Prevalence of Genetic Abnormalities in Patients with Multiple Myeloma and Its Clinical Relevance in a Developing Country like India

Introduction Multiple myeloma (MM) is a malignancy involving terminally differentiated plasma cells. Its incidence in India is about 0.7/1,00,000 population amounting to about 6,800 new cases a year A number of genomic aberrations are associated with MM, most of which confer prognostic significance. Cytogenetic abnormalities are a part of R-ISS score for prognostication which stratifies presence of del(17p), t(4;14) or t(14;16) as stage 3, mSMART is another risk stratification tool which divides MM into high risk and standard risk groups based on genetic aberrations. Hence it is evident that determining the genetic abnormality in MM is important. however, due to limited resources genetic testing is not routinely done and the data in the Indian population is limited. Objective: To estimate the prevalence of molecular cytogenetic abnormalities by Fluorescent in situ hybridization (FISH) analysis in patients with MM and to assess the co-relation with response to induction chemotherapy, relapse and overall survival. Material and Methods: 64 patients were included from January 2016 to December 2019 and followed up till June 2020. Interphase FISH study was performed either at diagnosis or at relapse, on bone marrow aspirate with panel of probes consisting of CKS1B (1q21-22), CDKN2C (1p32.3), D13S319 (13q14.2/13q34), IGH (14q32.33), p53 (17p13.1) and trisomy (5p15/9q22/15q22) (trisomies are considered as hyperdiploidy in this study). Plasma cell purification techniques were not applied prior to FISH analysis. Patients were divided into 2 risk groups; 1) high risk group with presence of del17p, del13q, amplification 1q, del1p and two or more aberrations with either of these and 2) standard risk group with presence of hyperdiploidy or no genetic abnormality. There was no difference in chemotherapy regimen between the 2 groups; 46 (71.8%) received bortezomib-thalidomide-dexamethasone, 10 (15.6%) received bortezomib-cyclophosphamide-dexamethasone, 2(3.1%) received bortezomib-lenalidomide-dexamethasone, 1(1.5%) received daratumumab-bortezomib-dexamethasone and 5(7.8%) received 2 drug chemotherapy. Patients who did not complete minimum follow up of 6 months either due to death or lost to follow up were excluded from the study. Institutional Ethics Committee's approval was taken. Results: Mean age of the population was 60.33 years and male to female ratio was 1.65. 46.87%, 28.13% and 25% of the study population were in the age group of ≤ 60, 61 - 65 and ≥66 years respectively. 12.3%, 43.8% and 43.8% were in R ISS stage 1, 2 and 3 respectively. FISH analysis was done on 61 out of 64 patients (remaining 3 were excluded due to hemodilute bone marrow sample). 22 (36.1%) patients had abnormal genetic aberration on FISH analysis with 10 (16.39%) having two or more abnormalities. The frequency of genetic aberrations was as follows; amplification 1q (13/61, 21.31%), del13q (9/61, 14.75%), hyperdiploidy (7/61, 11.47%), del17p (4/61, 6.55%), IgH rearrangement (3/61, 4.91%), and del1p (1/61, 1.6%). All 3 patients with IgH rearrangement had associated one or more high-risk genetic aberration and hence were included in high risk group. 31.1% of the patients were high risk and 68.9% were standard risk. The response to induction chemotherapy, incidence of relapse, time to 1st relapse and total number of relapses are shown in (table;1) and there was no significant difference between high risk and standard risk group. Overall survival in standard risk group at 2 and 5 years was 89.6% ± 5.8% and 78.6% ± 13.9% and in high risk group was 60.7% ± 13.2% and 29.5% ± 23.1% respectively (p value: 0.762). Overall survival was significantly lower in age group ≥66 years as compared to age group ≤ 60 years and 61 - 65 years (p value 0.001) and it was also significantly lower in R ISS stage 3 as compared to R ISS stage 1 and 2 (p value 0.006). Conclusion: More than one third patients of MM (36.1%) showed genetic abnormality, amplification 1q being the most frequent. Overall survival was significantly lower in older age group and R ISS stage 3 patients. Response to induction chemotherapy and relapse rate were similar in high and standard risk groups. Although overall survival was lower in high risk group, it was statistically not significant. This study highlights the importance of FISH analysis for disease stratification and prognostication which should be routinely practiced. Disclosures No relevant conflicts of interest to declare.

