Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1) associated with tumor recurrence in localized adenocarcinoma (EA) of the esophagus treated with surgery alone

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4564-4564
Author(s):  
G. Lurje ◽  
J. M. Leers ◽  
A. Pohl ◽  
A. Oezcelik ◽  
W. Zhang ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Tumor Recurrence ◽  
Prognostic Markers ◽  
Human Cancer ◽  
Univariate Analysis ◽  
Response To Therapy ◽  
Rank Test ◽  
P Value ◽  
Tissue Samples ◽  
Log Rank Test

4564 Background: Tumor angiogenesis is a well-recognized aspect of human cancer biology and is mediated at least in part by EGF and PAR-1, which in turn may impact the process of tumor growth and progression. Systemic tumor recurrence after curative resection continues to be a significant problem in the management of patients with localized EA. Further, it is being increasingly recognized that esophageal squamous cell carcinoma and EA are separate and distinct disease groups and need to be considered individually. We therefore designed a large retrospective study of EA patients to identify novel molecular markers of prognosis to better define tumor stage and progression, and help to define novel targets, as well as surrogate-endpoints of disease progression and response to therapy. Methods: Between 1992 and 2005 normal esophageal tissue samples from 239 patients with localized EA treated with surgery alone were obtained at University of Southern California medical facilities. The median follow-up was 3.2 years. 114 out of 239 (48%) patients had tumor recurrence, with a probability of 5-year recurrence of 0.62 ± 0.04. DNA was isolated from formalin-fixed paraffin-embedded specimens and 10 angiogenesis related and functional gene polymorphisms were analyzed using a PCR-RFLP and 5´-end [γ-33P] ATP-labeled PCR method. Results: PAR-1 -506 ins/del (p-value=0.003; log-rank test) and EGF +61 A>G (p-value=0.034; log-rank test) are adverse prognostic markers in univariate analysis. After adjusting for covariates (gender, T1-, N-category, type of surgery) in the multivariable model, "high-expression" variants of PAR-1 (any insertion allele) (RR: 1.81; adjusted p-value = 0.011) and EGF (A/A) (RR: 1; adjusted p-value=0.035) remained significantly associated with time to recurrence, compared to other genotype combinations of PAR-1 (RR: 1) and EGF (RR: 0.65). Conclusions: This study supports the role of functional EGF and PAR-1 polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence. Prospective and biomarker-embedded clinical trials are needed to validate our findings. [Table: see text]

Association of CD44s and CD44v6 expression with survival outcomes in malignant fibrious histiocytoma.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 44-44
Author(s):  
Matthias Peiper ◽  
Edwin Boelke ◽  
Christiane Matuschek ◽  
Nikolas H. Stoecklein ◽  
Christopher Poremba ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Prognostic Markers ◽  
Fibrous Histiocytoma ◽  
Soft Tissue Sarcomas ◽  
Tissue Microarrays ◽  
Rank Test ◽  
P Value ◽  
Bladder Tumors ◽  
Log Rank Test ◽  
Cd44v6 Expression

44 Background: New prognostic markers are being searched to determine the value of adjuvant and/or palliative treatment in soft tissue sarcomas (STS). Several studies showed that CD44 expression was associated with a better outcome in certain cancers, such as bladder tumors. The aim of this study was to evaluate the expression of CD44 in STS of the adult and to determine whether this correlates with the clinical outcome. Methods: We examined the clinical outcome of 34 adult MFH patients (19 males and 15 females, average age 62 years, median 63 years, ranged from 38 to 88 years) who underwent curative treatment The majority of patients received adjuvant radiotherapy (n = 25). No patients received initial adjuvant chemotherapy. The prognostic value of CD44s and isoform expression were evaluated by immunohistochemistry of tissue microarrays. Results: At first, we split the data for each variant of CD44 into two equally sized groups at the medians to the expression values (low and high). We apply a log rank test on the two groups and use the p value as an evaluation criterion for the usefulness of the grouping. CD44s and CD44v6 expression significantly correlated with an improved outcome whereas CD44v8 and h CD44 were not significant. Conclusions: CD44s and CD44v6 expression seem to be associated with improved survival in malignant fibrous histiocytoma.

