A prospective validation cohort study of baseline plasma cell-free DNA (cfDNA) as a prognostic biomarker in newly diagnosed glioblastoma (GBM).

2508 Background: Due to significant interpatient heterogeneity, survival outcomes vary widely in patients with GBM. Novel prognostic biomarkers are needed. We aimed to determine the prognostic impact of baseline plasma cfDNA concentration in patients with GBM. Methods: We analyzed 84 patients with newly diagnosed GBM and at least 7 months of follow-up time. The first 41 patients comprised a previously published derivation cohort (Bagley, Clin Cancer Res 2020). The subsequent 43 patients served as an independent validation cohort. cfDNA was extracted from plasma collected prior to initial surgical resection and quantified by qPCR for a 115 bp amplicon of the human ALU repeat element. Receiver operating characteristic (ROC) curve analysis was used in the derivation cohort to (1) assess the accuracy of plasma cfDNA concentration for predicting progression-free survival status at 7 months (PFS-7), a landmark based on the median PFS for newly diagnosed GBM (Stupp, N Engl J Med 2005), and (2) derive the optimal cutoff for dichotomizing patients into high- and low-cfDNA groups. In the validation cohort, logistic regression was used to measure the association of plasma cfDNA concentration (high vs. low) with PFS-7, adjusted for age, isocitrate dehydrogenase ( IDH) 1/2 mutational status, 0-6-methylguanine-methyltransferase ( MGMT) methylation, extent of resection, and performance status. Multivariate Cox regression was used for overall survival (OS) analysis. Results: In the derivation cohort, the optimal cutoff for plasma cfDNA was 25.0 ng/mL (area under the curve [AUC] = 0.663), with inferior PFS and OS in patients with cfDNA above this cutoff (PFS, median 4.9 vs. 9.5 months, log-rank p = 0.001; OS, median 8.5 vs. 15.5 months, log-rank p = 0.03). In the validation cohort, baseline plasma cfDNA concentration over the cutoff was independently associated with a lower likelihood of being alive and progression-free at 7 months (adjusted OR 0.13, 95% CI 0.02 – 0.75, p = 0.02). OS was also worse in in the validation cohort in patients with high plasma cfDNA (adjusted HR 3.0, 95% CI 1.1 – 8.0, p = 0.03). Conclusions: In patients with newly diagnosed GBM, high baseline plasma cfDNA concentration is associated with worse survival outcomes independent of other prognostic factors. Further validation in a larger, multicenter study is warranted.

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Establishment and Validation of an Integrated Model to Predict Postoperative Recurrence in Patients With Atypical Meningioma

Frontiers in Oncology ◽

10.3389/fonc.2021.754937 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiao-Yong Chen ◽

Jin-Yuan Chen ◽

Yin-Xing Huang ◽

Jia-Heng Xu ◽

Wei-Wei Sun ◽

...

Keyword(s):

Cox Regression ◽

Validation Cohort ◽

Clinical Laboratory ◽

External Validation ◽

Postoperative Recurrence ◽

Integrated Model ◽

Atypical Meningioma ◽

Tumor Diameter ◽

Roc Curve Analysis ◽

Training Cohort

BackgroundThis study aims to establish an integrated model based on clinical, laboratory, radiological, and pathological factors to predict the postoperative recurrence of atypical meningioma (AM).Materials and MethodsA retrospective study of 183 patients with AM was conducted. Patients were randomly divided into a training cohort (n = 128) and an external validation cohort (n = 55). Univariable and multivariable Cox regression analyses, the least absolute shrinkage and selection operator (LASSO) regression analysis, time-dependent receiver operating characteristic (ROC) curve analysis, and evaluation of clinical usage were used to select variables for the final nomogram model.ResultsAfter multivariable Cox analysis, serum fibrinogen >2.95 g/L (hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.05–5.63; p = 0.039), tumor located in skull base (HR, 6.59; 95% CI, 2.46-17.68; p < 0.001), Simpson grades III–IV (HR, 2.73; 95% CI, 1.01–7.34; p = 0.047), tumor diameter >4.91 cm (HR, 7.10; 95% CI, 2.52–19.95; p < 0.001), and mitotic level ≥4/high power field (HR, 2.80; 95% CI, 1.16–6.74; p = 0.021) were independently associated with AM recurrence. Mitotic level was excluded after LASSO analysis, and it did not improve the predictive performance and clinical usage of the model. Therefore, the other four factors were integrated into the nomogram model, which showed good discrimination abilities in training cohort (C-index, 0.822; 95% CI, 0.759–0.885) and validation cohort (C-index, 0.817; 95% CI, 0.716–0.918) and good match between the predicted and observed probability of recurrence-free survival.ConclusionOur study established an integrated model to predict the postoperative recurrence of AM.

