Association of a Novel Regulatory Polymorphism (-938C>A) in the BCL2 Gene with Disease Progression in Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2105-2105
Author(s):  
Holger Nueckel ◽  
Ulrich H. Frey ◽  
Ludger Sellmann ◽  
Jan Duerig ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cox Regression ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Prognostic Information ◽  
Regulatory Polymorphism ◽  
Bcl2 Gene

Abstract Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single nucleotide polymorphism in the BCL2 gene (−938C>A) in B-CLL. Bcl-2 protein expression in B-cells from CLL patients carrying the −938 AA genotype was significantly increased compared to AC and CC genotypes. Moreover, the −938C- and A-alleles differed with regard to the binding of nuclear proteins. Genotype distributions between 123 CLL patients (42 AA, 55 AC, 26 CC) and in 109 age-matched healthy controls (38 AA, 55 AC, 16 CC) were not significantly different suggesting that this polymorphism does not increase the susceptibility for B-CLL. However, time from first diagnosis to initiation of chemotherapy was significantly shorter in patients with −938AA genotype (38 months) compared to AC/CC genotypes (120 months; p=0.0077), especially in CD38 and ZAP-70 negative CLL patients. Multivariate Cox regression identified the BCL2 −938AA genotype as an independent prognostic factor for progression-free survival (hazard ratio, HR, 1.9; p=0.034) together with disease stage at diagnosis (HR 1.6; p=0.018) and ZAP-70 status (HR 2.9; p=0.001). Furthermore, the BCL2 −938C>A polymorphism in combination with the two common prognostic factors CD38 and ZAP70 status provides additional prognostic information beyond that obtained from single or double marker analysis. To the best of our knowledge this is the first report demonstrating the influence of a novel regulatory polymorphism in the BCL2 gene upon the progression of B-CLL, which, of course, requires confirmation from independent studies. On the other hand, the results presented here appear plausible with regard to differences on the protein level depending on genotype and the known impact of Bcl-2 on disease progression. Thus, our report exceeds other genetic association studies in that a mechanistic link between genotype and observed phenotype can be proposed. In conclusion, carriage of the BCL2 −938AA genotype is a novel unfavorable genetic marker in patients with B-CLL associated with increased Bcl-2 expression.

Association of a novel regulatory polymorphism (−938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 290-297 ◽  
Author(s):  
Holger Nückel ◽  
Ulrich H. Frey ◽  
Maja Bau ◽  
Ludger Sellmann ◽  
Jens Stanelle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cox Regression ◽  
Gene Promoter ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Genotype Distribution ◽  
Single Nucleotide ◽  
Regulatory Polymorphism ◽  
Time To First Treatment

Abstract Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (−938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The −938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the −938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with −938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2−938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2−938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.

CD38 Expression above 20% Predicts Disease Progression in Chronic Lymphocytic Leukemia and Is a Useful Prognostic Marker Where Cytogenetic and Molecular Markers Are Not Available

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4190-4190
Author(s):  
Sina Alipour ◽  
Heather Leitch ◽  
Linda M Vickars ◽  
Lynda M Foltz ◽  
Paul F Galbraith ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Lymphocyte Count ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Free Survival ◽  
Cd38 Expression