Novel prognostic markers for epithelioid malignant pleural mesothelioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20028-e20028 ◽  
Author(s):  
Rossella Bruno ◽  
Anello Marcello Poma ◽  
Greta Alì ◽  
Riccardo Giannini ◽  
Gianfranco Puppo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Malignant Pleural Mesothelioma ◽  
Prognostic Markers ◽  
Progression Free Survival ◽  
Prognostic Indicators ◽  
Rank Test ◽  
P Value ◽  
Pleural Mesothelioma ◽  
Genome Replication ◽  
Tissue Samples

e20028 Background: Malignant pleural mesothelioma (MPM) is a deadly asbestos related tumour. The median survival is about 12 months and MPM patients are usually offered with a multimodality approach. With regard to chemotherapy the treatment of choice is the antifolate pemetrexed in combination with cisplatin or carboplatin. The high variability in the survival of patients with similar characteristics make it challenging to identify reliable prognostic markers. In this study we sought novel prognostic markers for epithelioid MPM, by investigating the expression levels of 117 genes involved in cancer. Methods: Gene expression analysis was evaluated on RNA from 15 epithelioid MPM patients undergoing pleurectomy (fomalin-fixed paraffin-embedded tissue) using a custom panel on nanoString platform. All patients were treated with cisplatin plus pemetrexed chemotherapy. Patients were divided in two groups for each gene (high and low expression level) on the basis of median. The correlation between gene expression, overall survival (OS) and progression free survival (PFS) was carried out by Log-rank test (Kaplan Meier). Results: A poorer OS was associated with a higher expression of 3 genes: MCM2 (p-value 0.005), PLK1 (p-value 0.005) and CCNB2 (p-value 0.01). These findings were in agreement with TCGA data ( PROGgeneV2: enhancements on the existing database. BMC Cancer 2014). Moreover, PLK1 showed a significant correlation also with PFS (p-value 0.01). Conclusions: Several biomarkers have been suggested as MPM prognostic factors, but sensitive and specific ones for the clinical practice are still missing. Despite the relatively small number of tissue samples, related to the rarity of this tumour, we identified 3 genes as potential prognostic markers. MCM2 is involved in the initiation of genome replication, PLK1 and CCNB2 regulate cell cycle by promoting mitosis. All these genes proved to be not only useful prognostic indicators but also promising therapeutic targets as reported in functional studies on different cancer models. The validation of these new markers, particularly of PLK1 which is correlated also with PFS, may improve the prognostic stratification at diagnosis, providing information valuable in the management of MPM patients.

Prognostic Factors in the UK LRF CLL4 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 299-299 ◽  
Author(s):  
David Graham Oscier ◽  
Rachel Wade ◽  
Jenny Orchard ◽  
Zadie Davis ◽  
Giles Best ◽  
...  
Keyword(s):  
Risk Group ◽  
Univariate Analysis ◽  
Treatment Modalities ◽  
Rank Test ◽  
P Value ◽  
Cox Regression Analysis ◽  
Log Rank Test ◽  
Significant Difference ◽  
Trisomy 12 ◽  
Vh Genes

Abstract The LRF CLL4 trial randomised 777 previously untreated patients with Binet stage progressive A, B or C disease between January 1999 and October 2004 to receive either Chlorambucil, Fludarabine or Fludarabine and Cyclophosphamide. Interphase FISH for deletions of chromosome 6q, 11q, 13q, 17p and trisomy 12, IgVH gene mutational status (98% cut off), CD38 (7% cut off) and ZAP70 (10% cut off) expression were measured at randomisation on 579, 523, 535 and 478 patients respectively. Leukemic cells from 39 patients utilised the VH3-21 gene of whom 33 had homologous CDR3’s. Among the biological markers, log rank analysis showed that >20% p53 loss, del 11q, unmutated VH genes, high CD38 and high ZAP 70 correlated with disease progression or death (Table 1) but not deletion of chromosome 6q, 13q and trisomy 12 (p=0.7, 0.3 and 0.2 respectively). There was no difference in PFS or response duration between the 52 patients with 5–20% p53 loss and the 494 patients with no p53 loss. Multivariate Cox regression analysis showed that >20% p53 loss (p<0.0001), unmutated IgVH genes (p=0.0001), deletion of 11q (p=0.02) and male gender (p=0.03) were independent risk factors for short PFS. The effects of stage and age were overridden by FISH abnormalities. High ZAP70 expression was only significant when VH gene mutation status was not included in the model. CD38 expression was only significant in univariate analysis. Table 1 Variable Progression or Death/N Univariate p-value(log rank test) Gender Male 384/573 0.002 Female 111/204 17q(p53) No 131/546 <0.00005 Yes 21/33 IgVH Unmutated 105/203 <0.00005 Mutated 225/320 del 11q No 288/463 <0.00005 Yes 87/116 ZAP70 Negative 140/242 0.003 Positive 158/236 CD38 Negative 110/201 0.0001 Positive 227/334 Among the 320 unmutated cases there was no significant difference in PFS between those with 100% homology (227 cases) and those with 99% or 98% homology to the germline sequence (93 cases). Mutated VH3-21 cases were more likely to express ZAP70 than other mutated cases, p=0.004. Excluding patients with >20% p53 loss, patients using the VH3-21 gene had similar progression free survival (PFS) to those remaining patients with unmutated VH genes and an inferior PFS to those with mutated VH genes (2p=0.0001). The adverse prognostic significance of 11q deletions was not clearly evident in an interim analysis presented at ASH ‘05. Patients can now be divided into 3 risk groups (Table 2). This risk stratification provides the basis of evaluating differing treatment modalities for each risk group in subsequent clinical trials. Table 2 Risk Group Definition Progression or Death/N Univariate p-value (log-rank test) 3 yr PFS Poor >20%p53 loss 28/33 0% Standard Unmutated VH or 11q deletion or VH3-21 208/292 <0.00001 24.7% Good Mutated VH(excl VH3–21) 79/161 55.0%

