MO280VALIDATION OF AN ANCA ASSOCIATED VASCULITIS RENAL RISK SCORE IN THE SOUTH WEST OF ENGLAND

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ailish Nimmo ◽  
Arvind Singh ◽  
Jena Hopkins ◽  
Anna Rixon ◽  
Spoorthy Sreerama ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Kidney Biopsy ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Renal Survival ◽  
Anca Associated Vasculitis ◽  
Medium Risk

Abstract Background and Aims Determining the renal prognosis for patients with ANCA associated vasculitis (AAV) is important in guiding treatment decisions, including balancing the risks and benefits of aggressive immunosuppression, and informing patients of their likely trajectory. We examined the performance of the clinicopathologic risk stratification tool developed by Brix et al. 1 in determining renal outcomes in a cohort of AAV patients in the South West of England. Method A retrospective review of case notes of patients diagnosed with AAV between 2010 and 2020 from two renal units (Bristol and Plymouth) was performed. Patients were followed up until 1st August 2020. Demographic details, kidney function at presentation and initial treatment regime were collected alongside kidney biopsy data. The renal risk score divides patients into three groups determined as being at low, medium and high risk of adverse renal outcomes based on (1) the percentage of normal glomeruli on kidney biopsy, (2) the percentage of tubular atrophy and interstitial fibrosis on kidney biopsy and (3) eGFR at diagnosis. The outcome of interest was the development of end stage kidney disease (ESKD), defined as a dialysis requirement >3months or kidney transplantation. Patients were censored for death. Results In total 93 individuals were diagnosed with AAV over the study period; 51% were female and the median age at diagnosis was 69 years [IQR 60-78]. ANCA subclass was MPO positive in 73% of cases, PR3 positive in 19% and ANCA negative in 8%. At presentation, 42% had an eGFR below 15ml/min/1.73m2. With respect to risk scores, 17% of individuals were low risk (n=16), 52% were medium risk (n=48) and 31% were high risk (n=29). Median follow up was 3.2 years [IQR 1.3-5.9], over which time 18% of patients developed ESKD (1 in the low risk group, 7 in the medium risk group and 9 in the high risk group). A further 20% of patients died. A Kaplan-Meier survival curve (Figure 1) demonstrated worsening renal survival with rising risk group (Log-rank test, p=0.05). At 1 year, 74 patients (80%) were alive and in these individuals renal survival was 100% in the low risk group, 91% in medium risk group and 75% in the high risk group. Conclusion Overall, 18% of patients developed ESKD over a median follow up of 3.2 years. The renal risk score developed by Brix et al. helps prognosticate renal survival and may assist in shared decision making with patients regarding treatment options. The score demonstrates the importance of the degree of chronicity in determining renal survival. Further work in larger cohorts to compare the performance of the risk score in different subgroups of patients with AAV would be informative.

P0450END-STAGE RENAL DISEASE PREDICTION IN ANCA-ASSOCIATED GLOMERULONEPHRITIS AT BASELINE: UTILITY OF DIFFERENT APPROACHES IN CLINICAL PRACTICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Nikolay Bulanov ◽  
Ekaterina Stolyarevich ◽  
Anastasiia Zykova ◽  
Elizaveta Safonova ◽  
Ekaterina Karovaikina ◽  
...  
Keyword(s):  
High Risk ◽  
Renal Disease ◽  
Risk Group ◽  
Renal Involvement ◽  
Survival Rates ◽  
Low Risk ◽  
Renal Survival ◽  
Anca Associated Vasculitis ◽  
Medium Risk ◽  
Stage Renal Disease