Abstract The prognostic significance of CD38 expression and the cut off value has not been fully investigated. As CD38 is readily available test in patients with chronic lymphocytic leukemia (CLL), we investigated its role in prediction of disease progression when a cut off value of 20% is used. Progression free survival (PFS) was defined as the time from diagnosis to first treatment or last follow up. An electronic database search of pts with CLL who presented at St Paul’s Hospital between 1969 and 2007 was performed. Among 465 pts with CLL, 161 pts (35%) had their CD38 expression measured by flow cytometry. CD38 expression and its association with other prognostic factors such as age, Rai stage, lymphocyte count at diagnosis, gender and other immunophenotypic makers were analyzed. Out of 161 pts, positive CD38 expression (>20%) was found in 36 patients (22%). Comparing the baseline characteristics of the CLL pts with CD38+ and negative disease, we found CD38 positivity more common in male pts than in female pts (p=0.03). Also patients with CD38 positive disease tend to present with more advanced stage disease (p=0.056). Progression free survival at 2, 5 and 10y for the CD38+ CLL pts was 89%, 61% and 41% respectively compared with 95%, 81% and 62% for the CD38 negative group (p=0.03). Univariate analysis revealed the following factors as significant or marginally significant for disease progression: CD38+ (p=0.03), male gender (p=0.07), Rai stage (p<0.0001), lymphocyte count above 20 ×109/l at diagnosis (p<0.0001), CD5 expression <10% (p=0.01). On multivariate analysis, only disease stage at diagnosis (p<0.0001) and CD38 expression above 20% (p=0.04) retained significant and were predictive for disease progression. We conclude that CD38 expression above 20% at the time of diagnosis can be prognostically useful and predicts for disease progression and along with Rai staging can provide inexpensive tool to follow and monitor patients with CLL. Table: Characteristics of patients with CLL based on CD38 ≥20% and <20% Parameter CD38 ≥20% (%) CD38<20% (%) p value* *for differences between the groups. Number 36 125 Sex: M/F (ratio) 22/14 (1.6:1) 66/60 (1.1:1) 0.03 Age above 60 y 21 (58) 81 (65) 0.2 Rai stage: 0, 1+2, 3+4 20, 11, 5 (55, 31, 14) 100, 17, 1 (80, 14, 0) 0.056 Lymphocyte count above 20×109/l 9 (25) 23 (18) 0.3 CD5 <10% 6 (16) 29 (23) 0.3 Fig: Progression free survival for patients with CLL based on CD38 expression, cut off level 20%. Fig:. Progression free survival for patients with CLL based on CD38 expression, cut off level 20%.

scholarly journals Clinical, biochemical and genetic risk factors for 30-day and 5-year mortality in 518 adult patients subjected to cardiopulmonary bypass during cardiac surgery - the INFLACOR study.

2018 ◽  
Vol 65 (2) ◽  
pp. 241-250 ◽  
Author(s):  
Maciej Michał Kowalik ◽  
Romuald Lango ◽  
Piotr Siondalski ◽  
Magdalena Chmara ◽  
Maciej Brzeziński ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Genetic Association ◽  
Biochemical Parameters ◽  
Cox Regression ◽  
Association Studies ◽  
Nyha Class ◽  
Genetic Association Studies ◽  
Chronic Obstructive

There is increasing evidence that genetic variability influence patients’ early morbidity after cardiac surgery performed using cardiopulmonary bypass (CPB). The use of mortality as an outcome measure in cardiac surgical genetic association studies is rare. We publish the 30-day and 5-year survival analyses with focus on pre-, intra-, postoperative variables, biochemical parameters, and genetic variants in the INFLACOR (INFlAmmation in Cardiac OpeRations) cohort.In a series of prospectively recruited 518 adult Polish Caucasians who underwent cardiac surgery in which CPB was used, the clinical data, biochemical parameters, IL-6, soluble ICAM-1, TNFa, soluble E-selectin, and 10 single nucleotide polymorphisms were evaluated for their associations with 30-day and 5-year mortality.The 30-day mortality was associated with: pre-operative prothrombin international normalized ratio, intra-operative blood lactate, postoperative serum creatine phosphokinase, and acute kidney injury requiring renal replacement therapy (AKI-RRT) in logistic regression. Factors that determined the 5-year survival included: pre-operative NYHA class, history of peripheral artery disease and severe chronic obstructive pulmonary disease, intra-operative blood transfusion; and postoperative peripheral hypothermia, myocardial infarction, infection, and AKI-RRT in Cox regression. The serum levels of IL-6 and ICAM-1 measured three hours after operation were associated with 30-day and 5-year mortality, respectively. The ICAM1 rs5498 was associated with 30-day and 5-year survival with borderline significance.Different risk factors determined the early (30-day) and late (5-year) survival after adult cardiac surgery in which cardiopulmonary bypass was used. Future genetic association studies in cardiac surgical patients should adjust for the identified chronic and acute postoperative risk factors.

scholarly journals Downregulation and Prognostic Performance of MicroRNA 224 Expression in Prostate Cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 261-269 ◽  
Author(s):  
Konstantinos Mavridis ◽  
Konstantinos Stravodimos ◽  
Andreas Scorilas
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Prognostic Indicator ◽  
Disease Stage ◽  
Clinical Value ◽  
Prostate Tumors ◽  
Tissue Samples ◽  
Total Rna