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Treatment Outcome of Discontinued L-Asparaginase in Children with Standard-Risk Acute Lymphoblastic Leukemia: Tokyo Children’s Cancer Study Group (TCCSG) Study L99-15.

Blood ◽

10.1182/blood.v106.11.878.878 ◽

2005 ◽

Vol 106 (11) ◽

pp. 878-878 ◽

Cited By ~ 2

Author(s):

Chitose Ogawa ◽

Akira Ohara ◽

Atsushi Manabe ◽

Ryoji Hanada ◽

Hiroyuki Takahashi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Risk Group ◽

Lymphoblastic Leukemia ◽

Risk Groups ◽

High Risk Group ◽

P Value ◽

Group A ◽

Group B ◽

Standard Risk

Abstract BACKGROUND: L-asparaginase (L-asp) is one of the key drugs in the treatment of acute lymphoblastic leukemia (ALL) in children. However, L-asp often produces severe adverse effects including anaphylaxis resulting in its discontinuation. OBJECTIVE: To evaluate retrospectively the outcome of discontinuation of L-asp in patients with ALL. PATIENTS AND METHODS: Children newly diagnosed as ALL between 1999 and 2003 were consecutively enrolled on the TCCSG L99-15 study. Risk stratification was based on the age, initial white blood cell count, immunophenotype, cytogenetics and the response to prednisolone monotherapy. Totally, 267 (35%) out of 770 children were categorized into a standard-risk group (SR), 317 (41%) into a high-risk group (HR) and 186 (24%) into a very high-risk group (HEX). Allogeneic stem cell transplantation was indicated approximately in 50% of the HEX patients. L-asp was used 9 times in the induction phase in all the risk groups. The total number of L-asp administration all through the treatment was 19 in SR, 20 in HR and at least 10 in HEX. Patients were divided into two groups in the analysis: group A patients who received at least 50% of scheduled doses of L-asp and group B patients who received less than 50%. RESULTS: Remission was obtained in 259 (97%) patients in SR, 311 (98%) in HR and 171(92%) in HEX. In the patients who achieved remission and were analyzed, 195 (83.7%) in SR, 223 (78.8%) in HR and 123 (83.7%) in HEX received all the scheduled doses of L-asp. Event-free survival (EFS) (SE) and overall survival (OS) (SE) at 5 years for all the risk groups are shown in the table. Notably, EFS in group A (92.9%) and in group B (74.1%) in SR was significantly different (p=0.025). CONCLUSION: The outcome in patients who received less than 50% of scheduled dose of L-asp was inferior to that in the patients who received more than 50% of the scheduled dose. This suggests that modification or intensification of the treatment should be considered for the patients who discontinued L-asp in SR. EFS and OS in each group Risk group EFS ± SE(%) OS ± SE(%) (No. in A /B) group A group B p value group A group B p value SR (223 /10) 92.9±2.4 74.1±16.1 0.025 97.8±1.1 88.9±10.5 0.066 HR (269 /14) 78.5±3.2 66.7±19.2 0.969 88.9±2.6 50.0±25.0 0.158 HEX (142 /5) 58.2±5.5 75.5±21.7 0.514 75.6±4.3 80.0±17.9 0.873

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The Combination of SKY92 and ISS Provides a Powerful Tool to Identify Both High Risk and Low Risk Multiple Myeloma Cases, Validation in Two Independent Cohorts

Blood ◽

10.1182/blood.v126.23.2970.2970 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2970-2970 ◽

Cited By ~ 3

Author(s):

Martin van Vliet ◽

Joske Ubels ◽

Leonie de Best ◽

Erik van Beers ◽

Pieter Sonneveld

Keyword(s):