T-cell clonality in peripheral blood as a predictor of progression to systemic treatment in patients with stage IB mycosis fungoides (MF).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19538-e19538
Author(s):  
Suravi Raychaudhuri ◽  
Charli-Joseph Yann ◽  
Michelle Mintz ◽  
Laura Pincus ◽  
Chiung-Yu Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Systemic Treatment ◽  
Rank Test ◽  
P Value ◽  
Advanced Stage ◽  
Stage Ib ◽  
Log Rank Test ◽  
Secondary Outcomes

e19538 Background: A major unmet clinical need in the care of early-stage MF patients is the identification of those with a high risk of failing skin directed therapy or progressing to advanced disease. Herein, we inquired if the identification of a clonal T-cell receptor (TCR) gene rearrangement by PCR in peripheral blood could predict the clinical outcome, particularly the need for systemic treatment, in patients with stage IB MF. Methods: This is a retrospective cohort study of patients with stage IB MF who underwent peripheral blood TCR clonality analysis by PCR. The primary outcome of the study was time from diagnosis to initiation of systemic treatment. Secondary outcomes were: (1) time to progression to advanced-stage disease (stages IIB-IV) and (2) overall survival. Patients were censored at time of last clinical follow up. Log rank test was used to compare the survival distributions of the two groups; p value < 0.05 was considered significant. Results: From May 2014 to October 2019, 56 consecutive stage IB pts with > 6 months follow up were included in this analysis. Peripheral blood TCR clonality status was available in 42 patients: 18 pts had a positive TCR clone and 24 did not. Median follow up time was 36 months (range 8.5 – 198 months). At 3 years, 39% of patients with peripheral clone had progressed to systemic treatment versus 8% of those without a peripheral clone (log rank test, p-value = 0.003). For the secondary outcomes, at 3 years 17% of patients with peripheral clone had progressed to advanced stage versus 4% of those without (log rank test, p-value = 0.10); 5% of patients with peripheral clone had died versus 0% of those without (log rank test, p-value = 0.03). Conclusions: Detection of a predominant TCR clone by PCR in the peripheral blood is an important prognostic marker in the initial workup of MF, as its presence is highly correlated with subsequent progression to systemic treatment and death. If this finding is validated, it can be used to risk stratify and individualize therapy for MF patients.[Table: see text]

scholarly journals Epigenetic silencing of MEIS2 in prostate cancer recurrence

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Maibritt Nørgaard ◽  
Christa Haldrup ◽  
Marianne Trier Bjerre ◽  
Søren Høyer ◽  
Benedicte Ulhøi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Prostate Tissue ◽  
Rank Test ◽  
Transcriptional Expression ◽  
Tissue Samples ◽  
Whitney Test ◽  
Log Rank Test ◽  
Mann Whitney Test ◽  
Malignant Prostate

