◽  
Phase I ◽  
Risk Index ◽  
Phase I Trials ◽  
Serious Adverse Events

A Novel Risk Classification Model Predicts Overall Survival and Locoregional Surgery Benefit in Colorectal Patients with Distant Metastasis at the Initial Diagnosis

2020 ◽  
Author(s):  
Mo Chen ◽  
Tian-en Li ◽  
Pei-zhun Du ◽  
Junjie Pan ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Distant Metastasis ◽  
Cox Regression ◽  
Risk Group ◽  
Risk Groups ◽  
Risk Classification ◽  
Low Risk ◽  
Classification Model ◽  
Intermediate Risk

Abstract Background and aims: In this research, we aimed to construct a risk classification model to predict overall survival (OS) and locoregional surgery benefit in colorectal cancer (CRC) patients with distant metastasis.Methods: We selected a cohort consisting of 12741 CRC patients diagnosed with distant metastasis between 2010 and 2014, from the Surveillance, Epidemiology and End Results (SEER) database. Patients were randomly assigned into training group and validation group at the ratio of 2:1. Univariable and multivariable Cox regression models were applied to screen independent prognostic factors. A nomogram was constructed and assessed by the Harrell’s concordance index (C-index) and calibration plots. A novel risk classification model was further established based on the nomogram.Results: Ultimately 12 independent risk factors including race, age, marriage, tumor site, tumor size, grade, T stage, N stage, bone metastasis, brain metastasis, lung metastasis and liver metastasis were identified and adopted in the nomogram. The C-indexes of training and validation groups were 0.77 (95% confidence interval [CI] 0.73-0.81) and 0.75 (95% CI 0.72-0.78), respectively. The risk classification model stratified patients into three risk groups (low-, intermediate- and high-risk) with divergent median OS (low-risk: 36.0 months, 95% CI 34.1-37.9; intermediate-risk: 18.0 months, 95% CI 17.4-18.6; high-risk: 6.0 months, 95% CI 5.3-6.7). Locoregional therapies including surgery and radiotherapy could prognostically benefit patients in the low-risk group (surgery: hazard ratio [HR] 0.59, 95% CI 0.50-0.71; radiotherapy: HR 0.84, 95% CI 0.72-0.98) and intermediate risk group (surgery: HR 0.61, 95% CI 0.54-0.68; radiotherapy: HR 0.86, 95% CI 0.77-0.95), but not in the high-risk group (surgery: HR 1.03, 95% CI 0.82-1.29; radiotherapy: HR 1.03, 95% CI 0.81-1.31). And all risk groups could benefit from systemic therapy (low-risk: HR 0.68, 95% CI 0.58-0.80; intermediate-risk: HR 0.50, 95% CI 0.47-0.54; high-risk: HR 0.46, 95% CI 0.40-0.53).Conclusion: A novel risk classification model predicting prognosis and locoregional surgery benefit of CRC patients with distant metastasis was established and validated. This predictive model could be further utilized by physicians and be of great significance for medical practice.

Operating characteristics of two independent sample design in phase I trials in pediatric oncology

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9555-9555
Author(s):  
M. Raphael ◽  
M. Le Deley ◽  
G. Vassal ◽  
X. Paoletti
Keyword(s):  
High Risk ◽  
Phase I ◽  
Phase I Trial ◽  
Small Sample ◽  
Phase I Trials ◽  
Sample Sizes ◽  
Operating Characteristics ◽  
Serious Adverse Events ◽  
Baseline Characteristics ◽  
Pre Treatment