Abstract Background and Aims Despite significant progress in treatment of ANCA-associated vasculitis (AAV), at least 20% of patients with renal involvement develop end-stage renal disease (ESRD). Histopathologic classification by Berden et al, which addresses only glomerular pathology, has been used to predict renal outcome in ANCA-assoicted glomerulonephritis (ANCA-GN) since 2010.1 In 2018 Brix et al proposed ANCA renal risk score (ARRS), which combines assessment of morphological (percentage of normal glomeruli, tubular atrophy and interstitial fibrosis) and clinical parameters (estimated glomerular filtration rate) to predict probability of ESRD.2 The aim of our study was to compare clinical utility of these two methods. Methods In our retrospective study we enrolled 57 patients with ANCA-associated vasculitis, diagnosed according to Chapel Hill Consensus Conference (2012) definition and/or American College of Rheumatology (1990) criteria, with histologically proven renal involvement. There were 14 (24.6%) males and 43 (75.4%) females, median age at AAV onset was 48 (33; 57) years. Fifty-one (89.5%) patients were ANCA-positive. Eight (14.0%) patients were diagnosed with renal-limited AAV. Median Birmingham vasculitis activity score (BVAS v.3) at onset was 16 (13; 19). In each case ANCA-GN class was established according to Berden classification: focal (>50% normal glomeruli); crescentic (>50% cellular crescents); mixed (<50% normal, <50% crescentic, and <50% globally sclerotic glomeruli) or sclerotic (>50% globally sclerotic glomeruli). ARRS at onset was also retrospectively assessed and all patients were divided into three groups depending on the risk of ESRD: low risk (0 points), intermediate risk (2 to 7 points), or high risk (8 to 11 points). Thirteen patients (22.8%) developed ESRD after a median of 12 (6.5; 28) months. Renal survival rates were assessed by Kaplan-Meier method and compared by log-rank test. Results Among the 57 patients seven (12.3%) had focal, 10 (17.5%) – crescentic, 24 (43.2%) – mixed, and 16 (28.1%) – sclerotic ANCA-GN class according to Berden et al classification. 1- and 3-year renal survival rates were the highest (100% and 100% respectively) in focal, and the lowest in sclerotic class (67% and 50.2% respectively). 1- and 3- year renal survival was similar in crescentic (80% and 80% respectively) and mixed (80.6% and 80.6% respectively) classes (Fig. 1A). The differences were not statistically significant (Log-rank (Mantel-Cox) p = 0.17). Then we retrospectively re-evaluated all cases according to ARSS: 12 cases were classified as low-risk, 27 – as medium risk, 18 – as high risk. One-year and three-year survival rates were 100% and 100% in low-risk group, 86.1% and 74.2% in medium risk group, 50.6% and 50.6% in high risk group (Figure 1B). The differences were statistically significant (Log-rank (Mantel-Cox) p=0.003). Conclusion In our limited group of patients ANCA renal risk score classification provided better and more clear stratification of patients in terms of ESRD prediction than Berden classification. ARRS is a simple and valuable tool for assessment of renal survival prognosis which can contribute to personalized approach to the management of AAV.

Abstract 19763: Role of HAS-BLED Score on Major Bleeding in Atrial Fibrillation Undergoing Percutaneous Coronary Intervention With Drug-eluting Stents

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yoshitaka Ito ◽  
Kazuhiro Naito ◽  
Katsuhisa Waseda ◽  
Hiroaki Takashima ◽  
Akiyoshi Kurita ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
High Risk ◽  
Anticoagulant Therapy ◽  
Major Bleeding ◽  
Stent Implantation ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk

Background: While anticoagulant therapy is standard management for atrial fibrillation (Af), dual antiplatelet therapy (DAPT) is needed after stent implantation for coronary artery disease. HAS-BLED score estimates risk of major bleeding for patients on anticoagulation to assess risk-benefit in Af care. However, it is little known about usefulness of HAS-BLED score in Af patient treated with coronary stents requiring DAPT or DAPT plus warfarin (triple therapy: TT). The aim of this study was to evaluate the role of HAS-BLED score on major bleeding in Af patients undergoing DAPT or TT. Methods: A total of 837 consecutive patients were received PCI in our hospital from Jan. 2007 to Dec. 2010, and 66 patients had Af or paroxysmal Af at the time of PCI. Clinical events including major bleeding (cerebral or gastrointestinal bleeding) were investigated up to 3 years. Patients were divided into 2 groups based on HAS-BLED score (High-risk group: HAS-BLED score≥4, n=19 and Low-risk group: HAS-BLED score<4, n=47). DAPT therapy was required for a minimum 12 months after stent implantation and warfarin was prescribed based on physicians’ discretion. Management/change of antiplatelet and anticoagulant therapy during follow-up periods were also up to physicians’ discretion. Results: Baseline characteristics were not different between High-risk and Low-risk group except for age. Overall incidence of major bleeding was observed in 8 cases (12.1%) at 3 years follow-up. Major bleeding event was significantly higher in High-risk group compared with Low-risk group (31.6% vs. 4.3%, p=0.002). However, management of DAPT and TT was not different between the 2 groups. Among component of HAS-BLED score, renal dysfunction and bleeding contributed with increased number of the score. Conclusion: High-risk group was more frequently observed major bleeding events compared with Low-risk group in patients with Af following DES implantation regardless of antiplatelet/anticoagulant therapy.