Abstract Background Current diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, resulting in overdiagnosis and overtreatment of clinically insignificant tumors. Thus, to improve the management of PC, novel biomarkers are urgently needed. Results In this study, we integrated genome-wide methylome (Illumina 450K DNA methylation array (450K)) and RNA sequencing (RNAseq) data performed in a discovery set of 27 PC and 15 adjacent normal (AN) prostate tissue samples to identify candidate driver genes involved in PC development and/or progression. We found significant enrichment for homeobox genes among the most aberrantly methylated and transcriptionally dysregulated genes in PC. Specifically, homeobox gene MEIS2 (Myeloid Ecotropic viral Insertion Site 2) was significantly hypermethylated (p < 0.0001, Mann-Whitney test) and transcriptionally downregulated (p < 0.0001, Mann-Whitney test) in PC compared to non-malignant prostate tissue in our discovery sample set, which was also confirmed in an independent validation set including > 500 PC and AN tissue samples in total (TCGA cohort analyzed by 450K and RNAseq). Furthermore, in three independent radical prostatectomy (RP) cohorts (n > 700 patients in total), low MEIS2 transcriptional expression was significantly associated with poor biochemical recurrence (BCR) free survival (p = 0.0084, 0.0001, and 0.0191, respectively; log-rank test). Next, we analyzed another RP cohort consisting of > 200 PC, AN, and benign prostatic hyperplasia (BPH) samples by quantitative methylation-specific PCR (qMSP) and found that MEIS2 was significantly hypermethylated (p < 0.0001, Mann-Whitney test) in PC compared to non-malignant prostate tissue samples (AN and BPH) with an AUC > 0.84. Moreover, in this cohort, aberrant MEIS2 hypermethylation was significantly associated with post-operative BCR (p = 0.0068, log-rank test), which was subsequently confirmed (p = 0.0067; log-rank test) in the independent TCGA validation cohort (497 RP patients; 450K data). Conclusions To the best of our knowledge, this is the first study to investigate, demonstrate, and independently validate a prognostic biomarker potential for MEIS2 at the transcriptional expression level and at the DNA methylation level in PC.

Transplant Outcome Is Not Affected by Body Mass Index (BMI) in Patients with Haematological Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1991-1991
Author(s):  
Emmanouil Nikolousis ◽  
Shankaranarayana Paneesha ◽  
Kathy Holder ◽  
Lynn Bratby ◽  
Srinivas Pillai ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Hodgkin’S Lymphoma ◽  
Allogeneic Transplantation ◽  
Hodgkin's Lymphoma ◽  
Rank Test ◽  
P Value ◽  
Haematological Malignancies ◽  
Transplant Outcome ◽  
Log Rank Test ◽  
High Bmi

Abstract Bone marrow transplantation is frequently used as a consolidation therapy in patients with haematological malignancies to improve outcome. Obese individuals have larger absolute lean body and fat masses than non-obese individuals of the same age, gender and height, which might lead to altered pharmacokinetics of chemotherapeutic agents. Data on the impact of body mass on transplant outcome is conflicting. This study included 254 patients (M: 151; F: 103) with 283 transplant episodes (Autograft: 178, Allograft: 105). 81 patients had myeloma, 61 non Hodgkin’s lymphoma, 38 Hodgkin’s lymphoma, 34 acute myeloid leukaemia, 28 chronic lymphocytic leukaemia, 15 acute lymphoblastic leukaemia, 9 T cell non Hodgkin’s lymphoma, 6 each myelodysplasia and aplastic leukaemia and 1 each acute promyelocytic leukaemia and myelofibrosis. Statistical analysis was carried out using SPSS 13.0 for Windows. Overall survival (OS) and event free survival (EFS) were estimated by the Kaplan-Meier method. At transplantation 47% patients had normal & 52% high BMI. After a median follow-up of 14 month (range:0–75), mean OS in patients undergoing autograft with normal BMI was 52 months as compared to 54 with high BMI. Mean OS in patients undergoing allograft with normal BMI was 27 months as compared to 39 with high BMI (log rank test p value; autograft: 0.74 & allograft: 0.09). Odds Ratio for survival in autograft patients was 1.305 (95% CI: 0.611–2.786). For normal BMI patients OR for survival was 1.175(95% CI: 0.73–1.891), where as for high BMI patients 0.901 (95% CI: 0.678–1.197). Odds Ratio for survival in allograft patients was 0.512 (95% CI: 0.23–1.136). For normal BMI patients OR for survival was 0.751 (95% CI: 0.534–1.057), where as for high BMI patients 1.468 (95% CI: 0.921–2.341). Mean EFS in patients undergoing autograft with normal BMI was 42 months as compared to 50 with high BMI. Mean EFS in patients undergoing allograft with normal BMI was 26 months as compared to 48 with high BMI (log rank test p value; autograft: 0.4 & allograft: 0.3). This study shows that high BMI does not adversely impact on either OS or EFS in patients undergoing both autologous and allogeneic transplantation for haematological malignancies. On the contrary, the trend for OS appears to better in patients undergoing allograft with high BMI. We recommend patients with high BMI should not be excluded from having autologous transplantation. Studies with greater number of patients are needed to establish the potential beneficial impact of high BMI on survival in patients undergoing allogeneic transplantation. Figure Figure