9555 Background: The European Medicine Agency (EMEA) stated that the degree of pre-treatments can modify the patient's tolerance to new treatments in pediatrics oncology, and then suggested that exploration of this potential difference should be considered. It is current practice to split a phase I trial in two groups to identify the Maximum Tolerated Dose (MTD) in each group. Yet how relevant such approach is, has not been investigated. In particular, role of baseline characteristics has not been explored. Methods: We reanalyze a large phase I trial of CPT11 in which 80 children had been included (32 heavily pre-treated pts and 48 less heavily pre-treated) to determine if baseline characteristics were associated with the heaviness of pre-treatment and could predict serious adverse events. To investigate robustness of conclusions in the context of small sample sizes, we performed an extended simulation study. We explored dose recommendations in scenarios with group difference, as measured by Odds Ratio (OR), ranging from 1 (absence of difference) to 8 (large difference) and sample size increasing from 2 * 20 to 2*40. Results: We did not find any relation between the degree and pre- treatment and neither the risk of DLT nor the baseline characteristics in this pediatric trial. However robustness appeared to be critical with high risk of misidentification of MTD in each of the two groups, whatever the prognostic value. With a group difference corresponding to OR=8 and balanced sample sizes (2*20 pts), the same MTD was identified in 10% of the simulations. Even with larger sample sizes (2*40pts), this figure reached 24% for OR=3. There is also a very high risk of identifying two different MTD although the risk is similar in the two groups (52% for 40 × 2 patients). Conclusions: Two independent sample designs in pediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data. No significant financial relationships to disclose.

Predictive Value of Gross Extranodal Extension for Differentiated Thyroid Carcinoma Persistence/Recurrence

2021 ◽  
pp. 019459982110231
Author(s):  
Ying Kou ◽  
Guohua Shen ◽  
Zhuzhong Cheng ◽  
Anren Kuang
Keyword(s):  
High Risk ◽  
Thyroid Carcinoma ◽  
Risk Group ◽  
Differentiated Thyroid Carcinoma ◽  
Individual Risk ◽  
Intermediate Risk ◽  
Entire Cohort ◽  
Gene Group ◽  
Extranodal Extension ◽  
Disease Persistence

Objective We systematically investigated the predictive value of gross extranodal extension (gENE) for differentiated thyroid carcinoma persistence/recurrence. Study Design Retrospective study. Setting A tertiary care hospital. Methods This study was divided into 2 groups according to gENE status: the gENE group and non-gENE group. We compared the disease persistence/recurrence rates of these 2 groups in the entire cohort and by individual risk group (intermediate/high risk), analyzed whether gENE was an independent risk factor for disease persistence/recurrence, and explored the impact of gENE-specific features on disease persistence/recurrence. Results There were 989 patients who satisfied the inclusion criteria: 57 patients in the gENE group and 932 in the non-gENE group. The disease persistence/recurrence rate of the gENE group was higher than that of the non-gENE group in the entire cohort and by individual risk group ( P < .05 for each). Unexpectedly, the outcomes of the gENE group with intermediate risk were similar to those of the non-gENE group with high risk ( P = .72). For the entire cohort, gENE was an independent predictor for disease persistence/recurrence (odds ratio, 2.89; 95% CI, 1.39-6.00; P = .005). Specific features of gENE ( P > .05 for each) were not related to disease persistence/recurrence. Conclusion Patients with gENE and intermediate risk might be regraded as high risk. Specific features of gENE have no impact on disease persistence/recurrence.

scholarly journals Comparative risk assessment for the development of cardiovascular diseases in the Hungarian general and Roma population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter Piko ◽  
Zsigmond Kosa ◽  
Janos Sandor ◽  
Roza Adany
Keyword(s):  
Risk Factors ◽  
Risk Assessment ◽  
Cardiovascular Risk ◽  
Cardiovascular Diseases ◽  
High Risk ◽  
Risk Group ◽  
High Risk Group ◽  
Average Risk ◽  
Cvd Risk ◽  
Roma Population