A Four-gene Autophagy-related Prognostic Signature and Its Association With Immune Landscape in Lung Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Lumeng Luo ◽  
Minghe Lv ◽  
Xuan Li ◽  
Tiankui Qiao ◽  
Kuaile Zhao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Risk Score ◽  
Squamous Cell ◽  
Immune Suppression ◽  
Risk Group ◽  
Lung Squamous Cell Carcinoma ◽  
High Risk Group ◽  
Low Risk

Abstract Background: Recent advances in immune checkpoint inhibitors (ICIs) have dramatically changed the therapeutic strategy against lung squamous cell carcinoma (LUSC). In the era of immunotherapy, effective biomarkers to better predict outcomes and inform treatment decisions for patients diagnosed with LUSC are urgently needed. We hypothesized that immune contexture of LUSC is potentially dictated by tumor intrinsic events, such as autophagy. Thus, we attempted to construct an autophagy-related risk signature and examine its prediction value for immune phenotype in LUSC.Method: The expression profile of LUSC was obtained from the cancer genome atlas (TCGA) database and the profile of autophagy-related genes (ARGs) was extracted. The survival‑related ARGs (sARGs) was screened out through survival analyses. Random forest was performed to select the sARGs and construct a prognostic risk signature based on these sARGs. The signature was further validated by receiver operating characteristic (ROC) analysis and Cox regression. GEO dataset was used as an independent testing dataset. Patients were divided into high-risk and low-risk group based on the risk score. Then, gene set enrichment analysis (GSEA) was conducted between the two groups. The Single-Sample GSEA (ssGSEA) was introduced to quantify the relative infiltration of immune cells. The correlations between risk score and several main immune checkpoints were examined. And the ESTIMATE algorithm was used to calculate the estimate/immune/stromal scores of the LUSC. Results: Four ARGs (CFLAR, RGS19, PINK1 and CTSD) with the most significant prognostic values were enrolled to construct the risk signature. Patients in high-risk group had better prognosis than the low-risk group (P < 0.0001 in TCGA; P < 0.01 in GEO) and considered as an independent prognosis factor. We also found that high-risk group indicated an immune-suppression status and had higher levels of infiltrating regulatory T cells and macrophages, which are correlated with worse outcome. Besides, risk score showed a significantly positive correlation with the expression of PD-1 and CTLA4, as well as estimate score and immune score.Conclusion: This study established a novel autophagy-related four-gene prognostic risk signature, and the autophagy-related scores are associated with immune landscape of LUSC, with higher score indicating a stronger immune-suppression status.

scholarly journals P0357VALIDATION OF THE ANCA RENAL RISK SCORE IN A LONDON COHORT: POTENTIAL IMPACT OF TREATMENT ON PREDICTION OUTCOME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
PEK GHE TAN ◽  
Jennifer O'Brien ◽  
Megan Griffith ◽  
Marie Condon ◽  
Tom Cairns ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Risk Group ◽  
Risk Groups ◽  
Renal Outcome ◽  
Combination Regimen ◽  
Renal Survival ◽  
Medium Risk ◽  
Risk Patients ◽  
Potential Impact