High Resolution Array-CGH Provides New Insights Into the Prognosis of Chronic Lymphocytic Leukemia (CLL): Is 8p Loss Worse Than 17p Loss?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2339-2339
Author(s):  
Andrea Rinaldi ◽  
Michael Mian ◽  
Davide Rossi ◽  
Francesco Forconi ◽  
Clara Deambrogi ◽  
...  
Keyword(s):  
Cox Regression ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Western World ◽  
Clinical Parameters ◽  
Log Rank Test ◽  
The Impact

Abstract Abstract 2339 Poster Board II-316 BACKGROUND: CLL, the most common adult-onset leukemia in the Western world, has a heterogeneous clinical course. Many advances have led to a better understanding of its pathogenesis and to improvements in treatment strategies, but striking solutions are still missing. We conducted a study to evaluate the impact of genomic aberrations on the clinical course. METHODS: From January 1980 to May 2008, 395 frozen samples of CLL patients, were prospectively collected in four centers. Extracted DNA was analyzed with Affymetrix Human Mapping 6.0 arrays. Normal matched DNA was analyzed for one fourth of the cases. Correlations between minimal common regions (MCR) and clinical parameters were evaluated with the Fisherôs-exact test and their impact on OS with the log-rank test. A p-value after Bonferroni multiple test correction (MTC) (p-adj.) <0.05 was considered as statistically significant. Up to now 266 samples have been analyzed. RESULTS: Analysis of the clinical parameters (CPs) and known risk factors (Rai/Binet, age, doubling time, LDH, beta2, IGVH status, p53 mutations, telomere length, CD38, 11q, 17p) was consistent to previous published series. ZAP70 did not affect the clinical course, likely due inter-laboratories variability. After a median follow up of 53 months, 143/239 (60%) of the patients have started therapy and 63/261 (24%) died. 5-yr OS was 82%. Fisher test between the MCRs and CPs revealed an inverse relation between the presence of trisomy 12 by FISH and del13q14.3, an association between del17p and losses of 8p regions and between CD38 and 12q gain. Before MTC, 46 MCRs had a significant impact on OS and 67. After MTC, 3 regions maintained their role: 8p22 loss (38/248, 15%, p-adj.=0.002, median OS: 26 months vs. 48), 17p13.3-11.2 loss (20/248, 8%, p-adj.=0.001; median OS: 10 months vs. 48). In univariate analysis, the log-rank test among pts with 8p-/17p- (8/248, 3%), 8p- (30/248, 12%), 17p- (12/248, 5%), wild type (198/248, 80%) was statistically significant (p<0.001; see figure). Importantly, none of the analyzed clinical and biological parameters was associated with this aberration. CONCLUSIONS: Loss of 8p22 designated a CLL subgroup with a worse outcome among all patients and in the subset with 17p loss. Our data suggested that this aberration might constitute an independent prognostic factor to be evaluated in independent studies. Results, including a Cox regression model, will be presented on all 395 cases. Disclosures: No relevant conflicts of interest to declare.

Combining Proteomics and Gene Expression Profiling Identifies Proteins/Genes Associated with Short Overall Survival in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 197-197
Author(s):  
Ricky D Edmondson ◽  
Shweta S. Chavan ◽  
Christoph Heuck ◽  
Bart Barlogie
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Multivariate Analyses ◽  
Rank Test ◽  
P Value ◽  
Newly Diagnosed ◽  
Training Set ◽  
Test Set ◽  
Log Rank Test ◽  
Test Sets