Overall Survival ◽

High Risk ◽

Research Funding ◽

Prognostic Markers ◽

Risk Group ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Kaplan Meier ◽

Standard Risk

Abstract Introduction Multiple Myeloma (MM) is a heterogeneous disease with a strong need for robust markers for prognosis. Frequently occurring chromosomal abnormalities, such as t(4;14), gain(1q), and del(17p) etc. have some prognostic power, but lack robustness across different cohorts. Alternatively, gene expression profiling (GEP) studies have developed specific high risk signatures such as the SKY92 (EMC92, Kuiper et al. Leukemia 2012), which has shown to be a robust prognostic factor across five different clinical datasets. Moreover, studies comparing prognostic markers have indicated that the SKY92 signature outperforms all other markers for identifying high risk patients, both in single and multivariate analyses. Similarly, when assessing the prognostic value of combinations of various prognostic markers, the SKY92 combined with ISS was the top performer, and also enables detection of a low risk group (Kuiper et al. ASH 2014). Here, we present a further validation of the low and high risk groups identified by the SKY92 signature in combination with ISS on two additional cohorts of patients with diverse treatment backgrounds, containing newly diagnosed, previously treated, and relapsed/refractory MM patients. Materials and Methods The SKY92 signature was applied to two independent datasets. Firstly, the dataset from the Total Therapy 6 (TT6) trial, which is a phase 2 trial for symptomatic MM patients who have received 1 or more prior lines of treatment. The TT6 treatment regime consists of VTD-PACE induction, double transplant with Melphalan + VRD-PACE, followed by alternating VRD/VMD maintenance. Affymetrix HG-U133 Plus 2.0 chips were performed at baseline for n=55 patients, and OS was made available previously (Gene Expression Omnibus identifier: GSE57317). However, ISS was not available for this dataset. Secondly, a dataset of patients enrolled at two hospitals in the Czech Republic, and one in Slovakia (Kryukov et al. Leuk&Lymph 2013). Patients of all ages, and from first line up to seventh line of treatment were included (treatments incl Bort, Len, Dex). For n=73 patients Affymetrix Human Gene ST 1.0 array, OS (n=66), and ISS (n=58) was made available previously (ArrayExpress accession number: E-MTAB-1038). Both datasets were processed from .CEL files by MAS5 (TT6), and RMA (Czech), followed by mean variance normalization per probeset across the patients. The SKY92 was applied as previously described (Kuiper et al. Leukemia 2012), and identifies a High Risk and Standard Risk group. In conjunction with ISS, the SKY92 Standard Risk group is then further stratified into low and intermediate risk groups (Kuiper et al. ASH 2014). Kaplan-Meier plots were created, and the Cox proportional hazards model was used to calculate Hazard Ratios (HR), and associated 1-sided p-values that assess whether the SKY92 High Risk group has worse survival than SKY92 Standard Risk group (i.e. HR>1). Results Figure 1 shows the Kaplan Meier plots of the SKY92 High Risk and Standard Risk groups on the TT6 and Czech cohorts. On the TT6 dataset, the SKY92 signature identifies 11 out of 55 patients (20%) as High Risk. In both datasets, the SKY92 High Risk group has significantly worse overall survival, HR=10.3, p=7.4 * 10-6 (TT6), and HR=2.6, p=2.2 * 10-2 (Czech). In addition, the combination of SKY92 with ISS on the Czech dataset identifies a low risk group of 14 out of 61 patients (23%), with a five year overall survival estimate of 100% versus 28.7% in the SKY92 High Risk group (HR=inf). Robustness of the SKY92 signature is further demonstrated by the fact that it validates on both datasets, despite different microarray platforms being used. Conclusions The SKY92 high risk signature has been successfully validated on two independent datasets generated using different microarray platforms. In addition, on the Czech data, the low risk group (SKY92 Standard Risk combined with ISS 1) has been successfully validated. Together, this signifies the robust nature of the SKY92 signature for high and low risk prediction, across treatments, and with applicability in newly diagnosed, treated, and relapsed/refractory MM patients. Figure 1. Kaplan-Meier plots showing a significantly poorer overall survival in patients identified as SKY92 High Risk (red curves), relative to SKY92 Standard Risk, on both the TT6 (left), and Czech (middle) datasets, as well as a low risk group by SKY92 & ISS1 on the Czech dataset (green curve, right). Figure 1. Kaplan-Meier plots showing a significantly poorer overall survival in patients identified as SKY92 High Risk (red curves), relative to SKY92 Standard Risk, on both the TT6 (left), and Czech (middle) datasets, as well as a low risk group by SKY92 & ISS1 on the Czech dataset (green curve, right). Disclosures van Vliet: SkylineDx: Employment. Ubels:SkylineDx: Employment. de Best:SkylineDx: Employment. van Beers:SkylineDx: Employment. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding.