Abstract Background and Aims A renal risk score was recently developed to predict the risk of progression to end stage kidney disease (ESKD) in patients with ANCA-associated glomerulonephritis (ANCA-GN). The score defines three risk groups, each with distinct renal survival at 36 months: 68% of high-risk patients reaching ESKD, compared to 26% and 0% in the medium- and low-risk groups, respectively. The majority of patients (101/115) used to define the risk score were treated with IV cyclophosphamide and steroids. At our centre, we employ a combined low-dose IV cyclophosphamide, rituximab and oral corticosteroid induction regimen, with or without plasma exchange (PEX) depending on disease severity, for ANCA-GN. A recent cohort study suggested this combination regimen may lead to better renal survival. We thus hypothesized that choice of remission-induction treatment may affect prediction accuracy of the risk tool. We retrospectively test the validity of the ANCA renal risk score in patients with ANCA-GN treated at our centre. Method All patients with newly diagnosed, biopsy-proven ANCA-GN from 2006-19 were identified from local renal histopathology database. Patients with relapsing ANCA-GN, EGPA, other coexisting GN, or missing data on induction therapy or eventual renal outcome were excluded. ANCA-negative pauci-immune GN was included. Baseline demographics, ANCA serology, initial therapy and parameters in the ANCA risk score (including % normal glomeruli, % tubular atrophy and interstitial fibrosis (TAIF), and estimated glomerular filtration rate were collected. All patients were stratified using the risk tool and Kaplan Meier survival analysis was applied to examine the ESKD prediction. Subgroup analysis was then performed for patients who received the combination regimen of cyclophosphamide and rituximab. Results 178 patients with a median follow up of 44 month were included in the analysis. The median age was 62 years and 82 patients (46%) were female. 94(53%) were MPO-ANCA positive, 66(37%) PR3-ANCA positive, 15 (8%) ANCA-negative, and 3 (2%) were double PR3/MPO-ANCA positive. 148 (83%) patients received the combination regimen, and 45 had concurrent PEX. Total of 37 (21%) patients reached ESKD. 29 (78%) of these, developed ESKD within 36 months of initial diagnosis. Using the risk score, 64(36%), 76(43%) and 38(21%) patients were deemed low-, medium- and high-risk, respectively. Very distinct poor renal survival at 36 months was seen in high-risk group (55% reaching ESKD, p&lt;0.01), but was less apparent between low- (95%) and medium-risk (90%)(p=0.052) (Figure1); In the subgroup of patients treated with combination regimen without concurrent PEX, the high-risk subgroup continues to demonstrate poor renal survival at 36 months (60% ESKD), but renal survival between low- and medium-risk group were comparable (0 and 2% respectively, p=0.57) (Figure 2). Conclusion In our cohort, the ANCA Renal Risk Score reliably predicted rapid ESKD progression at 36-month in high-risk patients, but was less accurate for distinguishing patients with low-and medium-risk. The subgroup analysis suggested combined cyclophosphamide and rituximab therapy may have modified long-term renal outcome especially in the medium-risk cohort, influencing the accuracy of the prediction tool. Large multi-centre cohorts are required to further evaluate the potential impact of treatment on predicting outcome.

Application of a Validated Predictive Model for Venous Thromboembolism in Cancer to Patients with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 534-534
Author(s):  
Natasha Catherine Edwin ◽  
Jesse Keller ◽  
Suhong Luo ◽  
Kenneth R Carson ◽  
Brian F. Gage ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Discriminative Ability ◽  
Blood Institute ◽  
C Statistic