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A novel severity score to predict inpatient mortality in COVID-19 patients

Scientific Reports ◽

10.1038/s41598-020-73962-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

David J. Altschul ◽

Santiago R. Unda ◽

Joshua Benton ◽

Rafael de la Garza Ramos ◽

Phillip Cezayirli ◽

...

Keyword(s):

Severity Score ◽

Clinical Decision Making ◽

Risk Model ◽

Validation Cohort ◽

Clinical Decision ◽

International Normalized Ratio ◽

Severe Illness ◽

Roc Curve Analysis ◽

Derivation Cohort ◽

Mortality Incidence

Abstract COVID-19 is commonly mild and self-limiting, but in a considerable portion of patients the disease is severe and fatal. Determining which patients are at high risk of severe illness or mortality is essential for appropriate clinical decision making. We propose a novel severity score specifically for COVID-19 to help predict disease severity and mortality. 4711 patients with confirmed SARS-CoV-2 infection were included. We derived a risk model using the first half of the cohort (n = 2355 patients) by logistic regression and bootstrapping methods. The discriminative power of the risk model was assessed by calculating the area under the receiver operating characteristic curves (AUC). The severity score was validated in a second half of 2356 patients. Mortality incidence was 26.4% in the derivation cohort and 22.4% in the validation cohort. A COVID-19 severity score ranging from 0 to 10, consisting of age, oxygen saturation, mean arterial pressure, blood urea nitrogen, C-Reactive protein, and the international normalized ratio was developed. A ROC curve analysis was performed in the derivation cohort achieved an AUC of 0.824 (95% CI 0.814–0.851) and an AUC of 0.798 (95% CI 0.789–0.818) in the validation cohort. Furthermore, based on the risk categorization the probability of mortality was 11.8%, 39% and 78% for patient with low (0–3), moderate (4–6) and high (7–10) COVID-19 severity score. This developed and validated novel COVID-19 severity score will aid physicians in predicting mortality during surge periods.

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Correlation of chemotherapy delivery and survival outcomes of follicular lymphoma in the immunchemotherapy era.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8563 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8563-8563

Author(s):

Kitsada Wudhikarn ◽

Anna M Button ◽

Brian J. Smith ◽

Thomas Matthew Habermann ◽

Carrie A. Thompson ◽

...

Keyword(s):

Follicular Lymphoma ◽

Systemic Therapy ◽

Cox Regression ◽

Dose Intensity ◽

Survival Outcomes ◽

Lower Grade ◽

Newly Diagnosed ◽

University Of Iowa ◽

Clinicopathologic Factors

8563 Background: Optimal initial treatment of follicular lymphoma (FL) is unknown. Rituximab as monotherapy (R) or as a component of immunochemotherapy (R+Chemo) is established as effective and it is now reasonable to re-examine the role of chemotherapy dosing. We explored clinical features, systemic treatment and chemotherapy delivery with comparative effectiveness of delivered dose intensity (DDI) on outcomes. Methods: We reviewed the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource database along with medical records on newly diagnosed grade I-IIIa FL who received systemic therapy from 2002 to 2009. Presenting clinicopathologic factors, outcomes and systemic therapy details including doses of chemotherapy were collected. The event-free (EFS) and overall survival (OS) effects of systemic therapy and chemotherapy DDI were analyzed with multivariate Cox regression. Confounding effects of FLIPI, grade, stage, and age were considered in the analysis. Results: From 2002 to 2009, 631 newly diagnosed FL were enrolled. Median follow up duration was 52.7 months. We identified 322 grade I-IIIa FL treated with systemic therapy including 93 R and 229 R+Chemo. Age and stage were similarly distributed between the R and R+Chemo groups; however, patients in the R group had lower grade (p<0.01) and FLIPI (p=0.03). Multivariate analysis showed no significant differences in EFS (HR=1.24, p=0.28) or OS (HR=0.55, p=0.13) for R compared to R+Chemo. Among R-CVP or R-CHOP treated FL, DDI data were collected for 73 doxorubicin (dox) and 137 cyclophosphamide (cyc) patients. Eighty-five percent of patients received 90% or more pre-planned DDI. After controlling for confounding factors, higher cycDDI was associated with improved EFS (HR 0.55, P=0.04) and OS (HR 0.74, P=0.03). No significant OS or EFS effects of doxDDI were observed. Conclusions: Addition of chemotherapy to rituximab was not associated with a detectable difference in survival outcomes in grade I-IIIa FL at a median follow-up of 52.7 months. Among R+Chemo treated FL, chemotherapy was delivered completely in most patients and more completed delivery of cyclophosphamide was associated with improved EFS and OS.