AbstractCardiovascular diseases (CVDs) are the number one cause of death globally, and the early identification of high risk is crucial to prevent the disease and to reduce healthcare costs. Short life expectancy and increased mortality among the Roma are generally accepted (although not indeed proven by mortality analyses) which can be partially explained by the high prevalence of cardiovascular risk factors (CVRF) among them. This study aims to elaborate on the prevalence of the most important CVD risk factors, assess the estimation of a 10-year risk of development of fatal and nonfatal CVDs based on the most used risk assessment scoring models, and to compare the Hungarian general (HG) and Roma (HR) populations. In 2018 a complex health survey was accomplished on the HG (n = 380) and HR (n = 347) populations. The prevalence of CVRS was defined and 10-year cardiovascular risk was estimated for both study populations using the following systems: Framingham Risk Score for hard coronary heart disease (FRSCHD) and for cardiovascular disease (FRSCVD), Systematic COronary Risk Evaluation (SCORE), ACC/AHA Pooled Cohort Equations (PCE) and Revised Pooled Cohort Equations (RPCE). After the risk scores had been calculated, the populations were divided into risk categories and all subjects were classified. For all CVD risk estimation scores, the average of the estimated risk was higher among Roma compared to the HG independently of the gender. The proportion of high-risk group in the Hungarian Roma males population was on average 1.5–3 times higher than in the general one. Among Roma females, the average risk value was higher than in the HG one. The proportion of high-risk group in the Hungarian Roma females population was on average 2–3 times higher compared to the distribution of females in the general population. Our results show that both genders in the Hungarian Roma population have a significantly higher risk for a 10-year development of cardiovascular diseases and dying from them compared to the HG one. Therefore, cardiovascular interventions should be focusing not only on reducing smoking among Roma but on improving health literacy and service provision regarding prevention, early recognition, and treatment of lipid disorders and diabetes among them.

scholarly journals Multiple Myeloma Patients Undergoing Carfilzomib: Development and Validation of a Risk Score for Cardiovascular Adverse Events Prediction

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1631
Author(s):  
Anna Astarita ◽  
Giulia Mingrone ◽  
Lorenzo Airale ◽  
Fabrizio Vallelonga ◽  
Michele Covella ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Risk Assessment ◽  
Multiple Myeloma ◽  
Cardiovascular Risk ◽  
High Risk ◽  
Adverse Events ◽  
Risk Score ◽  
Risk Group ◽  
High Risk Group ◽  
Cardiovascular Risk Assessment

Cardiovascular adverse events (CVAEs) are linked to Carfilzomib (CFZ) therapy in multiple myeloma (MM); however, no validated protocols on cardiovascular risk assessment are available. In this prospective study, the effectiveness of the European Myeloma Network protocol (EMN) in cardiovascular risk assessment was investigated, identifying major predictors of CVAEs. From January 2015 to March 2020, 116 MM patients who had indication for CFZ therapy underwent a baseline evaluation (including blood pressure measurements, echocardiography and arterial stiffness estimation) and were prospectively followed. The median age was 64.53 ± 8.42 years old, 56% male. Five baseline independent predictors of CVAEs were identified: office systolic blood pressure, 24-h blood pressure variability, left ventricular hypertrophy, pulse wave velocity value and global longitudinal strain. The resulting ‘CVAEs risk score’ distinguished a low- and a high-risk group, obtaining a negative predicting value for the high-risk group of 90%. 52 patients (44.9%) experienced one or more CVAEs: 17 (14.7%) had major and 45 (38.7%) had hypertension-related events. In conclusion, CVAEs are frequent and a specific management protocol is crucial. The EMN protocol and the risk score proved to be useful to estimate the baseline risk for CVAEs during CFZ therapy, allowing the identification of higher-risk patients.

scholarly journals SARS-CoV-2 Seroprevalence in Healthcare Workers in Germany: A Follow-Up Study

2021 ◽  
Vol 18 (9) ◽  
pp. 4540
Author(s):  
Johannes Korth ◽  
Benjamin Wilde ◽  
Sebastian Dolff ◽  
Jasmin Frisch ◽  
Michael Jahn ◽  
...  
Keyword(s):  
High Risk ◽  
Healthcare Workers ◽  
Risk Group ◽  
Close Contact ◽  
Virus Transmission ◽  
High Risk Group ◽  
Low Risk ◽  
University Hospital ◽  
Intermediate Risk ◽  
Igg Antibody