INTRODUCTION The extensive use of prostate-specific antigen as a general prostate cancer biomarker has introduced the hazards of overdiagnosis and overtreatment. Recent studies have revealed the immense biomarker capacity of microRNAs (miRNAs) in prostate cancer. The aim of this study was to analyze the expression pattern of miR-224, a cancer-related miRNA, in prostate tumors and investigate its clinical utility. METHODS Total RNA was isolated from 139 prostate tissue samples. After the polyadenylation of total RNA by poly(A) polymerase, cDNA was synthesized with a suitable poly(T) adapter. miR-224 expression was assessed by quantitative real-time PCR and analyzed with the comparative quantification cycle method, Cq(2−ΔΔCq). We performed comprehensive biostatistical analyses to explore the clinical value of miR-224 in prostate cancer. RESULTS miR-224 expression was significantly downregulated in malignant samples compared with benign samples (P < 0.001). Higher miR-224 expression levels were found in prostate tumors that were less aggressive (P = 0.017) and in an earlier disease stage (P = 0.018). Patients with prostate cancer who were positive for miR-224 had significantly enhanced progression-free survival intervals compared with miR-224–negative patients (P = 0.021). Univariate bootstrap Cox regression confirmed that miR-224 was associated with favorable prognosis (hazard ratio 0.314, P = 0.013); nonetheless, multivariate analysis, adjusted for conventional markers, did not identify miR-224 as an independent prognostic indicator. CONCLUSIONS miR-224 is aberrantly expressed in prostate cancer. Its assessment by cost-effective quantitative molecular methodologies could provide a useful biomarker for prostate cancer.

CD1d Expression Is Higher In Chronic Lymphocytic Leukemia Patients With Unfavorable Prognosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5278-5278
Author(s):  
Agnieszka Bojarska-Junak ◽  
Iwona Hus ◽  
Anna Dmoszynska ◽  
Jacek Rolinski
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Staining Intensity ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Inkt Cells ◽  
Cd38 Expression

Abstract Chronic lymphocytic leukemia (CLL) is characterized by a very heterogeneous clinical course, which is slow and indolent in most of the patients, however some patient experience rapid disease progression and anticancer therapy is required shortly after the diagnosis. Many issues in CLL development and progression are still unclear. The functional consequences of CD1d expression on tumour cells are not well understood. However, increasing evidence suggests that they may affect iNKT cells.The role of CD1d expression in CLL immunopathogenesis remains undefined. In this study, we investigated the potential role of CD1d in CLL by analyzing the level of CD1d expression on leukemic B cells in peripheral blood of120 patients and assessed its correlation with prognostic markers such as ZAP-70 and CD38 expression, Rai stages and unfavourable cytogenetic changes.Measuring CD1d expression by flow cytometry and qRT-PCR, we showed lower CD1d molecule and CD1d mRNA expression in B cells of CLL patients than of healthy controls. The frequency of CD1d+/CD19+ cells, CD1d staining intensity and CD1d transcript levels increased with the disease stage. CD1d expression was positively associated with ZAP-70 and CD38 expressions as well as with unfavourable cytogenetic changes (17p deletion, 11q deletio),. We established the relationship between high CD1d expression and shorter time to treatment and overall survival. The percentage of CD1d+/CD19+cells inversely correlated with the percentage of iNKT cells. iNKT cells ζ-chain expression was downregulated in the high-CD1d group.These results suggest that high CD1d expression is associated with poor prognosis of CLL and might be involved in disease progression. Disclosures: No relevant conflicts of interest to declare.

High-Level Expression of ROR1 Associates with Early Disease Progression in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1713-1713 ◽  
Author(s):  
Bing Cui ◽  
Liguang Chen ◽  
Laura Z. Rassenti ◽  
Emanuela M. Ghia ◽  
Jian Yu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Research Funding ◽  
Cox Regression ◽  
Lymphocytic Leukemia ◽  
Training Dataset ◽  
High Level Expression ◽  
Mutation Status ◽  
Delayed Entry ◽  
Validation Set ◽  
High Level