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Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

Frontiers in Oncology ◽

10.3389/fonc.2021.684621 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fortunato Morabito ◽

Giovanni Tripepi ◽

Riccardo Moia ◽

Anna Grazia Recchia ◽

Paola Boggione ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Doubling Time ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Prognostic Role ◽

Mutational Status ◽

Binet Stage ◽

Time To First Treatment

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT>12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.

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Prognostic significance of pathologic nodal positivity in non-metastatic patients with renal cell carcinoma who underwent radical or partial nephrectomy

Scientific Reports ◽

10.1038/s41598-021-82750-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sung Han Kim ◽

Boram Park ◽

Eu Chang Hwang ◽

Sung-Hoo Hong ◽

Chang Wook Jeong ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Partial Nephrectomy ◽

Renal Cell ◽

Cox Regression ◽

Prognostic Significance ◽

Multivariable Analysis ◽

Survival Outcomes ◽

Prognostic Impact ◽

Cox Regression Analysis

AbstractThis retrospective, five-multicenter study was aimed to evaluate the prognostic impact of pathologic nodal positivity on recurrence-free (RFS), metastasis-free (MFS), overall (OS), and cancer-specific (CSS) survivals in patients with non-metastatic renal cell carcinoma (nmRCC) who underwent either radical or partial nephrectomy with/without LN dissection. A total of 4236 nmRCC patients was enrolled between 2000 and 2012, and followed up through the end of 2017. Survival measures were compared between 52 (1.2%) stage pT1-4N1 (LN+) patients and 4184 (98.8%) stage pT1-4N0 (LN−) patients using Kaplan–Meier analysis with the log-rank test and Cox regression analysis to determine the prognostic risk factors for each survival measure. During the median 43.8-month follow-up, 410 (9.7%) recurrences, 141 (3.3%) metastases, and 351 (8.3%) deaths, including 212 (5.0%) cancer-specific deaths, were reported. The risk factor analyses showed that predictive factors for RFS, CSS, and OS were similar, whereas those of MFS were not. After adjusting for significant clinical factors affecting survival outcomes considering the hazard ratios (HR) of each group, the LN+ group, even those with low pT stage, had similar to or worse survival outcomes than the pT3N0 (LN−) group in multivariable analysis and had significantly more relationship with RFS than MFS. All survival measures were significantly worse in pT1-2N1 patients (MFS/RFS/OS/CSS; HR 4.12/HR 3.19/HR 4.41/HR 7.22) than in pT3-4N0 patients (HR 3.08/HR 2.92/HR 2.09/HR 3.73). Therefore, LN+ had an impact on survival outcomes worse than pT3-4N0 and significantly affected local recurrence rather than distant metastasis compared to LN− in nmRCC after radical or partial nephrectomy.

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Analysis of metabolism-related gene signature for prognosis prediction of clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16580 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16580-e16580

Author(s):

Dalong Cao ◽

Yuchen Liao ◽

Guoqiang Wang ◽

Shangli Cai ◽

Guohai Shi

Keyword(s):

