Prognostic Significance of Immunohistochemical Markers in Classical Hodgkin Lymphoma Response to Treatment A Study of 59 Cases.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 972-972 ◽  
Author(s):  
Danielle Canioni ◽  
Benedicte Deau ◽  
Pierre Taupin ◽  
Jacques Bosq ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
Treatment Response ◽  
Hodgkin Lymphoma ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Rank Test ◽  
Classical Hodgkin Lymphoma ◽  
High Power Field ◽  
Mixed Cellularity ◽  
P53 Expression ◽  
Immunohistochemical Markers

Abstract Classical Hodgkin lymphoma (cHL) belongs to the most curable lymphomas in adults. Some cHL however, are primary refractory to usual treatments including anthracyclins regimen. Currently, only clinical factors are considered as relevant for prognosis. In a previous study of a small cohort of patients, we showed that some immunohistochemical markers could help for predicting the treatment response of cHL. In this study, we extended the markers and increased the number of included patients. We performed a retrospective study on pre-treatment biopsy specimen of 59 patients, 18 with primary refractory cHL and 41 responders to chemotherapy and free of disease for at least 3 years. Most refractory cHL had a nodular sclerosis (NS) histological type, except one which was a mixed cellularity type. Thirty six responders had a NS type, 3 patients had a mixed cellularity type and the 2 others an interfollicular cHL. The semi-quantitative immunohistochemical study used CD20, CD3, CD30, bcl2, p53, Ki67, TiA1 and c-kit antibodies. The results were statistically evaluated using a Fisher ’s exact test or a Wilcoxon sum rank test depending on the variable studied. CD30 and Ki67 stained strongly Hodgkin (Hg) and Reed-Sternberg (RS) cells regarless the response status. In contrast, these cells expressed significantly less frequently CD20 in refractory cHL than in responders (p= 0.032) and were never stained with CD3. P53 and bcl2 had a significantly higher expression on Hg or RS cells in refractory cHL (median = 63% & 51%) compared to responders (median = 40% & 12%) (p=0.004 & p=0.015 respectively). The cytotoxic marker TiA1 stained significant higher number of small lymphocytes in refractory cHL (median=42.5 per high power field (hpf)) compared to responders (median= 21 per hpf) (p= 0.0006). C-kit antibody was negative in Hg or RS cells but stained significant more mastocytes in refractory cHL (median=9 per hpf) comparing to responders (median=3.8 per hpf) (p= 0.001). These results indicate that immunohistochemical markers are useful in cHL and should be used in association with clinical parameters for predict the cHL treatment response. The prognostic significance of CD20 expression in cHL is controversial but in this study seems predictive of a better treatment response and is merely a marker of different gene expression program that may be associated with a more favorable outcome. A high bcl2 and p53 expression in refractory cHL supports the notion that an intact apoptosis cascade is essential for cell killing effect of chemotherapy. The increasing of TiA1 and c-kit positive cells raises the importance of the environmental non-neoplastic cells in cHL and suggests that targeted therapy against mast cells could improve prognosis of refractory cHL.

Clinical and biological implication of defective p53 pathway in multiple myeloma (MM)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17516-17516
Author(s):  
W. J. Chng ◽  
T. Price-Troska ◽  
S. Van Wier ◽  
S. Jacobus ◽  
E. Blood ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Electrophoretic Pattern ◽  
P53 Mutation ◽  
Response To Treatment ◽  
Rank Test ◽  
Allelic Loss ◽  
Similar Response ◽  
Newly Diagnosed ◽  
P53 Mutations ◽  
P53 Expression