Abstract ROR1 is a type-1 tyrosine kinase-like orphan-receptor that ordinarily is expressed during embryogenesis, but that also is found on leukemia cells of patients (pts) with chronic lymphocytic leukemia (CLL). In prior studies we found ROR1 served as a receptor for Wnt5a, which could promote survival/growth of CLL cells. We found Wnt5a in the plasma is significantly higher in pts with CLL (3.2±1.6 ng/ml (mean ±S.D.), N = 36) than in healthy adults (0.14±0.16 ng/ml, N=14, p<0.01) and also may be elaborated by accessory cells in the CLL microenvironment. On the other hand, reducing expression of ROR1 on CLL cells via siRNA adversely affected leukemia-cell survival. We hypothesized that expression of ROR1 in CLL could play a role in the pathogenesis and/or progression of this disease. Early studies failed to define differences in the expression level of ROR1 on CLL cells of different pts in a small cohort. However, upon further analyses, we observed heterogeneity in the expression levels of ROR1 among samples of different pts in larger cohort. We investigated whether the level of ROR1 expression was associated with disease progression in a cohort of 1,568 CLL pts followed by CLL Research Corium (CRC). CLL samples were uniformly examined for the expression of ROR1 using the same preparation of an Alexa-647-conjugated anti-ROR1 mAb (4A5) and a standardized procedure by the CRC Tissue Core. We used 10 CLL cases, and tested ROR1 expression at 3 different time-points for each case. We found ROR1 expression was stable over time in all CLL cases. Then, we randomly segregated pt samples into either of two cohorts, one a training set of 797, and the other a validation set of 773 cases. For the 797 cases in the training dataset, we used the profile-likelihood method in a Cox regression model of treatment-free survival (TFS) from diagnosis to determine the optimal threshold level of ROR1 expressionthat could segregate pts into 2 subgroups. In the training cohort, 294 pts were stratified into a "ROR1-Low" subgroup and 503 pts were assigned to a "ROR1-High" subgroup, defining a threshold absolute mean fluorescence intensity of CLL cells stained for ROR1 of 29. The subgroup of pts in the ROR1- High subgroup had a median TFS of 6.0 years, whereas those pts in the ROR1-Low subgroup had a median TFS of 11.0 years. We applied this threshold to segregate the 773 samples of the validation cohort into ROR1-High and ROR1-Low subgroups. We found that high-level expression of ROR1retained its strong predictive adverse effect on TFS in this validation set. The subgroup of pts in the ROR1- High subgroup had a median TFS of 5.7 years, whereas those pts in the ROR1-Low subgroup had a median TFS of 11.8 years. The immunoglobulin heavy-chain variable region (IGHV) mutation status was known for 593 of the 797 samples in the training set (74%) and 586 of the 773 samples in the validation set (76%). A significantly lower percentage of the ROR1-Low cases (34%, or 69 of 203) used unmutated IGHV than did the ROR1-High cases (54%, or 209 of 390) (p<0.001). Nonetheless, using a multivariate Cox regression model with either a non-delayed entry or a delayed entry, we observed that high-level expression of ROR1 had predictive value for short TFS (non-delayed entry HR 1.4, p<0.05; delayed entry HR 1.9, p<0.001) even when the IGHV mutation status was taken into consideration (non-delayed entry HR 2.8, p<0.001; delayed entry HR 2.7, p<0.001). Taken together, this study demonstrates that there is heterogeneity in the expression of ROR1 on CLL B cells. Furthermore, we find that a high level expression of ROR1 is associated with early disease progression in pts with CLL. Table 1. Number of cases with high versus low ROR1 and mutated versus unmutated IGHV in the training and validation cohort Training Dataset Validation Dataset ROR1 MFI distribution (Median) 0~475 (35.5) 0~424(34.6) ROR1Low with Mutated IGHV 139 132 ROR1Low with Unmutated IGHV 64 84 ROR1High with Mutated IGHV 181 156 ROR1High with Unmutated IGHV 209 214 Total With Known IGHV Mutation Status 593 586 Disclosures Keating: Celgene Corp.: Consultancy; Glaxo-Smith-Kline Inc.: Other: Advisory board. Kay:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Tolero Pharma: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrd:Acerta Pharma BV: Research Funding. Gribben:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche/Genentech: Honoraria; Pharmacyclics: Honoraria; Gilead: Honoraria. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2748-2755 ◽  
Author(s):  
Jan Dürig ◽  
Holger Nückel ◽  
Andreas Hüttmann ◽  
Elisabeth Kruse ◽  
Tanja Hölter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Cell Clone ◽  
Expression Profiles ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Disease Stage ◽  
Unsupervised Hierarchical Cluster