Abstract Abstract 197 We and others have used gene expression profiling to classify multiple myeloma into high and low risk groups; here, we report the first combined GEP and proteomics study of a large number of baseline samples (n=85) of highly enriched tumor cells from patients with newly diagnosed myeloma. Peptide expression levels from MS data on CD138-selected plasma cells from a discovery set of 85 patients with newly diagnosed myeloma were used to identify proteins that were linked to short survival (OS < 3 years vs OS ≥ 3 years). The proteomics dataset consisted of intensity values for 11,006 peptides (representing 2,155 proteins), where intensity is the quantitative measure of peptide abundance; Peptide intensities were normalized by Z score transformation and significance analysis of microarray (SAM) was applied resulting in the identification 24 peptides as differentially expressed between the two groups (OS < 3 years vs OS ≥ 3 years), with fold change ≥1.5 and FDR <5%. The 24 peptides mapped to 19 unique proteins, and all were present at higher levels in the group with shorter overall survival than in the group with longer overall survival. An independent SAM analysis with parameters identical to the proteomics analysis (fold change ≥1.5; FDR <5%) was performed with the Affymetrix U133Plus2 microarray chip based expression data. This analysis identified 151 probe sets that were differentially expressed between the two groups; 144 probe sets were present at higher levels and seven at lower levels in the group with shorter overall survival. Comparing the SAM analyses of proteomics and GEP data, we identified nine probe sets, corresponding to seven genes, with increased levels of both protein and mRNA in the short lived group. In order to validate these findings from the discovery experiment we used GEP data from a randomized subset of the TT3 patient population as a training set for determining the optimal cut-points for each of the nine probe sets. Thus, TT3 population was randomized into two sub-populations for the training set (two-thirds of the population; n=294) and test set (one-third of the population; n=147); the Total Therapy 2 (TT2) patient population was used as an additional test set (n=441). A running log rank test was performed on the training set for each of the nine probe sets to determine its optimal gene expression cut-point. The cut-points derived from the training set were then applied to TT3 and TT2 test sets to investigate survival differences for the groups separated by the optimal cutpoint for each probe. The overall survival of the groups was visualized using the method of Kaplan and Meier, and a P-value was calculated (based on log-rank test) to determine whether there was a statistically significant difference in survival between the two groups (P ≤0.05). We performed univariate regression analysis using Cox proportional hazard model with the nine probe sets as variables on the TT3 test set. To identify which of the genes corresponding to these nine probes had an independent prognostic value, we performed a multivariate stepwise Cox regression analysis. wherein CACYBP, FABP5, and IQGAP2 retained significance after competing with the remaining probe sets in the analysis. CACYBP had the highest hazard ratio (HR 2.70, P-value 0.01). We then performed the univariate and multivariate analyses on the TT2 test set where CACYBP, CORO1A, ENO1, and STMN1 were selected by the multivariate analysis, and CACYBP had the highest hazard ratio (HR 1.93, P-value 0.004). CACYBP was the only gene selected by multivariate analyses of both test sets. Disclosures: No relevant conflicts of interest to declare.

Human Herpes Virus 6 Infection in 54 Patients after Allogeneic Hematopoietic Stem Cell Transplantation: Clinical Manifestations and Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3899-3899
Author(s):  
Raffaella Greco ◽  
Lara Crucitti ◽  
Sara Racca ◽  
Roee Dvir ◽  
Francesca Lorentino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Clinical Manifestations ◽  
Rank Test ◽  
P Value ◽  
Hematopoietic Stem ◽  
Clinical Complications ◽  
Log Rank Test ◽  
Blue Line