17516 Background: The p53 tumor suppressor is commonly inactivated by mutations. Even in tumors without mutations, there are defects in the response to p53 activation. In MM, the prognostic significance of p53 mutation is unknown, while there has been no systematic study of p53 function. We seek to address these issues in this study. Methods: p53 mutation was studied by conformation sensitive gel electrophoresis with primers encompassing exons 1 to 10 followed by sequencing of DNA fragments with altered electrophoretic pattern in newly diagnosed MM patients entered into ECOG E9486 trial where patients were randomized to receive variations of melphalan-based conventional chemotherapy (VBMCP). Fisher’s exact tests were used to compare variables between patients. Kaplan-Meier survival curves were compared using the log-rank test. To investigate p53 function, we analyzed the expression of p53, and 3 of its transcriptional targets, APAF1, p21 and MDM2, in a separate cohort of 15 normal plasma cells (PC), 14 MGUS, 13 smoldering myeloma (SMM) and 101 MM (73 new and 28 relapsed) from the Mayo Clinic who had gene expression profiling performed on the Affymetrix U133A chip (Santa Clara, Ca). Results: Two hundred and sixty-eight patients had enough materials for study and were included in the analysis. The prevalence of p53 mutation was 3% (n = 9). Five of the 9 patients (56%, p = 0.001) with mutations also had p53 deletion (studied by fluorescent in-situ hybridization) resulting in bi-allelic loss of p53. Soft tissue plasmacytomas (37% v 7%, p = 0.018), and among the common translocations, t(4;14) and t(14;16) (50% v 18%) were more common in patients with p53 mutations. Despite similar response to treatment, those with p53 mutation had very short OS (16.7 v 41.4 months, p < 0.001). There was induction of p53 expression in MGUS and SMM with concurrent induction of APAF1, p21 and MDM2 whereas loss of this pattern was frequent in MM (45% in new MM and 60% in relapse MM compared to 15% in MGUS/SMM (p = 0.03)). Conclusions: p53 mutations are relatively rare in newly diagnosed MM patients but portend a short survival. However, functional abnormalities of p53 are prevalent and may be important in progression from MGUS/SMM to MM. [Table: see text]

Immunohistochemical Markers Can Be of Predictive Value in Hodgkin’s Lymphoma Response to Treatment. A Preliminary Study of 23 Cases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3123-3123
Author(s):  
Danielle Canioni ◽  
Benedicte Deau ◽  
Pierre Taupin ◽  
Richard Delarue ◽  
Viorel Vasiliu ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Residual Disease ◽  
Response To Therapy ◽  
Histological Type ◽  
Hodgkin's Lymphoma ◽  
Response To Treatment ◽  
Rank Test ◽  
High Power Field ◽  
Neoplastic Cells ◽  
Immunohistochemical Markers

Abstract Hodgkin’s lymphoma (HL) belongs to the most curable tumor diseases in adults and about 80% of patients can be cured with modern treatment strategies. However, some HL are primary refractory to usual treatments including a first line of anthracyclins based regimen and have more than 50% of residual disease after treatment. Currently, clinical parameters are considered as main relevant factors for prognosis. Herein, in order to predict value of some other factors on treatment response, we evaluate immunohistochemical markers of apoptosis, proliferation and of environmental non neoplastic cells in HL. A retrospective study was performed on pre-treatment biopsy specimen of 23 patients presenting with HL treated with the same anthracyclin based regimen, 8 primary refractory HL (non responders or relapse occurring within one year) and 15 good responders (free of disease for 2 or 3 years) to chemotherapy. These patients ranged in age from 23 to 52 years old (median= 36.5 years) for refractory HL and from 21 to 75 years old (median= 37.9 years) for good responders (n.s). All refractory HL, except one for whom histological type could not be defined because of a too small biopsy, had a nodular sclerosis (NS) histological type. The histological type was NS in 13 responding patients and mixed cellularity for the 2 others (n.s). The semi-quantitative immunohistochemical study used bcl2, p53, Ki67, TiA1 and c-kit antibodies. The results were statistically evaluated using a Wilcoxon sum rank test. Ki67 was strongly expressed on Hodgkin (Hg) and Reed-Sternberg (RS) cells whatever patients were refractory or responders to chemotherapy. By contrast, p53 and bcl2 had a significantly higher expression on Hg or RS cells in refractory patients (median= 90%&60%) compared to responding HL (median= 42.5 & 8%)( p=0.0001 & p=0.026 respectively). The cytotoxic marker TiA1 stained a significantly higher number of small lymphocytes in refractory HL (median= 53 per high power field (hpf)) compared to responding patients (median= 24/hpf)(p=0.0003). C-kit antibody was negative on Hg or RS cells but stained significantly more mastocytes in refractory HL (median= 13/hpf) comparing to responders (median= 3.8/hpf) (p=0.001). These results indicate that some immunohistochemical markers may be useful for predicting the response to therapy of HL. A high expression of bcl2 and p53 in refractory HL supports the notion that an intact apoptosis cascade is essential for killing effect of chemotherapy. The increase of TiA1 and c-kit positive cells emphasizes the importance of the environmental non neoplastic cells in HL. A larger study is mandatory to confirm these preliminary results.

