MicroRNA 181a (miR-181a) expression as a prognosticator in cytogenetically normal acute myeloid leukemia (CN AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7001-7001
Author(s):  
S. Schwind ◽  
G. Marcucci ◽  
K. Maharry ◽  
M. D. Radmacher ◽  
S. P. Whitman ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Risk Group ◽  
Continuous Variable ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Multivariable Analyses ◽  
The Mean ◽  
Cebpa Mutations

7001 Background: We showed recently that CEBPA mutations (mut) in CN AML are associated with better outcome and a unique microRNA expression profile, including miR-181a upregulation. Here we tested if miR-181a expression can predict outcome independently. Methods: We analyzed 187 de novo CN AML adult patients (pts) aged <60 years (y; median 45) similarly treated on CALGB 9621 and 19808. Of these, 122 had molecular high risk [FLT3-ITD or NPM1 wild type (wt)] and 65 low risk (no FLT3-ITD, NPM1 mut) CN AML. FLT3, NPM1, CEBPA, MLL, and WT1 mutations, and ERG and BAALC expression were analyzed centrally. miR-181a expression was measured in pretherapy marrow using OSUCCC v3.0 arrays. The mean of 2 miR-181a probe log intensities was used as a continuous variable for analyses. Results: Higher miR-181a levels (miR-181a↑) were associated with CEBPA mut, NPM1 wt, no FLT3-TKD, lower ERG expression, higher %FAB M1/M2, lower WBC and age, higher blood blasts, and lower % gum hypertrophy. miR-181a↑ tended to associate with more complete remissions (CRs; p = .07) and significantly associated with longer disease-free (DFS; p = .05) and overall (OS; p = .01) survival (median follow-up 6.5 y for pts alive). A stronger prognostic impact of miR-181a was observed in the molecular high risk group, where miR-181a↑ predicted more CRs (p = .03), and longer DFS (p = .0002) and OS (p = .0001). In multivariable analyses of the molecular high risk group, miR-181a↑independently predicted CR, and longer DFS and OS (Table). For descriptive purposes, we dichotomized pts at the median miR-181a expression value. For high v low miR-181a expressers, CR rates were 84% vs 72% and 5 y DFS and OS rates 43% vs 18% and 48% vs 19%, respectively. Conclusions: miR-181a expression is a prognostic marker in CN AML, mainly in the molecular high risk group, where it predicts outcome independently of other variables including CEBPA mutations. As miR-181a↑ confer better treatment response, novel approaches increasing miR-181a levels might benefit not only CN but also other AML pts. [Table: see text] No significant financial relationships to disclose.

scholarly journals Hip resurfacing revision rates: radiological audit of risk factors

2011 ◽  
Vol 93 (4) ◽  
pp. 314-316
Author(s):  
N Ramisetty ◽  
KM Krishnan ◽  
PF Partington
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Revision Rate ◽  
Risk Group ◽  
Hip Resurfacing ◽  
High Risk Group ◽  
Long Term Follow Up ◽  
The Mean

INTRODUCTION We performed a retrospective radiological audit of the hip resurfacings carried out in our trust over a five-year period. Abnormal cup inclination angle (CIA) and stem shaft angle (SSA) are recognised risk factors for revision in hip resurfacing. Our aims were to identify the CIA and SSA for hip resurfacings in our trust, to determine the revision rate in a CIA of ≥60° and an SSA of >0° varus, thereby identifying a high risk group for close, long-term follow up. METHODS A total of 247 patients underwent hip resurfacing in our trust between April 2003 and March 2008. The CIA and SSA were recorded. Of the 247 patients, 26 were excluded as there were no appropriate radiographs and so results were analysed for 221 patients. RESULTS The mean CIA was 47.6°. Over a third of the patients (34%) had a CIA of >50° and 13% had >60°. The mean SSA was 1.4° varus. Over two-thirds of the patients (67%) had a varus SSA. There were six revisions but one was excluded as it was secondary to infection. The revision rate was 10% in patients with a CIA of ≥60° and 1% in those with a CIA of <60° (p=0.017), and 1% in a varus and 4% in a valgus SSA (p>0.05) respectively. CONCLUSIONS The measurement of the CIA and SSA in hip resurfacings has identified a high risk group for close long-term follow up. There is already a 10% revision rate in those patients with a CIA of >60°. Hip resurfacing may generate a large revision burden in the ‘average’ surgeon's hands and all hospitals/surgeons should review their radiological outcomes critically and identify those at risk of revision.