Cox Regression ◽

Validation Cohort ◽

Clear Cell ◽

Gene Signature ◽

Related Gene ◽

Prognostic Signature ◽

Training Set ◽

Roc Curve Analysis ◽

Cell Renal Cell Carcinoma ◽

Risk Patients

e16580 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by a dysregulation of changes in cellular metabolism. However, the prognostic value of metabolism-related genes in ccRCC have not been systematically profiled. In this study, a candidate prognostic gene signature of metabolism in ccRCC was explored. Methods: The clinical and gene expression profiles of ccRCC patients were downloaded from the TCGA, GEO and three clinical trials (CheckMate 009, CheckMate 010, CheckMate 025), and the metabolism-related gene set was downloaded from MSigDB. Differential expression analysis and LASSO Cox regression with binomial deviance minimization criteria were applied to identify and build a metabolism-based signature. The prognostic significance of the signature was further evaluated with the Receiver Operating Characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analysis was performed to evaluate the impact of each variable on OS. Furthermore, the prediction power of the signature has been validated using different ccRCC cohort. Results: In this study, a signature of 8 metabolism-related genes (ANGPT2, ATP6V1B1, CACNA1E, CD163L1, EPN2, HOXD11, PROS1, SHOX2) was constructed as being significantly associated with overall survival (OS) among patients with ccRCC, which differentiated ccRCC patients into high- and low-risk subgroups. The Kaplan-Meier (KM) analysis showed that the survival rate of the low-risk patients was significantly higher than that of the higher-risk patients (hazard ratio (HR) in training set, 0.25 [95% CI, 0.14-0.44; P < 0.001]; testing set, 0.28 [95% CI, 0.10-0.76; P = 0.008]; validation cohort (clinical trials), 0.47 [95% CI, 0.33-0.68; P < 0 .001]; validation cohort (GSE29609), 0.25, [95% CI, 0.08-0.88; P = 0 .01]). ROC curve analysis of the prognostic signature showed that the areas under curve (AUC) for the 1-, 3-, and 5-year OS in all cohort were more than 0.70 (AUC of the signature for 3 year in the training set and validation cohort were 0.816 and 0.708, respectively, and 0.807 and 0.702, respectively, for the 5- year OS). Further more, a nomogram based on the signature was constructed and showed an accurate prediction for prognosis in ccRCC. Conclusions: Taken together, we identified the key metabolism-related genes and constructed a robust prognostic signature for the prognostic predictor of ccRCC patients, which maybe help personalized management of ccRCC patients.

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High Cereblon Protein Expression Correlates with Improved Response and Survival in Myeloma Patients Treated with Lenalidomide

Blood ◽

10.1182/blood.v120.21.931.931 ◽

2012 ◽

Vol 120 (21) ◽

pp. 931-931 ◽

Cited By ~ 6

Author(s):

Alexander Klimowicz ◽

Paola Neri ◽

Andrew Belch ◽

Michelle Dean ◽

Li Ren ◽

...

Keyword(s):