Abstract Background Patients with multiple myeloma (MM) have a 9-fold increased risk of developing venous thromboembolism (VTE). Current guidelines recommend pharmacologic thromboprophylaxis in patients with MM receiving an immunomodulatory agent in the presence of additional VTE risk factors (NCCN 2015, ASCO 2014, ACCP 2012). However, putative risk factors vary across guidelines and no validated VTE risk tool exists for MM. Khorana et al. developed a VTE risk score in patients with solid organ malignancies and lymphoma (Blood, 2008). We sought to apply the Khorana et al. score in a population with MM. Methods We identified patients diagnosed with MM within the Veterans Health Administration (VHA) between September 1, 1999 and December 31, 2009 using the International Classification of Diseases (ICD)-03 code 9732/3. We followed the cohort through October 2014. To eliminate patients with monoclonal gammopathy of undetermined significance and smoldering myeloma, we excluded patients who did not receive MM-directed therapy within 6 months of diagnosis. We also excluded patients who did not have data for hemoglobin (HGB), platelet (PLT) count, white blood count (WBC), height and weight, as these are all variables included in the Khorana et al. risk model. Height and weight were assessed within one month of diagnosis and used to calculate body mass index (BMI). We measured HGB, PLT count, and WBC count prior to treatment initiation: within two months of MM diagnosis. A previously validated algorithm, using a combination of ICD-9 code for VTE plus pharmacologic treatment for VTE or IVC filter placement, identified patients with incident VTE after MM diagnosis (Thromb Res, 2015). The study was approved by the Saint Louis VHA Medical Center and Washington University School of Medicine institutional review boards. We calculated VTE risk using the Khorana et al. score: We assigned 1 point each for: PLT ≥ 350,000/μl, HGB < 10 g/dl, WBC > 11,000/μl, and BMI ≥ 35 kg/m2. Patients with 0 points were at low-risk, 1-2 points were considered intermediate-risk and ≥3 points were termed high-risk for VTE. We assessed the relationship between risk-group and development of VTE using logistic regression at 3- and 6-months. We tested model discrimination using the area under the receiver operating characteristic curve (concordance statistic, c) with a c-statistic range of 0.5 (no discriminative ability) to 1.0 (perfect discriminative ability). Results We identified 1,520 patients with MM: 16 were high-risk, 802 intermediate-risk, and 702 low-risk for VTE using the scoring system in the Khorana et al. score. At 3-months of follow-up, a total of 76 patients developed VTE: 27 in the low-risk group, 48 in the intermediate-risk group, and 1 in the high-risk group. At 6-months of follow-up there were 103 incident VTEs: 41 in the low-risk group, 61 in the intermediate-risk group, and 1 in the high-risk group. There was no significant difference between risk of VTE in the high- or intermediate-risk groups versus the low-risk group (Table 1). The c-statistic was 0.56 at 3-months and 0.53 at 6-months (Figure 1). Conclusion Previously, the Khorana score was developed and validated to predict VTE in patients with solid tumors. It was not a strong predictor of VTE risk in MM. There is a need for development of a risk prediction model in patients with MM. Figure 1. Figure 1. Disclosures Carson: American Cancer Society: Research Funding. Gage:National Heart, Lung and Blood Institute: Research Funding. Kuderer:Janssen Scientific Affairs, LLC: Consultancy, Honoraria. Sanfilippo:National Heart, Lung and Blood Institute: Research Funding.

scholarly journals The predictive role of Ki-67 protein in determining the aggressiveness of primary malignant bone tumors. A retrospective study

2019 ◽  
Vol 2 (2) ◽  
pp. 91-95
Author(s):  
Ioan-Mihai Japie ◽  
Dragoș Rădulescu ◽  
Adrian Bădilă ◽  
Alexandru Papuc ◽  
Traian Ciobanu ◽  
...  
Keyword(s):  
High Risk ◽  
Ewing Sarcoma ◽  
Bone Tumors ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
The Other ◽  
Malignant Bone Tumors ◽  
Ki 67