Gene and microRNA (miRNA) Expression Signatures and Prognostic Significance of CEBPA Mutations in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML) with High-Risk Molecular Features: A Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 104-104
Author(s):  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
Tamara Vukosavljevic ◽  
...  
Keyword(s):  
High Risk ◽  
Mirna Expression ◽  
De Novo ◽  
Risk Group ◽  
High Risk Group ◽  
Wild Type ◽  
Mirna Signature ◽  
Good Outcome ◽  
Molecular Features ◽  
Cebpa Mutations

Abstract Although CEBPA mutations (CEBPA+) have been reported to predict favorable outcome in CN-AML, their prognostic value has not been evaluated in the context of such established prognostic molecular markers in CN-AML as the combination of FLT3-ITD and NPM1 mutational status and BAALC and ERG expression. 169 adults aged <60 years (yrs) with untreated, de novo CN-AML, enrolled on CALGB protocols 9621 or 19808 that included autologous stem cell transplantation for consolidation, were analyzed for CEBPA+ by DNA PCR amplification/direct sequencing. Testing for BAALC and ERG expression, FLT3-ITD, FLT3-TKD, MLL-PTD and NPM1 mutations (NPM1+) was performed centrally in pretreatment marrow or blood samples. Unexpectedly, CEBPA+ patients (pts) were more likely to have FLT3-ITD/NPM1 high-risk molecular features [ie, FLT3-ITD+ and/or NPM1 wild-type (NPM1wt)] than low-risk molecular features (FLT3-ITD-/NPM1+; 26 v 3 pts, respectively; P=.001). Thus, we focused subsequent analyses on FLT3-ITD/NPM1 high-risk pts (n=109) that included 90% of the CEBPA+ pts. In this group, a microarray gene-expression signature of 2,342 probes, 59% of which were downregulated in CEBPA+ pts, separated CEBPA+ and CEBPA wild-type (CEBPAwt) pts [false discovery rate (FDR)=.01]. Among the 20 most downregulated probes in CEBPA+ pts, 9 corresponded to Homeobox genes (HOXA3, A5, A9, A10, B2, B3, MEIS1). Also downregulated in CEBPA+ pts were other Homeobox genes (HOXA1, A2, A4, A6, A7, B4, B5, B6), FLT3, RUNX1 and RAS superfamily members, while CEBPA and GATA1 were upregulated. Additionally, a 13-probe microRNA (miRNA) expression signature distinguished CEBPA+ from CEBPAwt pts (FDR=.11). This signature shared features with a previously reported miRNA-signature predictive of clinical outcome in FLT3-ITD/NPM1 high-risk CN-AML (Radmacher et al. JCO 2007;25:359s). Eight miRNA probes for miRNA 181 family members were upregulated in CEBPA+ pts; an association between miRNA 181 family upregulation and good outcome was a major feature of the previously reported outcome miRNA signature. A probe for miRNA 194, whose downregulation was associated with good outcome in the prior outcome signature, was also downregulated in CEBPA+ pts. Consistent with these findings, CEBPA+ status predicted better outcome in the FLT3-ITD/NPM1 high-risk group. CEBPA+ pts had a better event-free survival (EFS) than CEBPAwt pts (P<.0001), with estimated 3-yr EFS rates of 57% and 17%, respectively. In a multivariable analysis, CEBPA+ independently predicted longer EFS (P=.0004; hazard ratio=0.30; 95%CI=0.15–0.58), after adjusting for ERG expression (P=.03). In summary, we report that CN-AML pts with CEBPA+ mostly have FLT3/NPM1 high-risk molecular features, and that the FLT3/NPM1 high-risk group can be subdivided based on the presence or absence of CEBPA+ into 2 subsets characterized by strong gene- and miRNA-expression signatures and different outcome. It is likely that testing for CEBPA+ at diagnosis will improve molecular risk-based classification of de novo CN-AML and aid in risk-adapted treatment stratification. Gene- and miRNA-expression profiling may provide insights into disease biology leading to development of novel therapies.