Regulatory T Lymphocytes and Tumor-Associated Macrophages Have No Impact On Treatment Response and Survival in Brazilian Patients with Classical Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4777-4777
Author(s):  
Mariane Cristina Gennari Assis ◽  
Antonio H. F. M. Campos ◽  
José Salvador Rodrigues de Oliveira ◽  
Fernando A Soares ◽  
Joyce M. K. Silva ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Treatment Response ◽  
Hodgkin Lymphoma ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Public Hospitals ◽  
Response To Treatment ◽  
Classical Hodgkin Lymphoma ◽  
Tumor Associated Macrophages ◽  
Different Populations

Abstract Abstract 4777 Understanding the mechanisms of how tumor microenvironment of classical Hodgkin lymphoma (cHL) fosters immune privilege and survival of Hodgkin-Reed-Sternberg (HRS) cells is crucial for the development of new biomarkers and therapy strategies. Recently, infiltrating regulatory T CD4+CD25+FOXP3+ lymphocytes (Tregs) and tumor-associated macrophages CD68+ (TAMs) have been shown to play a role in HRS immune evasion, disease progression and survival. However, data arising from studies of different populations of cHL patients are conflicting. Purpose: In this study, we evaluated the importance of infiltrating Tregs and TAMs in a subset of 130 cHL patients treated in public hospitals in southeast Brazil and correlated these findings with Epstein-Barr virus (EBV) presence in HRS cells. Material and Methods: Tissue microarrays were constructed using diagnostic biopsies available in 130 patients and stained with CD4, CD8, CD25, FOXP3, CD15, CD30, CD68 e LMP1. Quantification of TAMs and Tregs was performed using automated slide scanning and image analysis (Aperio ScanScope XT Slide Scanner and Aperio ImageScope Software with Aperio Positive Pixel Count Sample Macro algorithm). Immunohistochemical scoring ranged from 1 to 4 for the antibodies tested, with higher scores indicating a greater proportion of positive cells. For Tregs and TAMs quantification, score 1 was considered negative (≤ 25 % of Tregs or TAMs) and scores 2, 3, and 4 (more than 25 % of positive cells) were considered positive. All patients underwent similar chemotherapy protocols. For the present study, only cHL patients whose histology could be confirmed and EBV-association established were studied. Results: From the 130 cHL patients selected for this study, 56 (43%) were classified as EBV related and 74 (57%) EBV non-related cHL. The expression of Tregs (CD4/CD25/FOXP3) was more common in the EBV related cHL group (p=0.02). TAMs did not correlate with EBV presence in HRS cells. Response to treatment, either complete response or partial response, and relapse rate were independent of Tregs and TAMs quantification and EBV status. Increased Tregs and TAMs in the tumor microenvironment did not influence event-free survival (EFS) and overall survival (OS). For further analysis, we stratified our patients into 4 groups, according to Tregs and TAMs quantification and EBV status and we still did not find any difference on EFS and OS. Additionally, stratified survival analysis according to age, stage and IPS-risk group did not identify any impact of Tregs and TAMs quantification on EFS and OS. Conclusion: This study demonstrates that increased Tregs and TAMs in the tumor microenvironment of cHL patients neither correlate with treatment response nor survival. Additionally, increased Tregs correlated with EBV presence in HRS cells. It is well known that the incidence of EBV-related cHL in developing countries is different from that in developed ones, as well as the severity of the disease at presentation, with advanced disease being more common at diagnosis. Our results, although different from those recently published, probably reflect the reality of the Brazilian population enrolled in the public health system, highlighting the importance of studying the same disease and their potential biomarkers within different populations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic Significance of New Immunohistochemical Markers in Refractory Classical Hodgkin Lymphoma: A Study of 59 Cases

PLoS ONE ◽  
2009 ◽  
Vol 4 (7) ◽  
pp. e6341 ◽  
Author(s):  
Danielle Canioni ◽  
Bénédicte Deau-Fischer ◽  
Pierre Taupin ◽  
Vincent Ribrag ◽  
Richard Delarue ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Prognostic Significance ◽  
Classical Hodgkin Lymphoma ◽  
Immunohistochemical Markers

scholarly journals Evaluation of Prognostic and Predictive Significance of Circulating MicroRNAs in Ovarian Cancer Patients

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ann Rita Halvorsen ◽  
Gunnar Kristensen ◽  
Andy Embleton ◽  
Cybil Adusei ◽  
Maria Pilar Barretina-Ginesta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Rank Test ◽  
Specific Marker ◽  
High Grade ◽  
Standard Chemotherapy ◽  
Validation Set ◽  
Serous Tumors