Bone Marrow ◽

Regression Analysis ◽

Protein Expression ◽

Research Funding ◽

Cox Regression ◽

Survival Outcomes ◽

Newly Diagnosed ◽

Bone Marrow Biopsies ◽

Kaplan Meier ◽

Z Scores

Abstract Abstract 931 Background: Cereblon (CRBN), an adaptor protein of the Cul4A-DDB1-ROC1 ubiquitin E3 ligase complex was recently identified as a primary target of thalidomide teratogenicity and as essential requirement for IMiDs mediated cytotoxicity in multiple myeloma (MM) cells in vitro (Zhu YX et al, 2011). We have undertaken the current study to confirm the association between cereblon protein expression and the clinical response to lenalidomide. Methods: We constructed tissue microarrays (TMA) using bone marrow biopsies collected immediately prior to initiating therapy with lenalidomide. Fluorescence immunohistochemistry was performed using a polyclonal anti-CRBN antibody (HDA045910, Sigma-Aldrich) at a dilution of 1:4000, with 3 minutes of antigen retrieval at 121°C in a decloaking chamber in a pH=9 Tris/EDTA-based buffer (S2367, Dako). Tissue microarray slides were scanned on a HistoRx PM-2000 and digital images where analyzed with AQUA analysis software to determine the CRBN AQUA scores (protein expression = AQUA scores defined as the average CRBN pixel intensity within CD138 positive cells). CRBN AQUA scores where standardized on the Z-distribution (Z= X-μ/σ). The clinical parameters, response criteria and survival outcomes (PFS and OS) of these patients were defined according to the international uniform response criteria. The Kaplan-Meier method was used to estimate OS and PFS. Multivariate analysis was performed using the Cox regression method. Results: 42 patients with newly diagnosed (71.4%) or relapsed / refractory (28.6%) MM patients treated with lenalidomide and dexamethasone (MM009, MM016 or MM020 trials) and available pre-treatment bone marrow biopsies were included in this analysis. In this cohort, median age was 68 (range 46–88), median Hb 114 g/L (range 77–145), median Calcium 2.35 mmol/L (range 1.62–2.82), median creatinine 91.5 μmoles/L (range 44–500), high LDH in 21.4%, median albumin 35.5 g/L (range 23–47), β2 microglobulin 4.66 mg/L (range 1.2–35.19), ISS I 19%, II 35.7% and III 45.3% and high-risk cytogenetics (del17p13, t(4;14) by FISH) in 26.6%. Response CR/nCR was observed in 13/42 (31 %), PR in 21/42 (50%), MR in 4/42 (9.5%) and PD in 4/42 (9.5%). With a median follow-up of 22.4 months (range 0.72–65.6), 28/42 (67%) progressed with mPFS 19.53 months (95% CI 8.57–30.496) and mOS 28.733 months (95% CI 24.061–33.406). Cereblon expression or AQUA normalized Z scores ranged from -1.419 to 3.895. Kaplan Meier log-rank survival analysis were generated based on CRBN normalized AQUA Z scores with the bottom (Q4) and top quartiles (Q1-3) defined as CRBN-low or CRBN-high groups respectively. PFS was significantly shorter in CRBN-low (5.633 months) versus CRBN-high (19.733 months; p= 0.008). Similarly, OS was also reduced in CRBN-low patients (11.4 versus 30.467 months; p=0.033). In univariate Cox regression analysis, cereblon protein expression was significantly associated with PFS (HR 0.322; 95% CI 0.133–0.780; p=0.012) and OS (HR 0.323; 95% CI 0.108–0.970; p=0.044). Cereblon expression remained an independent predictor of PFS (HR 0.161; p=0.01) but not for OS when ISS and cytogenetics were included in multivariate regression analysis. In the CRBN-high group only 5/31 patients (16.1%), compared to 54.5% (6/11) in the CRBN-low group, failed to respond (≤MR) to lenalidomide. Similar to the protein tissue array analysis, low CRBN mRNA was also significantly associated with shorter PFS (p=0.008) in a chip microarray analysis of CRBN expression (Affymetrix probe 222533_at) in a cohort of 32 MM patients treated with lenalidomide and dexamethasone. Cereblon protein expression (AQUA normalized Z score) significantly correlated with CRBN mRNA microarray values (Affymetrix probe 222533_at) in 17 patients with matching protein and mRNA samples (Spearman's rho 0.417; p= 0.048). In contrast, and confirming the specificity of cereblon for response to IMiDs, no association between cereblon protein expression and response to therapy or survival outcomes (PFS/OS) was observed in a independent cohort of newly diagnosed MM patients (n=37) treated with bortezomib induction therapy and ASCT. Conclusion: Using an automated, observer-independent and fully quantitative approach, our studies confirm the association between cereblon protein expression and response to lenalidomide in MM. Disclosures: Neri: Johnson ans Johnson: Research Funding. Bahlis:Johnson and Johnson: Honoraria, Research Funding; Celgene: Honoraria.

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Methscore As a New Prognostic Tool for Complex DNA Methylation Changes Assessment in Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-137380 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Sarka Sestakova ◽

Cyril Šálek ◽

Dávid Kundrát ◽

Ivana Ježíšková ◽

Jiří Mayer ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Methylation Level ◽

Myeloid Leukemia ◽

Research Funding ◽

Cox Regression ◽

Validation Cohort ◽

Prognostic Impact ◽

Logrank Test ◽

Acute Myeloid

Changes in DNA methylation are characteristic for patients with acute myeloid leukemia (AML) and many studies have reported the prognostic significance of these epigenetic aberrations. We aimed for a complex evaluation of DNA methylation changes in AML patients at diagnosis. Therefore, we designed a sequencing panel targeting 239 regions annotated to 186 genes previously described in literature as having a prognostic impact or being commonly associated with AML pathogenesis (e.g. WT1, HOX genes). We used diagnostic whole-blood DNA samples of adult AML patients who were treated with curative intent starting with 3+7 induction regimen. In the testing cohort, we sequenced 128 AML patients and 11 samples from healthy donors. We analyzed another 50 AML patients from partner institution University Hospital Brno as an independent validation cohort. The libraries were prepared using SeqCap Epi Enrichments System (Roche) and sequenced on MiSeq instrument (Illumina). Data were processed in Linux opensource software and further analyzed in R. For each sample, we measured the methylation level of nearly 50 000 CpGs. In the testing cohort, we used the Cox regression to evaluate the effect of each CpG's methylation level on overall survival (OS). As a result, we found 1961 CpGs significantly effecting the OS (p<0.05) annotated to 141 genes. In gene ontology analysis, these loci were mainly connected to transcription and RNA regulation, DNA binding, and embryonic development. In 1097 CpGs, higher methylation indicated better outcome and, on the contrary, a poorer prognosis in the remaining 864 CpGs. Next, we used linear combination of the methylation levels and Cox's beta regression coefficients for each CpG to count a summarizing value that we called MethScore. Patients with lower MethScore (n=64) had markedly longer OS and event-free survival (EFS) than patients with higher MethScore (n=64, Logrank test for OS: p<2e-16, for EFS: p<2e-12). To further specify the prognostically most influential CpGs out of the selected 1961 loci, we subjected them individually to Cox multivariate regression analysis together with age, leukocytes count, cytogenetics, FLT3-ITD mutation, and transplantation in the 1st complete remission. Only 625 CpGs remained significant (p<0.05) and from these, we calculated MethScore-MVA via the same procedure as MethScore. MethScore-MVA was also very well predictive of patients' survival (Logrank test comparing patients with higher and lower MethScore-MVA for OS: p<7e-14, for EFS: p<2e-10). MethScore and MethScore-MVA proved to be the most significant variables in multivariate Cox regression for both OS (p=2e-12 and p=2e-13) and EFS (p=2e-12 and p=3e-12, respectively). To validate these results, we counted MethScore and MethScore-MVA for 50 patients from the validation cohort and performed the same Cox multivariate analysis. MethScore remained highly significant for both OS and EFS (p=0.002 and p=0.004, respectively). MethScore-MVA was significant for OS (p=0.02) but not for EFS (p=0.09). Here, we present the MethScore as a novel complex characterization of predictive DNA methylation changes in patients with AML. MethScore might be used as a new surrogate marker that could enrich the currently used cytogenetic and genetic markers to refine the prognostication of newly diagnosed AML patients. This study was supported by the Ministry of Health of the Czech Republic, project for conceptual development of research organizations (00023736, IHBT). Disclosures Šálek: Amgen: Consultancy, Honoraria, Research Funding. Mayer:Celgene: Research Funding.