Abstract BACKGROUND: Human herpesvirus type 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic hematopoietic stem cell transplantation (AlloSCT). HHV-6 is a member of the beta herpesvirus subfamily (genus Roseolovirus). HHV-6 infection is recognized as the cause of a febrile disease and exanthem subitum in early childhood. Approximately 60% of solid organ transplant and 40% of patients after alloSCT experienced HHV-6 reactivation. Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, some clinical reports suggest that HHV-6 can facilitate the occurrence of severe clinical complications of alloSCT, increasing transplant-related mortality. METHODS: From January 2009 to February 2013, we retrospectively evaluated 54 consecutive adult patients (median age 50 years) who developed positivity to HHV-6 after alloSCT for high-risk hematological malignancies. Stem cell donors were family haploidentical (37), HLA identical sibling (8), unrelated volunteer (6), cord blood (3). The viral load was determined by quantitative PCR (Nanogen Advanced Diagnostic S.r.L) in cell-free body fluids such as plasma, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), bone marrow (BM) aspirates or in gastrointestinal biopsies. RESULTS: Median time from alloSCT to HHV-6 reactivation was 34 days (range: 0-705). Thirty-one patients presented HHV-6 positive in plasma, 9/54 in BM, 33/54 in gut biopsies or BAL, 7/54 in CSF. At the time of viral positivity all pts were receiving acyclovir as viral prophylaxis except five. Twenty-nine patients had acute graft versus host disease (GvHD). Twenty-two out of these twenty-nine patients experienced a grade III-IV acute GvHD, requiring high dose steroids in twenty-six cases. A concomitant CMV positivity was detected in 15/54 patients. The median absolute count of CD3+ lymphocytes was 207 cells/mcl. In 52/54 cases we reported HHV-6 clinical manifestations: fever (43), skin rash (22), hepatitis (19), diarrhoea (24), encephalitis (10), BM suppression (18), delayed engraftment (11). HHV-6 positivity led to antiviral pharmacological treatment in 37/54 cases, using as first choice therapy foscarnet. Amongst the total fifty-four patients with documented HHV-6 positivity thirty-one solved the clinical event. However the mortality rate was relatively high in this population (overall survival (OS) ±SE at 1 year after HHV-6 reactivation was 38% ± 7%), mainly related to severe infections or GvHD. A better OS is significantly associated with CD3+ cells ≥200/mcl at the time of HHV-6 reactivation (fig 1) (OS at 1 year 63% compared to 11% for patients with CD3 <200/mcl; HR: 0.27, 95% CI 0.12-0.54, p=0.0002). The overall survival of these patients was also positively affected by the absence of acute GvHD grade III-IV at time of viral reactivation (HR: 0.03, 95% CI 1.08-4.03, p=0.03) and by the complete disease remission at time of HSCT (HR:0.26, 95% CI 0.07-0.89, p=0.03). In this analysis the overall survival was not significantly influenced by steroids administration (HR: 1.36, 95% CI 0.71-2.60, p=0.36), time after alloSCT (HR: 1.30, 95% CI 0.51-3.33, p=0.59), type of antiviral prophylaxis (HR: 1.02, 95% CI 0.45-2.33, p=0.96), plasma viral load (HR:1.18, 95% CI 0.51-2.76, p=0.69) and organ involvement (HR:1.14, 95% CI 0.59-2.20, p=0.70). CONCLUSIONS: This retrospective study confirms a correlation of HHV-6 with high morbidity and mortality rates after alloSCT, thus suggesting a regular HHV-6 monitoring in alloSCT recipients. The regular monitoring of HHV-6 DNA, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Despite HHV-6 detection typically occurred early after alloSCT, a better immune reconstitution has the potential to improve clinical outcome. Figure 1: Overall survival after alloSCT in HHV-6 positive patients: green line showed patients with more than 200/mcl CD3+ cells, blue line the ones with less than 200/mcl CD3+ cells at HHV-6 reactivation. P value is provided by Log Rank test. Figure 1:. Overall survival after alloSCT in HHV-6 positive patients: green line showed patients with more than 200/mcl CD3+ cells, blue line the ones with less than 200/mcl CD3+ cells at HHV-6 reactivation. P value is provided by Log Rank test. Disclosures Bonini: MolMed S.p.A.: Consultancy.

Tailored Approaches for Refined Prognostication in Chronic Lymphocytic Leukemia Patients with Mutated Versus Unmutated Immunoglobulin Receptors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3199-3199
Author(s):  
Panagiotis Baliakas ◽  
Theodoros Moysiadis ◽  
Anastasia Hadzidimitriou ◽  
Aliki Xochelli ◽  
Mattias Mattsson ◽  
...  
Keyword(s):  
High Risk ◽  
Low Risk ◽  
Rank Test ◽  
P Value ◽  
Paired Comparisons ◽  
Intermediate Risk ◽  
Log Rank Test ◽  
Recurrent Mutations ◽  
Prognostic Indices ◽  
Very High