scholarly journals Sernbo score predicts survival after intracapsular hip fracture in the elderly

2013 ◽  
Vol 95 (1) ◽  
pp. 29-33 ◽  
Author(s):  
EJC Dawe ◽  
E Lindisfarne ◽  
T Singh ◽  
I McFadyen ◽  
P Stott
Keyword(s):  
Hip Fracture ◽  
High Risk ◽  
Risk Group ◽  
Characteristic Curve ◽  
Social Situation ◽  
High Risk Group ◽  
Low Risk ◽  
Risk Of Death ◽  
Intracapsular Hip Fracture ◽  
The Mean

Introduction The Sernbo score uses four factors (age, social situation, mobility and mental state) to divide patients into a high-risk and a low-risk group. This study sought to assess the use of the Sernbo score in predicting mortality after an intracapsular hip fracture. Methods A total of 259 patients with displaced intracapsular hip fractures were included in the study. Data from prospectively generated databases provided 22 descriptive variables for each patient. These included operative management, blood tests and co-mobidities. Multivariate analysis was used to identify significant predictors of mortality. Results The mean patient age was 85 years and the mean follow-up duration was 1.5 years. The one-year survival rate was 92% (±0.03) in the low-risk group and 65% (±0.046) in the high-risk group. Four variables predicted mortality: Sernbo score >15 (p=0.0023), blood creatinine (p=0.0026), ASA (American Society of Anaesthesiologists) grade >3 (p=0.0038) and non-operative treatment (p=0.0377). Receiver operating characteristic curve analysis showed the Sernbo score as the only predictor of 30-day mortality (area under curve 0.71 [0.65–0.76]). The score had a sensitivity of 92% and a specificity of 51% for prediction of death at 30 days. Conclusions The Sernbo score identifies patients at high risk of death in the 30 days following injury. This very simple score could be used to direct extra early multidisciplinary input to high-risk patients on admission with an intracapsular hip fracture.

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.

scholarly journals Pre-Enucleation Chemotherapy in Advanced Intraocular Retinoblastoma. Central America Follow Up: AHOPCA II

2016 ◽  
Vol 2 (3_suppl) ◽  
pp. 75s-75s
Author(s):  
Sandra Luna-Fineman ◽  
Soad L. Alabi ◽  
Mauricio E. Castellanos ◽  
Yessika Gamboa ◽  
Ligia Fu ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Central America ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
High Risk Group ◽  
Globe Rupture ◽  
Neo Adjuvant Chemotherapy ◽  
Standard Risk