AbstractIntroduction: In order to diagnose and stage malignant bone tumors, the pathologic examination of harvested pieces with immunohistochemistry test is necessary; they also provide information regarding the prognosis on a medium to long term. Among tissular biomarkers with potential predictive value, a raised Ki-67 protein level is used to determine the risk of local recurrence or metastasis.Material and method: This study was performed on 50 patients with primary malignant bone tumors admitted in the Traumatology and Orthopedy Department of University Emergency Hospital, Bucharest. Patients repartition according to diagnosis was the following: 21 patients with osteosarcoma, 18 patients with chondrosarcoma, 6 patients with Ewing sarcoma, 3 patients with malignant fibrous histiocytoma, and 2 with fibrosarcoma. The follow-up period was between 12 and 72 months with a mean of 26 months.Results: Patients were aged between 18 and 77 years old, with a mean age of 41,36. There were 22 women and 28 men. No sex or age difference was notable for the tumor outcome. After calculating the Ki-67 LI, 36 patients were included in the high-risk group (Ki-67 LI > 25%), while 14 had a low risk for metastasis and local relapse (Ki-67 < 25%). The low-risk patients had chondrosarcoma (8 patients), osteosarcoma (5 patients), and fibrosarcoma (1 patient). During the follow-up, 8 patients, all belonging to the high risk group, developed metastasis, while 5 patients developed local recurrences; 4 patients who relapsed belonged to the high risk group and 1 to the low risk group. Metastases developed in 3 patients with osteosarcoma, 2 with Ewing sarcoma, 2 with chondrosarcoma and 1 patient with fibrosarcoma. Most metastases occurred within one year after surgery. The other fibrosarcoma patient developed local recurrence after 6 months, while the other local recurrences occurred in osteosarcoma patients (2 cases) and 1 in a Ewing sarcoma patient and chondrosarcoma patient.Conclusions: Our study concluded that while Ki-67 LI values are useful in determining the aggressivity of primary malignant bone tumors, it should always be used in conjunction with the clinical, imaging and anatomopathological diagnosis methods in order to accurately predict the patients’ outcome.

scholarly journals Validation of Clinical Prognostic Models and Integration of Genetic Biomarkers of Drug Resistance in CLL Patients Treated with Ibrutinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 186-186 ◽  
Author(s):  
Inhye E. Ahn ◽  
Xin Tian ◽  
Maher Albitar ◽  
Sarah E. M. Herman ◽  
Erika M. Cook ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
Prognostic Models ◽  
Discovery Cohort ◽  
Treatment Naïve ◽  
Equity Ownership

Abstract Introduction: We previously reported a prognostic scoring system in CLL using pre-treatment factors in patients treated with ibrutinib [Ahn et al, 2016 ASH Annual Meeting]. Here we present long-term follow-up results and validation of the prognostic models in a large independent cohort of patients. We also determine the incidence of resistance-conferring mutations in BTK and PLCG2 genes in different clinical risk groups. Methods and Patients: The discovery cohort comprised 84 CLL patients on a phase II study with either TP53 aberration (deletion 17p or TP53 mutation) or age ≥65 years (NCT01500733). The validation cohort comprised 607 patients pooled from four phase II and III studies for ibrutinib in treatment-naïve or relapsed/refractory CLL (NCT01105247; NCT01578707; NCT01722487; NCT01744691). All patients received single-agent ibrutinib 420mg once daily. We used Cox regression models to identify independent predictors of PFS, Kaplan-Meier method to estimate probabilities of PFS, log-rank test to compare PFS, and Cochran-Armitage trend test to compare the incidence of mutation among subgroups. We used R version 3.5.0 or SAS® version 9.3 for statistical analyses. For biomarker correlation, we tested cellular DNA or cell-free DNA collected from patients in the discovery cohort with the targeted sequencing of BTK and PLCG2 genes. Result: At a median follow-up of 5.2 years, 28 (33.3%) of 84 patients in the discovery cohort progressed or died. 52 (61.9%) patients had treatment-naïve CLL. Independent factors of PFS on univariate analysis were; TP53 aberration, prior treatment, and β-2 microglobulin (B2M) >4mg/L (P<0.05 for all tests). Unmutated IGHV and advanced Rai stage (III/IV) showed a trend toward inferior outcome without reaching statistical significance. Because higher levels of B2M were associated with relapsed/refractory CLL, we performed two multivariate Cox regression models to assess B2M and prior treatment status separately. Risk groups were determined by the presence of TP53 aberration, advanced Rai stage, and B2M >4mg/L for Model 1, and TP53 aberration, advanced Rai stage, and relapsed/refractory CLL for Model 2 (Table 1). The high-risk group had all three adverse risk factors; the intermediate-risk group had two risk factors; and the low-risk group, none or one. The median PFS of the high-risk group was 38.9 months for Model 1 and 38.4 months for Model 2, and was significantly shorter than those of intermediate and low-risk groups. In the validation cohort, 254 (41.8%) of 607 patients progressed or died at a median follow-up of 4.2 years. 167 (27.5%) patients had treatment-naïve CLL. Both models showed statistically significant differences in PFS by risk groups (Table 1). For the high-risk group, 4-year PFS was 30.2% in Model 1 and 30.5% in Model 2, which were inferior to those of intermediate (53.4 and 52.4%) and low-risk groups (68.7 and 73.7%). Model 1 classified 20% of patients and Model 2 classified 28% of patients to the high-risk group. BTK and PLCG2 mutations are common genetic drivers of ibrutinib resistance in CLL. To determine whether the incidence of these mutations correlates with prognostic risk groups, we performed targeted sequencing of BTK and PLCG2 of samples collected from patients in the discovery cohort. We used cell-free DNA for patients who received long-term ibrutinib (≥3 years) and had low circulating tumor burden, and cellular DNA, for samples collected within 3 years on ibrutinib or at progression. Of 84 patients, 69 (82.1%) were tested at least once, and 37 (44.0%) were tested at least twice. The frequency of testing was similar across the risk groups by two models (P>0.05). The cumulative incidences of mutations at 5 years in the low-, intermediate-, and high-risk groups were: 21.4%, 44.8% and 50%, respectively, by Model 1 (P=0.02); and 22.6%, 41.4% and 66.7%, respectively, by Model 2 (P=0.01). Conclusion: We developed and validated prognostic models to predict the risk of disease progression or death in CLL patients treated with ibrutinib. Risk groups classified by three commonly available pre-treatment factors showed statistically significant differences in PFS. The clinically-defined high-risk disease was linked to higher propensity to develop clonal evolution with BTK and/or PLCG2 mutations, which heralded ibrutinib resistance. Disclosures Albitar: Neogenomics Laboratories: Employment. Ma:Neogenomics Laboratories: Employment. Ipe:Pharmacyclics, an AbbVie Company: Employment, Other: Travel; AbbVie: Equity Ownership. Tsao:Pharmacyclics LLC, an AbbVie Company: Employment. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Dean:CTI BioPharma Corp.: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Equity Ownership. Wiestner:Pharmacyclics LLC, an AbbVie Company: Research Funding.