SARS-CoV-2 is a worldwide challenge for the medical sector. Healthcare workers (HCW) are a cohort vulnerable to SARS-CoV-2 infection due to frequent and close contact with COVID-19 patients. However, they are also well trained and equipped with protective gear. The SARS-CoV-2 IgG antibody status was assessed at three different time points in 450 HCW of the University Hospital Essen in Germany. HCW were stratified according to contact frequencies with COVID-19 patients in (I) a high-risk group with daily contacts with known COVID-19 patients (n = 338), (II) an intermediate-risk group with daily contacts with non-COVID-19 patients (n = 78), and (III) a low-risk group without patient contacts (n = 34). The overall seroprevalence increased from 2.2% in March–May to 4.0% in June–July to 5.1% in October–December. The SARS-CoV-2 IgG detection rate was not significantly different between the high-risk group (1.8%; 3.8%; 5.5%), the intermediate-risk group (5.1%; 6.3%; 6.1%), and the low-risk group (0%, 0%, 0%). The overall SARS-CoV-2 seroprevalence remained low in HCW in western Germany one year after the outbreak of COVID-19 in Germany, and hygiene standards seemed to be effective in preventing patient-to-staff virus transmission.

Association of pathological response to neoadjuvant pembrolizumab with tumor PD-L1 expression and high disease-free survival (DFS) in patients with resectable, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6006-6006
Author(s):  
Trisha Michel Wise-Draper ◽  
Vinita Takiar ◽  
Michelle Lynn Mierzwa ◽  
Keith Casper ◽  
Sarah Palackdharry ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Disease Free Survival ◽  
Immune Checkpoint Blockade ◽  
Skin Wound ◽  
High Risk Group ◽  
Pathological Response ◽  
Intermediate Risk ◽  
Positive Margins ◽  
Post Surgery

6006 Background: Patients with resected HNSCC, with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year DFS of 65% and 69%, respectively. Immune checkpoint blockade improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiotherapy (RT) synergizes with anti-PD-1. Therefore, we administered the PD-1 inhibitor pembrolizumab (pembro) pre- and post-surgery with adjuvant RT +/- cisplatin in patients with resectable, locoregionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093). Methods: Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin (40mg/m2 X 6) for patients with high-risk and intermediate-risk features, respectively. The primary endpoint was 1-year DFS estimated by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Pathological response (PR) to neoadjuvant pembro was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE), defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. PR was classified as no (NPR, < 20%), partial (PPR, ≥20% and < 90%) and major (MPR, ≥90%). Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS). Results: Ninety-two patients were enrolled. Seventy-six patients received adjuvant pembro and were evaluable for DFS. Patient characteristics included: median age 58 (range 27 – 80) years; 32% female; 88% oral cavity, 8% larynx, and 3% human papillomavirus negative oropharynx; 86% clinical T3/4 and 65% ≥2N; 49 (53%) high-risk (positive margins, 45%; ECE, 78%); 64% (44/69 available) had PD-L1 CPS ≥1. At a median follow-up of 20 months, 1-year DFS was 67% (95%CI 0.52-0.85) in the high-risk group and 93% (95%CI 0.84-1) in the intermediate-risk group. Among 80 patients evaluable for PR, TE scoring resulted in 48 NPR, 26 PPR and 6 MPR. Patients with PPR/MPR had significantly improved 1-year DFS when compared with those with NPR (100% versus 68%, p = 0.01; HR = 0.23). PD-L1 CPS ≥ 1 was not independently associated with 1-year DFS, but was highly associated with MPR/PPR (p = 0.0007). PPR/MPR in PD-L1 CPS < 1, ≥1 and ≥20, were estimated as 20, 55 and 90%, respectively. Grade ≥ 3 adverse events occurred in 62% patients with most common including dysphagia (15%), neutropenia (15%), skin/wound infections (10%), and mucositis (9%). Conclusions: PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC. Clinical trial information: NCT02641093.