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Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.710558 ◽

2021 ◽

Vol 9 ◽

Author(s):

Chufeng Gu ◽

Xin Gu ◽

Yujie Wang ◽

Zhixian Yao ◽

Chuandi Zhou

Keyword(s):

Overall Survival ◽

High Risk ◽

Immune Cell ◽

Risk Group ◽

Staging System ◽

Risk Groups ◽

Tnm Staging ◽

High Risk Group ◽

Immune Cell Infiltration ◽

Tnm Staging System

ObjectivesUveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients.MethodsSingle-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model.ResultsHigher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p < 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy.ConclusionWe developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM.

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Pretreatment Cytogenetic Abnormalities Are Predictive of Induction Success, Cumulative Incidence of Relapse and Overall Survival in Patients >60 Years of Age with Newly Diagnosed Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v106.11.3293.3293 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3293-3293

Author(s):

Richard F. Schlenk ◽

Sabine Kayser ◽

Martina Morhardt ◽

Konstanze Döhner ◽

Hartmut Döhner ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Myeloid Leukemia ◽

Risk Group ◽

Normal Karyotype ◽

Risk Groups ◽

High Risk Group ◽

Newly Diagnosed ◽

Balanced Translocations ◽

Acute Myeloid

Abstract Purpose: Karyotype at diagnosis provides the most important prognostic information in younger adults with acute myeloid leukemia (AML). However, there are few data available looking in particular at patients (pts.) above 60 years of age. We prospectively analyzed 361 elderly pts. with newly diagnosed AML. All pts. were treated within the AMLHD98B treatment trial and received intensive induction and consolidation therapy. Pts. exhibiting a t(15;17) received an age-adjusted AIDA-regimen. Median follow-up time was 48 months. The median age was 67 years (range 60–85 years). Results: 160 pts. had a normal karyotype (44%); 48 pts. (13%) exhibited the balanced translocations t(8;21) (n=12), inv(16) (n=14), t(15;17) (n=11), or t(11q23) (n=11); in the absence of these balanced translocations, 73 pts. exhibited a single aberration, 179 pts. two aberrations, and 61 pts. a complex karyotype (≥3 aberrations; including 44 pts. with 5 or more aberrations). Analyses were normalized to the complete remission (CR) rate (52%), cumulative incidence of relapse (CIR) (77%) and overall survival (OS) (13%) after 4 years of pts. with normal karyotype. Pts. exhibiting a t(15;17) showed a significantly better CIR (29%) and OS (55%), whereas pts. with the other balanced translocations [t(8;21), inv(16)/t(16;16) and t(11q23)] did not differ from pts. with normal karyotype. The limited backward selected Cox-model for OS [t(15;17) excluded] revealed two risk groups: standard-risk [normal karyotype, t(8;21), inv(16), t(11q23), +8 and +11 in absence of a complex karyoytpe] and high-risk [all other aberrations]. The CR rates were 56% and 18%, and the OS-rates after 4 years for the standard- (n=223) and the high-risk group (n=127) were 15% and 0%, respectively. The MRC risk classification system for patients >55 years applied to our patients revealed CR- and OS-rates after 4 years of 73% and 19%, 47% and 12%, as well as 7% and 0% for the low (n=26), intermediate (n=282) and high risk groups (n=44), respectively [t(15;17) excluded]. In conclusion, our risk classification system identified a large high-risk group (36%) of elderly patients with AML who did not benefit from intensive chemotherapy.

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Identification of Differential Methylation Markers Among Cytogenetic Risk Groups of Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.1464.1464 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1464-1464

Author(s):

Min Fang ◽

Xiaoyu Qu ◽

Jerry Davison ◽

Liping Du ◽

Frederick R. Appelbaum ◽

...

Keyword(s):