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First-Line Treatment with Rituximab Improves Survival of Patients with Post-Transplant Lymphoproliferative Disease (PTLD).

Blood ◽

10.1182/blood.v104.11.1406.1406 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1406-1406 ◽

Cited By ~ 7

Author(s):

E. Gonzalez-Barca ◽

E. Domingo-Domenech ◽

J. Gomez-Codina ◽

F. Capote ◽

E. Flores ◽

...

Keyword(s):

Prognostic Factors ◽

Causes Of Death ◽

Cox Regression ◽

Performance Status ◽

B Cell Lymphoma ◽

Response To Treatment ◽

Rank Test ◽

Prognostic Impact ◽

Cox Regression Analysis ◽

Disseminated Disease

Abstract Purpose: to compare the response rate and survival between patients diagnosed of PTLD and treated with front-line rituximab and those not treated with rituximab. Patients and Methods: 108 patients with PTLD have been studied from January 1996 to January 2004. Survival curves were expressed as Kaplan-Meier plots and were compared by the Log-rank test. A multivariate Cox regression analysis was performed to asses the effect of prognostic factors on survival. Results: median age was 55 years (limits: 18–73). 70% were males. The transplanted organ was: kidney 46%, liver 28%, heart 16%. Median time between transplant and PTLD was 59 months, 25% were diagnosed during the first year after the transplant. The most frequent histological subtypes were: large B-cell lymphoma 53% and polymorphic SLPT 13%. 70% were EBV +. Clinical characteristics at diagnosis were: disseminated disease: 52%, extra-nodal disease: 81%, ECOG 3 2: 43%, LDH >N: 60%, IPI 3 3: 40%. Treatments used were: reduction of immunosuppression 91%, chemotherapy 59%, rituximab 33%, antiviral 13%. Response to treatment was: CR 46%, PR 13% failure 11%, not evaluable (early deceased): 29%. With a median follow-up of 15,2 months, survival was: OS 21% and EFS 15%. Forty-six (43%) patients died. The causes of death were: lymphoma progression 15 (33%), infection 15 (33%), toxicity 16 (34%). Survival of patients treated with rituximab was significantly better than the general group: OS 76% (p=0.007) and EFS 70% (p=0.02). Among patients treated with rituximab, 8 (23%) patients died. The significant bad prognostic factors for EFS in the multivariate analysis were: disseminated disease (RR: 2, 95% IC:1,02–3,8; p=0,04), ECOG 3 2 (RR: 5, 95% IC:2,6–9,8; p=0,0001), not been treated with rituximab (RR: 3,8, 95% IC: 1,7–10; p=0,001). IPI did not have prognostic impact. Conclusions: survival of patients with PTLD is low with conventional therapy, and the main causes of death are toxicity and infections. Treatment with Rituximab significantly improves their survival. Patients with disseminated disease and bad performance status have worse prognosis. IPI is not a useful index of prognosis in patients with PTLD.

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