A Hypoxia-related LncRNA Signature Predicts Survival of Primary Lower-grade glioma

2021 ◽  
Author(s):  
Yanjia Hu ◽  
Jing Zhang ◽  
Jing Chen
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Cox Regression ◽  
Risk Group ◽  
Enrichment Analysis ◽  
High Risk Group ◽  
Gene Set Enrichment Analysis ◽  
Lower Grade ◽  
Prognostic Signature ◽  
Gene Set Enrichment

Abstract Background Hypoxia-related long non-coding RNAs (lncRNAs) have been proven to play a role in multiple cancers and can serve as prognostic markers. Lower-grade gliomas (LGGs) are characterized by large heterogeneity. Methods This study aimed to construct a hypoxia-related lncRNA signature for predicting the prognosis of LGG patients. Transcriptome and clinical data of LGG patients were obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). LGG cohort in TCGA was chosen as training set and LGG cohorts in CGGA served as validation sets. A prognostic signature consisting of fourteen hypoxia-related lncRNAs was constructed using univariate and LASSO Cox regression. A risk score formula involving the fourteen lncRNAs was developed to calculate the risk score and patients were classified into high- and low-risk groups based on cutoff. Kaplan-Meier survival analysis was used to compare the survival between two groups. Cox regression analysis was used to determine whether risk score was an independent prognostic factor. A nomogram was then constructed based on independent prognostic factors and assessed by C-index and calibration plot. Gene set enrichment analysis and immune cell infiltration analysis were performed to uncover further mechanisms of this lncRNA signature. Results LGG patients with high risk had poorer prognosis than those with low risk in both training and validation sets. Recipient operating characteristic curves showed good performance of the prognostic signature. Univariate and multivariate Cox regression confirmed that the established lncRNA signature was an independent prognostic factor. C-index and calibration plots showed good predictive performance of nomogram. Gene set enrichment analysis showed that genes in the high-risk group were enriched in apoptosis, cell adhesion, pathways in cancer, hypoxia etc. Immune cells were higher in high-risk group. Conclusion The present study showed the value of the 14-lncRNA signature in predicting survival of LGGs and these 14 lncRNAs could be further investigated to reveal more mechanisms involved in gliomas.

scholarly journals A Risk Signature of Nine Autophagy-Related Genes Associated With Immune Microenvironment and Clinical Prognosis in Wilms Tumor

2021 ◽  
Author(s):  
Shaopei Ye ◽  
Wenbin Tang ◽  
Ke Huang
Keyword(s):  
Regression Analysis ◽  
High Risk ◽  
Risk Score ◽  
Cox Regression ◽  
Wilms Tumor ◽  
Risk Group ◽  
High Risk Group ◽  
Differentially Expressed ◽  
Clinical Prognosis ◽  
Cox Regression Analysis

Abstract Background: Autophagy is a biological process to eliminate dysfunctional organelles, aggregates or even long-lived proteins. . Nevertheless, the potential function and prognostic values of autophagy in Wilms Tumor (WT) are complex and remain to be clarifed. Therefore, we proposed to systematically examine the roles of autophagy-associated genes (ARGs) in WT.Methods: Here, we obtained differentially expressed autophagy-related genes (ARGs) between healthy and Wilms tumor from Therapeutically Applicable Research To Generate Effective Treatments(TARGET) and The Cancer Genome Atlas (TCGA) database. The functionalities of the differentially expressed ARGs were analyzed using Gene Ontology. Then univariate COX regression analysis and multivariate COX regression analysis were performed to acquire nine autophagy genes related to WT patients’ survival. According to the risk score, the patients were divided into high-risk and low-risk groups. The Kaplan-Meier curve demonstrated that patients with a high-risk score tend to have a poor prognosis.Results: Eighteen DEARGs were identifed, and nine ARGs were fnally utilized to establish the FAGs based signature in the TCGA cohort. we found that patients in the high-risk group were associated with mutations in TP53. We further conducted CIBERSORT analysis, and found that the infiltration of Macrophage M1 was increased in the high-risk group. Finally, the expression levels of crucial ARGs were verifed by the experiment, which were consistent with our bioinformatics analysis.Conclusions: we emphasized the clinical significance of autophagy in WT, established a prediction system based on autophagy, and identified a promising therapeutic target of autophagy for WT.

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