scholarly journals Identification of a Prognostic Signature Associated With the Homeobox Gene Family for Bladder Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Bingqi Dong ◽  
Jiaming Liang ◽  
Ding Li ◽  
Wenping Song ◽  
Jinbo Song ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Gene Family ◽  
Risk Score ◽  
Risk Group ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
High Risk Group ◽  
Low Risk ◽  
Prognostic Signature

Background: Bladder cancer (BLCA) is a common malignant tumor of the genitourinary system, and there is a lack of specific, reliable, and non-invasive tumor biomarker tests for diagnosis and prognosis evaluation. Homeobox genes play a vital role in BLCA tumorigenesis and development, but few studies have focused on the prognostic value of homeobox genes in BLCA. In this study, we aim to develop a prognostic signature associated with the homeobox gene family for BLCA.Methods: The RNA sequencing data, clinical data, and probe annotation files of BLCA patients were downloaded from the Gene Expression Omnibus database and the University of California, Santa Cruz (UCSC), Xena Browser. First, differentially expressed homeobox gene screening between tumor and normal samples was performed using the “limma” and robust rank aggregation (RRA) methods. The mutation data were obtained with the “TCGAmutation” package and visualized with the “maftools” package. Kaplan–Meier curves were plotted with the “survminer” package. Then, a signature was constructed by logistic regression analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using “clusterProfiler.” Furthermore, the infiltration level of each immune cell type was estimated using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, the performance of the signature was evaluated by receiver-operating characteristic (ROC) curve and calibration curve analyses.Results: Six genes were selected to construct this prognostic model: TSHZ3, ZFHX4, ZEB2, MEIS1, ISL1, and HOXC4. We divided the BLCA cohort into high- and low-risk groups based on the median risk score calculated with the novel signature. The overall survival (OS) rate of the high-risk group was significantly lower than that of the low-risk group. The infiltration levels of almost all immune cells were significantly higher in the high-risk group than in the low-risk group. The average risk score for the group that responded to immunotherapy was significantly lower than that of the group that did not.Conclusion: We constructed a risk prediction signature with six homeobox genes, which showed good accuracy and consistency in predicting the patient’s prognosis and response to immunotherapy. Therefore, this signature can be a potential biomarker and treatment target for BLCA patients.