Abstract 57a Purpose: A significant percentage of patients in Central America present with buphthalmos, carrying a high risk of globe rupture and orbital contamination. In 2007, AHOPCA introduced chemotherapy before enucleation in children with buphthalmos. Methods: Patients with advanced intraocular disease were considered standard-risk and underwent enucleation. Those with diffuse invasion of choroid, postlaminar optic nerve, or anterior chamber invasion received 4-6 cycles of adjuvant chemotherapy (vincristine, carboplatin, etoposide). Patients with buphthalmos or perceived to be at risk for abandonment were considered high-risk, given 2-3 cycles of chemotherapy before enucleation to compete 6 cycles regardless of pathology. All cases were discussed via online meetings. Results: From 2007 to 2014, 396 patients were enrolled; 240 had IRSS stage I (174 unilateral). 143 had upfront enucleation, 95 had pre-enucleation chemotherapy, 1 is pending enucleation and 1 abandoned before enucleation. The standard-risk group 69 had risk pathology and 76 had no risk factors; 125 had no events, 5 abandoned 11 relapsed/progressed and 2 died of toxicity. Of 95 high-risk group, 8 abandoned, 20 relapse/progressive, 6 had toxic deaths and 61 are alive at last follow-up (median time of 4 years). Of high risk group, 55 were unilateral, 82% are alive. At 7 years OS (abandonment-censored) was 95±0.02 and 79±0.04 for standard-risk and high-risk (p=0.008). Conclusion: AHOPCA addressed advanced intraocular disease with an innovative approach. In eyes with buphthalmos and patients with risk of abandonment, neo-adjuvant chemotherapy is effective, when followed by post-enucleation chemotherapy. This approach avoids ocular rupture and intensified therapy, and reduces refusal/abandonment rate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Long Term Follow-up Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 846-846
Author(s):  
Vikram Mathews ◽  
Biju George ◽  
Kavitha M Lakshmi ◽  
Auro Viswabandya ◽  
Ezhilarasi Chendamarai ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Single Agent ◽  
High Risk Group ◽  
Reproductive Age ◽  
Newly Diagnosed ◽  
Long Term Follow Up ◽  
Good Risk

Abstract Abstract 846 We had previously reported a well tolerated regimen using single agent arsenic trioxide (ATO) (Blood 2006:107; 2627) leading to durable remissions in patients with newly diagnosed acute promyelocytic leukemia (APL). Briefly, the regimen consisted of ATO (10mg/day for adults and 0.15mg/kg/day for pediatric patients) for up to 60 days in induction; this was followed by a 28 day consolidation after a 4 week break. Four weeks after completion of consolidation, patients received ATO for 10 days/month for 6 months. A concern with the previous report was the relatively short duration of follow up. Here we report the long term follow-up data of the same cohort. As previously reported, 72 newly diagnosed cases of APL were enrolled. 62 patients (86.1%) achieved hematological remission. The remaining died prior to achieving remission. There were no primary induction failures. Twenty two (30.6%) of these patients were considered good risk group (WBC count at diagnosis <5×109/L and a platelet count >20×109/L), the rest were considered high risk. Since publication of the last report an additional 7 patients have relapsed to give a total of 13 relapses, 2 were in the good risk group and the remaining 11 in the high risk group. The relapses in the good risk group were salvaged with an autologous SCT and have durable continued second remissions. The median time to relapse was 1.5 years. Five (38.52%) of these relapses occurred beyond 2 years and included both relapses in the good risk group. At a median follow-up of 58 months the 5-year Kaplan-Meier overall survival (OS), event free survival (EFS) and disease free survival (DFS) of the entire cohort was 74.22±5.26%, 68.93±5.52% and 80.00±5.17% respectively. The 5-year OS and EFS of the good risk and high risk group was 100±00% vs. 63.30±6.9% and 90.00±6.71% vs. 59.66±6.99% respectively. Beyond induction, all deaths followed relapse of disease. There were no second malignancies reported. Besides the previously reported toxicities, which were mild and transient in most cases, there were no new toxicities that were reported on continued follow up of these cases. Since completion of therapy, in spite of counseling and advising against pregnancy, 3 males and 4 females in the reproductive age group have had 8 normal children. No abortions, still births or fetal defects were reported among patients in the reproductive age group in this cohort. Hair and nail samples from 5 cases that had completed maintenance therapy more than 24 months earlier have been collected for analysis, the results of which are awaited. At our center the cost of administering this regimen is a quarter of that of a conventional ATRA plus anthracycline based regimen. Additionally, after the initial induction therapy the rest of the treatment did not require hospital admission nor did it result in any Grade III/IV hematological toxicity. Single agent ATO based regimen as reported previously is well tolerated, results in durable remissions and does not have any significant late side effects. In the good risk group it is associated with excellent clinical outcomes while in the high risk group additional interventions are probably required to reduce the risk of late relapses. In a resource constrained environment it is probably the best option. Disclosures: No relevant conflicts of interest to declare.