High Risk ◽

Risk Group ◽

Risk Groups ◽

High Risk Group ◽

Differential Methylation ◽

The Other ◽

P Value ◽

Single Region ◽

The Right ◽

Methylation Ratio

Abstract Abstract 1464 Aberrant DNA methylation has been shown as an important mechanism in the progression from myelodysplasia (MDS) to acute myeloid leukemia (AML), leading to use of the demethylating agents, 5-azacitidine and decitabine, for treatment of both disorders. While these drugs produce responses, the ability to distinguish potential responders from potential non-responders remains limited. The purpose of this work was to bring new technology to study this problem. Recent studies demonstrated that promoter DNA methylation is not randomly distributed in AML blasts but rather is highly organized and associated with biologically distinct AML subtypes. Because cytogenetics at presentation is the most important prognostic factors in predicting response to therapy, remission duration and overall survival in AML, we aimed to identify differentially methylated genomic regions (DMR) in cytogenetically defined risk groups of AML. Published literature suggested that the new comprehensive high-throughput array-based relative methylation analysis (CHARM) has the highest sensitivity and specificity among all the array-based genome profiling methods and should be the most accurate means to identify methylation markers. It is a customized NimbleGen HD2 array of tiled 50mer-probes typically separated by 30–40 bases covering approximately 4.6 million CpG sites across the genome. This assay is highly quantitative for approximately 100,000 independent CpG sites. We performed methylation profiling with CHARM on 15 age-matched patients divided into 3 groups (n=5 in each): (1) high-risk AML, defined as patients with a complex or monosomal karyotype, inv(3)/t(3;3), t(6;9), or FLT3-ITD; (2) intermediate-risk AML, defined as patients with normal karyotype, trisomy 8, t(9;11), or others; (3) low-risk AML, defined as patients with t(8;21) or inv(16). Five age-matched normal individuals served as control. Randomly fractionated DNA was divided into two equal portions with and without McrBC treatment, which cleaves methylated DNA, then size-fractionated, purified and subject to whole-genome amplification prior to hybridization with the CHARM array. Data analysis was performed with R and Bioconductor. AML patients showed a very strong hypermethylation signature as compared with the normal control blood. A unique set of DMRs was identified which distinguishes between any two risk groups. The number of DMRs and those with p -values < 0.01 are shown in Table 1. There were fewer methylation discriminators between low- and mid-risk groups than between high-risk and the other risk groups. Figure 1 shows the comparison between high-risk group and other risk groups highlighting the 12 top DMRs with lowest p -values. In silico validation of the DMRs identified by CHARM verified previously reported aberrant hypermethylation of tumor suppressor genes like p15CDKN2B, discriminating normal from AML patients, CDH1 promoter hypermethylation in high-risk AML compared with mid-risk AML, and HOXB3 hypomethylation in mid-risk AML compared with both low-risk and high-risk AML, etc. Technical validation using quantitative bisulfite pyrosequencing on 8 genes, including DCC, DUOX2, NEFL, and PITX1, demonstrated an 87.5% concordant rate with CHARM. Testing of additional AML samples with validated markers are underway to confirm the top DMRs identified, which may serve as useful biomarkers to predict response to azacitidine and decitabine.Table 1Number of DMRsNumber with p-value < 0.01Normal blood VS at risk3768311Low-risk VS mid-risk156530Low-risk VS high-risk247573Mid-risk VS high-risk2651107Figure 1.Results from the CHARM analysis on AML patients stratified by cytogenetic risk, highlighting comparison between the high-risk and other risk groups. The top twelve differentially methylated regions ( DMRs) with p -value < 0.01 are shown. Box-and-whisker plots to the left of the dashed vertical line in each panel present the log2 methylation ratio of the high-risk group and the other two risk groups combined, in a single region of differential methylation. To the right of the dashed line the high-risk group is compared with each of the other groups. Each panel's header text identifies the genomic region.Figure 1. Results from the CHARM analysis on AML patients stratified by cytogenetic risk, highlighting comparison between the high-risk and other risk groups. The top twelve differentially methylated regions ( DMRs) with p -value < 0.01 are shown. Box-and-whisker plots to the left of the dashed vertical line in each panel present the log2 methylation ratio of the high-risk group and the other two risk groups combined, in a single region of differential methylation. To the right of the dashed line the high-risk group is compared with each of the other groups. Each panel's header text identifies the genomic region. Disclosures: No relevant conflicts of interest to declare.

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A Novel Ferroptosis-related Gene Signature for Prognosis Prediction in Glioma

10.21203/rs.3.rs-829477/v1 ◽

2021 ◽

Author(s):