scholarly journals Development and validation of a ferroptosis-related prognostic model in pancreatic cancer

2021 ◽  
Author(s):  
Chen-jie Qiu ◽  
Xue-bing Wang ◽  
Zi-ruo Zheng ◽  
Chao-zhi Yang ◽  
Kai Lin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
High Risk ◽  
Risk Score ◽  
Prognostic Model ◽  
Immune Cell ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Immune Cell Infiltration

Abstract Background: The purpose of this study was to identify ferroptosis-related genes (FRGs) associated with the prognosis of pancreatic cancer and to construct a prognostic model based on FRGs. Methods: Based on pancreatic cancer data obtained from The Cancer Genome Atlas database, we established the prognostic model from 232 FRGs. A nomogram was constructed by combining the prognostic model and clinicopathological features. Gene Expression Omnibus datasets and tissue samples obtained from our center were utilized to validate the model. Relationship between risk score and immune cell infiltration was explored by CIBERSORT and TIMER.Results: The prognostic model was established based on four FRGs (ENPP2, ATG4D, SLC2A1 and MAP3K5) and can be an independent risk factor in pancreatic cancer (HR 1.648, 95% CI 1.335-2.035, p < 0.001). Based on the median risk score, patients were divided into a high-risk group and a low-risk group. The prognosis of the low-risk group was significantly better than that of the high-risk group. In the high-risk group, patients treated with chemotherapy had a better prognosis. The nomogram showed that the model was the most important element. Gene set enrichment analysis identified three key pathways, namely, TGFβ signaling, HIF signaling pathway and adherens junction. The prognostic model can also affect the immune cell infiltration, such as macrophages M0, M1, CD4+T cell and CD8+T cell. Conclusion: A ferroptosis-related prognostic model can be employed to predict the prognosis of pancreatic cancer. Ferroptosis can be an important marker and immunotherapy can be a potential therapeutic target for pancreatic cancer.

scholarly journals A Four-Gene-Based Prognostic Model Predicts Overall Survival in Patients With Cutaneous Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoxia Tong ◽  
Xiaofei Qu ◽  
Mengyun Wang
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Risk Score ◽  
Cutaneous Melanoma ◽  
Cox Regression ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Rank Test ◽  
Score Model

BackgroundCutaneous melanoma (CM) is one of the most aggressive cancers with highly metastatic ability. To make things worse, there are limited effective therapies to treat advanced CM. Our study aimed to investigate new biomarkers for CM prognosis and establish a novel risk score system in CM.MethodsGene expression data of CM from Gene Expression Omnibus (GEO) datasets were downloaded and analyzed to identify differentially expressed genes (DEGs). The overlapped DEGs were then verified for prognosis analysis by univariate and multivariate COX regression in The Cancer Genome Atlas (TCGA) datasets. Based on the gene signature of multiple survival associated DEGs, a risk score model was established, and its prognostic and predictive role was estimated through Kaplan-Meier (K-M) analysis and log-rank test. Furthermore, the correlations between prognosis related genes expression and immune infiltrates were analyzed via Tumor Immune Estimation Resource (TIMER) site.ResultsA total of 103 DEGs were obtained based on GEO cohorts, and four genes were verified in TCGA datasets. Subsequently, four genes (ADAMDEC1, GNLY, HSPA13, and TRIM29) model was developed by univariate and multivariate Cox regression analyses. The K-M plots showed that the high-risk group was associated with shortened survival than that in the low-risk group (P &lt; 0.0001). Multivariate analysis suggested that the model was an independent prognostic factor (high-risk vs. low-risk, HR= 2.06, P &lt; 0.001). Meanwhile, the high-risk group was prone to have larger breslow depth (P&lt; 0.001) and ulceration (P&lt; 0.001).ConclusionsThe four-gene risk score model functions well in predicting the prognosis and treatment response in CM and will be useful for guiding therapeutic strategies for CM patients. Additional clinical trials are needed to verify our findings.

Sign in / Sign up

Export Citation Format

Share Document