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course. Recent studies have shown that CD38 surface expression on the malignant cell clone may serve as a prognostic marker in that CD38+ patients with B-CLL are characterized by advanced disease stage, lesser responsiveness to chemotherapy, and shorter survival than CD38− patients. To further investigate the molecular phenotype of these 2 clinical subgroups, we compared the gene expression profiles of CD38+ (n = 25) with CD38− (n = 45) B-CLL patients using oligonucleotide-based DNA chip microarrays representative of approximately 5600 genes. The results showed that B-CLLs display a common gene expression profile that is largely independent of CD38 expression. Nonetheless, the expression of 14 genes differed significantly between the 2 groups, including genes that are involved in the regulation of cell survival. Furthermore, unsupervised hierarchical cluster analysis of 76 B-CLL samples led to the separation of 2 major subgroups, comprising 20 and 56 patients. Clustering to the smaller group was due in part to the coordinate high expression of a large number of ribosomal and other translation-associated genes, including elongation factors. Importantly, we found that patients with high expression of translation factors were characterized by a more favorable clinical course with significantly longer progression-free survival and reduced chemotherapy requirements than the remaining patients (P < .05). Our data show that gene expression profiling can help identify B-CLL subtypes with different clinical characteristics. Furthermore, our results suggest a role of translation-associated genes in the pathogenesis of B-CLL.

Re-challenge with BRAF-directed treatment: A multi-institutional retrospective study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9512-9512 ◽  
Author(s):  
Sara Valpione ◽  
Matteo S. Carlino ◽  
Joanna Mangana ◽  
Meghan Mooradian ◽  
Grant A. McArthur ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Cox Regression ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Complete Response ◽  
Subsequent Treatment ◽  
Disease Stage ◽  
Kaplan Meier ◽  
Clinically Significant ◽  
Metastatic Sites

9512 Background: Most patients treated with BRAF inhibitors (BRAFi) +/- MEK inhibitors (MEKi) eventually progress on treatment. Along with genetic acquired resistance, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse outcomes for patients (pts) retreated with BRAF-directed therapy. Methods: 116 pts who received BRAFi based therapy and, after a break, were re-challenged with BRAFi +/- MEKi treated at 14 centres in Europe, US, and Australia were analysed for progression free survival (PFS) and response rate (RR), as well as factors predicting overall survival (OS) (demographics, disease stage, treatment, LDH level, duration of first BRAFi treatment, reason for first BRAFi discontinuation and interval between BRAFi stop and re-challenge). Multivariate Cox regression, regression trees and Kaplan Meier method were used. Results: Median duration of 1st BRAFi +/- MEKi treatment was 9.4 months (mts) and 7.7 mts for the subsequent treatment after discontinuation (immunotherapy 72%, other 17 %, drug holiday 11%). Brain metastases were present in 51 pts (44%). RR to re-challenge with BRAFi +/- MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease 24% and progressive disease (PD) 30%, 4% missing. Of 80 pts who previously discontinued BRAFi for PD, 31 (39%) responded (30 PR and 1 CR). Median OS from retreatment was 9.8 mts. Independent prognostic factors for survival at re-challenge included number of metastatic sites (HR = 1.32 for each additional organ with metastases, p < .001), LDH (HR = 1.37 for each multiple of the upper normal limit, p < .001), while combination of BRAFi+MEKi conferred a better prognosis vs BRAFi alone (HR = 0.5, p = .006). Pts with < 3 metastatic sites treated with BRAFi and MEKi had a better survival (median OS not reached) and pts with ≥ 3 metastatic sites and raised LDH treated with BRAFi alone had the worse outcome (median OS 4 mts). Number of metastatic sites (HR = 1.44, p < .001) and combination of BRAFi and MEKi (HR = 0.45, p < .001) were independent prognostic factors for PFS (median 5.0 mts). Conclusions: Re-challenge with BRAFi +/- MEKi induces a clinically significant response and should be considered for selected cases.

Metastatic and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associated With Disease Progression

2011 ◽  
Vol 29 (17) ◽  
pp. 2372-2377 ◽  
Author(s):  
Francesco Panzuto ◽  
Letizia Boninsegna ◽  
Nicola Fazio ◽  
Davide Campana ◽  
Maria Pia Brizzi ◽  
...  
Keyword(s):  
Risk Factor ◽  
Disease Progression ◽  
Cox Regression ◽  
Locally Advanced ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Major Risk Factor ◽  
Proliferation Index ◽  
Risk Of Progression ◽  
Endocrine Carcinomas

Purpose Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. Patients and Methods In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. Results Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%. Conclusion The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

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