Abstract The classification of CLL patients according to the somatic hypermutation status (SHM) of the immunoglobulin heavy variable (IGHV) genes, namely mutated (M-CLL) versus unmutated (U-CLL), reflects fundamental differences in disease biology and clinical course. Realizing this, here we followed a compartmentalized approach and addressed the issue of prognostication separately for M-CLL and U-CLL. In a multi-institutional cohort of 2366 patients [M-CLL, n=1364 (58%); U-CLL, n=1002 (42%)] consolidated within ERIC, the European Initiative in CLL, we assessed the clinical impact of 'traditional' (age and clinical stage at the time of diagnosis, gender, CD38 expression, FISH detected abnormalities included in the Döhner hierarchical model of cytogenetic aberrations), and novel prognosticators (recurrent mutations within the TP53, SF3B1, NOTCH1, MYD88, and BIRC3 genes; IGHV gene usage; membership in stereotyped subsets) within M-CLL and U-CLL. Our statistical approach was based both on Cox regression models and recursive partitioning algorithms; internal validation was performed via bootstrapping procedures. Given the retrospective nature of our study, time-to-first-treatment (TTFT) was the primary endpoint. As expected, M-CLL exhibited significantly longer TTFT compared to U-CLL [median TTFT: not yet reached (M-CLL) vs 1.9 years (95% CI: 0.01-12.3 years, U-CLL), p<0.0001]. Advanced clinical stages (Binet B-C) were associated with shorter TTFT in both M-CLL and U-CLL; a significantly worse outcome was also identified for Binet C versus Binet B cases (p<0.0001). Binet A patients received our special focus, representing 90% and 67% of M-CLL and U-CLL studied cases, respectively. Amongst Binet A M-CLL cases, TP53 aberrations [TP53abs, deletions of chromosome 17p, del(17p) and/or TP53 mutations], stereotyped subset #2 membership and trisomy 12 were identified as equally adverse prognostic indicators [median TTFT: 5.5 (95% CI: 0.2-12.8), 4 (95% CI: 0.6-6.8) and 7.3 (95% CI: 0.7-13.4) years, respectively; p-value: non-significant when applying the log-rank test for all paired comparisons); of note, TP53abs were mutually exclusive with the other two features. Amongst Binet A U-CLL cases, TP53abs, SF3B1 mutations and deletion of chromosome 11q [del(11q)] had an overall similar adverse impact [median TTFT for TP53abs, SF3B1 mutations and del(11q): 1.8 (95% CI: 0.01-4.4), 2 (95% CI: 0.01-7.7) and 2.1 (95% CI: 0.01-8.1) years, respectively, p-value: non-significant when applying the log-rank test for all paired comparisons]. Within the remaining Binet A U-CLL cases [i.e. those lacking TP53abs and/or SF3B1 mutations and/or del(11q)], the only parameter associated with shorter TTFT was male gender (median TTFT: 3.5 years, 95% CI: 0.5-8.1 years). Based on these findings, we developed two prognostic indices for assessing TTFT tailored specifically to M-CLL and U-CLL, respectively. Within M-CLL (Figure 1A), 4 subgroups were identified: (i) very high risk: Binet C with identical 5- and 10-year treatment-probability (TP) of 92%; (ii) high risk: Binet B, 5y-TP and 10y-TP: 64% and 84%, respectively; (iii) intermediate risk: Binet A with one of the following: TP53abs or +12 or subset #2 membership, 5y-TP and 10y-TP: 40% and 55%, respectively; and (iv) low risk: Binet A nonTP53abs/+12/subset#2, 5y-TP and 10y-TP: 12% and 25%, respectively. Within U-CLL (Figure 1B), 5 subgroups were identified: (i) very high risk: Binet C with 5- and 10-year TP of 100%; (ii) high risk: Binet B, identical 5y-TP and 10y-TP: 90% and 100%, respectively; (iii) intermediate risk: Binet A with one of the following: TP53abs or SF3B1 mutations or del(11q), 5y-TP and 10y-TP: 78% and 98%, respectively; (v) low risk: Binet A, male nonTP53abs/SF3B1mut/del(11q), 5y-TP and 10y-TP: 65% and 85%, respectively and (iv) very low risk: Binet A, female nonTP53abs/SF3B1mut/del(11q), 5y-TP and 10y-TP: 45% and 65%, respectively. In conclusion, we identified clinicobiological parameters with distinct prognostic implications for M-CLL and U-CLL. These parameters were used in order to develop prognostic indices tailored to SHM status that were found capable of distinguishing subgroups with markedly different outcomes. We argue that such a compartmentalized approach may supersede previous attempts, thus overcoming the pronounced heterogeneity of CLL and optimizing prognostication. PB and TM contributed equally as first authors Figure 1 Figure 1. Disclosures Rosenquist: Gilead Sciences: Speakers Bureau.

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