Tian Lan ◽

Die Wu ◽

Wei Quan ◽

Donghu Yu ◽

Sheng Li ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Cox Regression ◽

Risk Group ◽

Risk Groups ◽

Gene Signature ◽

High Risk Group ◽

Differential Analysis ◽

Related Gene ◽

Cox Regression Analysis

Abstract Background: Glioma is a fatal brain tumor characterized by invasive nature, rapidly proliferation and tumor recurrence. Despite aggressive surgical resection followed by concurrent radiotherapy and chemotherapy, the overall survival (OS) of Glioma patients remains poor. Ferroptosis is a unique modality to regulate programmed cell death and associated with multiple steps of tumorigenesis of a variety of tumors.Methods: In this study, ferroptosis-related genes model was identified by differential analysis and Cox regression analysis. GO, KEGG and GSVA analysis were used to detect the potential biological functions and signaling pathway. The infiltration of immune cells was quantified by Cibersort.Results: The patients’ samples are stratified into two risk groups based on 4-gene signature. High-risk group has poorer overall survival. The results of functional analysis indicated that the extracellular matrix-related biologic functions and pathways were enriched in high-risk group, and that the infiltration of immunocytes is different in two groups.Conclusion: In summary, a novel ferroptosis-related gene signature can be used for prognostic prediction in glioma. The filtered genes related to ferroptosis in clinical could be a potential extra method to assess glioma patients’ prognosis and therapeutic.

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Identification of Eight Surface Molecules with Survival Predictive Power in B Cell Chronic Lymphocytic Leukemia (B-CLL): A Proposal for a Scoring System.

Blood ◽

10.1182/blood.v104.11.2797.2797 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2797-2797

Author(s):

Valter Gattei ◽

Paolo Sonego ◽

Stefania Russo ◽

Riccardo Bomben ◽

Michele Dal Bo ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Predictive Power ◽

Risk Group ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Z Score ◽

Surface Molecules

Abstract Studies of gene expression profiling of B-CLL cells revealed a phenotype related to experienced B cells, although only a subset of B-CLLs has IgVH mutations. With the aim to identify the immunophenotypic profile associated with a different prognosis, we investigated by flow cytometry the expression of 36 surface molecules (cell-adhesion molecules, integrins, complement activity regulators, myeloid, T and B markers) in 125 B-CLLs, all characterized for IgVH mutations and survival. To recognize the surface molecules with survival predictive power, univariate Cox proportional-hazards analysis was applied to antigen expression values with overall survival as dependent variable. Once identified the antigens whose expression correlated with a z score of ±2.5 (P<0.005) or greater, the maximally selected log-rank statistics were applied to define the optimal cut-off values yielding the best separation of two subgroups with different survival. According to this approach, the following eight antigens were selected (cut-off values in parenthesis): CD55 (30%), CD62L (30%), CD49c (40%), CD11c (20%), CD54 (50%), CD25 (15%), CD79b (65%), CD38 (30%). The first six antigens had negative z score and therefore were identified as favorable prognosticators, while CD79b and CD38 had positive z score, hence were associated with shorter overall survival (negative prognosticators). To build-up a scoring system, we assigned score “1” to each positive prognosticator when its expression was above the designated cut-off (score “0” if below), and score “0” to each negative prognosticator when its expression was above the cut-off (score “1” if below). A total score ranging from 0 to 8 points was therefore obtained in 102/125 cases in which the expression of all the eight markers was available. Three risk groups were identified: i) high-risk (29 cases), score 0–3; ii) intermediate-risk (38 cases), score 4–6; iii) low-risk (35 cases), score 7–8. These three groups differed greatly for survival probabilities (p=5x10–13 by the log-rank test). All patients belonging to the low-risk group were alive throughout the follow-up duration, whereas mean survivals for intermediate- and high-risk groups were 173 months (p=0.032) and 61 months (p=2.0x10–9), respectively. Several relationship between risk groups and other variables was studied: i) patients included in high- and intermediate-risk groups had the same male to female (M:F) ratio (1.4), while the M:F ratio of patients included in low-risk group (group 3) was lower (0.7); ii) Rai’s stage distribution was comparable in the three groups, with the exception of stage “0”, which was significantly less frequent in the high-risk group (p=0.04); iii) if % IgVH mutations (2% cut-off) was checked, mutated to unmutated (M:UM) ratios were 4.8, 2.6 and 0.8 in low-, intermediate- and high-risk groups, respectively (p=0.006); iv) as compared to high-risk group, low- and intermediate-risk groups were characterized by a higher number of B-CLL cases with a IgVH mutational status consistent with antigen-driven selection (20/24 and 17/26 vs. 7/13). In conclusion, the present study introduces a novel predictive tool based on the expression of eight surface molecules, easily investigable, which can stratifies populations of B-CLL patients in three distinct risk categories.