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 MON-LB83 The Initial Dose of 131I as a Potential Independent Predictor for Residual/Relapsed Disease in Pediatric Differentiated Thyroid Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Carmen L Bustamante Escobar ◽  
Yong Bao
Keyword(s):  
Thyroid Cancer ◽  
High Risk ◽  
Initial Dose ◽  
Risk Group ◽  
Risk Category ◽  
Intermediate Risk ◽  
The Mean ◽  
Relapsed Disease ◽  
Disease Free

Abstract Introduction: In the guidelines for management of pediatric Differentiated Thyroid Cancer (DTC) 131I therapy is recommended for treatment of iodine-avid persistent locoregional disease that cannot be resected as well as iodine-avid distant metastases. To date, no consensus has been reached regarding the 131I dose for treatment of DTC in children. We report our institutional experience and highlight the initial dose of 131I as a potential independent predictor of residual/relapsed disease. Methods: We performed a retrospective analysis of all pediatric patients diagnosed with DTC between 2010 and 2018. The cohort included all patients up to 21 years of age, with minimal length of follow-up of 24 months. The risk stratification was done following the American Thyroid Association guidelines for pediatric DTC. We defined residual/relapsed disease as detectable thyroglobulin and positive anatomical lesions in imaging studies during the follow-up period. The log-rank test was used to evaluate disease-free survival. The P value was set at &lt; 0.05. Results: Among 59 eligible patients, females were 69.5% (n=41) and males were 30.5% (n=18). The mean age at diagnosis was 16 years (9-21 years). All patients were alive at follow-up (median, 42 months; range 24 to 144 months). Fifty-eight patients had classic papillary thyroid cancer (PTC) and only 1 patient had follicular thyroid cancer. Among the patient with PTC, 39.6% (23/58) had follicular-variant PTC, 8.6% (5/52) had diffuse-sclerosing PTC and 17.2% (10/58) had other variants. Nineteen (32%), 30 (51%), and 10 (17%) had low-risk, intermediate-risk, and high-risk disease, respectively. Within the Low-risk group, 68% (13/19) received 131I. The mean initial dose was 60.9 mCi [26-150 mCi]. Eighty four percent (11/13) received ≤100 mCi and 27% (3/11) had residual/relapsed disease. Fifteen percent (2/13) received &gt;100 mCi and none had residual/relapsed disease. Sixteen percent (1/6) of patients without 131I therapy had residual/relapsed disease. (P=0.48) Within the Intermediate-risk group, all 30 patients received 131I. The mean initial dose was 97.5 mCi [27.3-215 mCi]. Sixty percent (18/30) received ≤100 mCi and 38.8% (7/18) had residual/relapsed disease. Forty percent (12/30) received &gt;100 mCi and 16.6 % (2/12) had residual/relapsed disease. (P=0.15) Within the High-risk group all 10 patients received 131I. The mean initial dose was 159.9 mCi [129.3-384 mCi]. Fifty percent (5/10) received ≤150 mCi and 60% (3/5) had residual/relapsed disease. Fifty percent (5/5) received &gt;150 mCi and 20% (1/5) had residual/relapsed disease. (P=0.2) Conclusion: There are no statistical differences of disease-free rate between the initial dose of 131I among all risk categories. However, the use of more than 100 mCi in the intermediate-risk category and more than 150 mCi in the high-risk category may be recommended.

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