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Establishment of an immune-related gene pairs model to predict colon adenocarcinoma prognosis

10.21203/rs.3.rs-35654/v2 ◽

2020 ◽

Author(s):

Jihang Luo ◽

Puyu Liu ◽

Leibo Wang ◽

Yi Huang ◽

Yuanyan Wang ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Risk Group ◽

Colon Adenocarcinoma ◽

Risk Groups ◽

High Risk Group ◽

Related Gene ◽

Immune Genes ◽

Gene Pairs ◽

Immune Related Gene

Abstract Background Colon cancer is the most common type of gastrointestinal cancer and has high morbidity and mortality. Colon adenocarcinoma(COAD) is the main pathological type of colon cancer. There is a lot of evidence describing the correlation between the prognosis of COAD and the immune system. The objective of the current study was the development of a robust prognostic immune-related gene pairs (IRGPs) model for estimating overall survival of COAD. Methods The gene expression profiles and clinical information of patients with colon adenocarcinoma come from TCGA and GEO databases and are divided into training and validation cohorts. Immune genes were selected which show significantly association with prognosis. Results Among 1647 immune genes, a 17 IRGPs model was built which was significantly associated with OS in the training cohort. In the training and validation data set, the IRGPs model divided patients into high-risk groups and low-risk groups, and the prognosis of the high-risk group was significantly worse( P <0.001). Univariate and multivariate Cox proportional hazard analysis confirmed the feasibility of this model. Functional analysis confirmed that multiple tumor progression and stem cell growth-related pathways in high-risk groups were up-regulated. T cells regulatory and Macrophage M0 were significantly highly expressed in the high-risk group. Conclusion We successfully constructed an IRGPs model that can predict the prognosis of COAD, which provides new insights into the treatment strategy of COAD.

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Retrospective Comparative Analysis of POPF Using Fistula Risk Score According to Pancreaticoenterostomy Method

International Surgery ◽

10.9738/intsurg-d-20-00033.1 ◽

2021 ◽

Vol 105 (1-3) ◽

pp. 559-563

Author(s):

Seungmin Lee ◽

Kwang Yeol Paik

Keyword(s):

High Risk ◽

Pancreatic Fistula ◽

Risk Score ◽

Risk Group ◽

Risk Groups ◽

High Risk Group ◽

Postoperative Pancreatic Fistula ◽

Clinical Risk Score ◽

Reconstructive Methods ◽

Fistula Risk Score

Background The aim of this study is to examine whether pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ) is the better reconstructive method to reduce postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) according to the fistula risk. Methods An institutional database was reviewed for patients undergoing PD between January 2008 and August 2019. A total of 159 patients were stratified into 4 groups according to the Clinical Risk Score-Pancreatic Fistula. POPF according to 4 risk groups was compared between PJ and PG. Results Of the 159 patients, 82 underwent PG (51.6%) and 77 underwent PJ (48.4%) reconstruction. POPF rate was 17.1% (n = 14) in the PG group and 12.9% (n = 10) in the PJ group (P = 0.51). POPF rates were not different in intermediate, low, and negligible risks between 2 reconstructive methods. In the high-risk group (n = 47), there were 4 POPFs (22.2%) in PJ group and 9 (31.0%) in the PG group, respectively (P = 0.74). Conclusion In PD, there was no superior method of reconstruction with regard to POPF, even in high-risk glands.

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Language Development in 2-Year-Old Normal and Risk Infants

PEDIATRICS ◽

10.1542/peds.59.6.982 ◽

1977 ◽

Vol 59 (6) ◽

pp. 982-986

Author(s):

Judith Zarin-Ackerman ◽

Michael Lewis ◽

John M. Driscoll

Keyword(s):

High Risk ◽

Risk Group ◽

Birth Asphyxia ◽

Normal Subjects ◽

High Risk Group ◽

Age Group ◽

Language Tests ◽

Group A ◽

Language Measures ◽

Early Trauma

A variety of language measures was obtained on two groups of 2-year-old infants matched for social class but differing in terms of birth conditions. One group, a high risk group, contained infants who suffered from RDS, birth asphyxia, hypercalcemia, and hyperglycemia while another group consisted of normal infants. The results of the language tests revealed that the high risk group showed poorer performance than the normal subjects. Other tests of perceptual-cognitive development revealed little difference between the groups. The data suggest that the assessment of early trauma needs to employ a variety of measures, especially those which are related to the unfolding skills appropriate for the particular age group studied.

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