Ovarian cancer patients are recognized with poor prognosis. This study aimed to identify microRNAs in plasma for predicting response to treatment and outcome. We have investigated microRNAs in plasma from ovarian cancer patients enrolled in a large multicenter study (ICON7), investigating the effect of adding bevacizumab to standard chemotherapy in patients diagnosed with epithelial ovarian cancer. Patients with different histology, grade, and FIGO stages were included (n=207) in this study. Screening of 754 unique microRNAs was performed in the discovery phase (n=91) using TaqMan Low Density Arrays. The results were validated using single assays and RT-qPCR. Low levels of miR-200b, miR-1274A (tRNALys5), and miR-141 were significantly associated with better survival, confirmed with log-rank test in the validation set. The level of miR-1274A (tRNALys5) correlated with outcome was especially pronounced in the high-grade serous tumors. Interestingly, low level of miR-200c was associated with 5-month prolongation of PFS when treated with bevacizumab compared to standard chemotherapy. We found prognostic significance of miR-200b, miR-141, and miR-1274A (tRNALys5) in all histological types, where miR-1274A (tRNALys5) may be a specific marker in high-grade serous tumors. The level of miR-200c may be predictive of effect of treatment with bevacizumab. However, this needs further validation.

scholarly journals Expression of heat shock proteins in classical Hodgkin lymphoma: correlation with apoptotic pathways and prognostic significance

2011 ◽  
Vol 58 (7) ◽  
pp. 1072-1080 ◽  
Author(s):  
Almudena Santón ◽  
Mónica García-Cosío ◽  
Eva Cristóbal ◽  
Alejandro Pascual ◽  
Alfonso Muriel ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Hodgkin Lymphoma ◽  
Prognostic Significance ◽  
Classical Hodgkin Lymphoma ◽  
Apoptotic Pathways ◽  
Shock Proteins

scholarly journals Tumor Microenvironment in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma before and after Anti-PD-1 Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Artem A. Gusak ◽  
Kirill V. Lepik ◽  
Natalia B. Mikhailova ◽  
Elena Kondakova ◽  
Yuri R. Zalaylov ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Observational Studies ◽  
Principal Investigator ◽  
Immune Checkpoints ◽  
Rank Test ◽  
Classical Hodgkin Lymphoma ◽  
Significance Level ◽  
Cell Counts ◽  
Before And After

Background.Tumor tissue in classical Hodgkin Lymphoma (cHL) contains 1-10% malignant Hodgkin/Reed-Sternberg cells and a significant number of immune cells in the tumor microenvironment that are characterized by expression of inhibitory molecules (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT). Despite overall effectiveness of anti-PD-1 treatment many patients still have relapsed or refractory (r/r) disease, therefore the search for predictive/prognostic biomarkers in patients on immunotherapy is highly demanded. Materials and methods.The study included 39 primary tumor specimens from patients with r/r cHL obtained before starting the treatment with nivolumab (primary biopsies). Specimens from 11 patients were studied before and after treatment (sequential biopsies). Treatment response was evaluated by PET-CT according to LYRIC criteria. Immunohistochemical staining for CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT was performed with an automated staining system (Bond III; Leica Biosystems). The slides were scanned with Aperio ScanScope XT (AperioTechnologies Inc.) and were analyzed with ImageScope Analysis software (Aperio Technologies) и Qupath (https://qupath.github.io). We explored progression-free survival (PFS) depending on the proportion of cells positive for CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT in the tumor microenvironment and analyzed the changes of these parameters between primary and sequential biopsies after treatment with nivolumab. Statistical analysis was performed using SPSS software (v.23). Data on sequential biopsies were analyzed with the Wilcoxon signed-rank test. PFS was calculated with the Kaplan-Meier method. The significance level was p ≤ 0.05. Results.A significant correlation was found in primary biopsies group between the value of CD163 and CTLA-4 (correlation coefficient -0,62, p &lt; 0.05). There was no significant association between PFS and proportion of cells positive for CD68, PD-1, TIM-3, CTLA-4, TIGIT, LAG-3 in primary biopsies group. ROC analysis allowed to establish a 9% cut-off value of CD163 expression, dividing these patients into subgroups of CD163high and CD163low. In the CD163low group, the two-year PFS was 19,1% (95% CI 6%-37,7%) with a median PFS of 8,8 months (95% CI 5,7-12) and in the CD163high group - 53,8% (95% CI 28,4%-73,7%) with a median of 24,8 months (95% CI 18,8 - 39,2). In sequential biopsies, a statistically significant increase in numbers of PD-1+ and TIGIT+ T-cells and depletion of CD68+ and CD163+ cells was observed compared to corresponding cell counts in primary biopsies (median PD-1 - 3% vs 10%; median TIGIT - 10% vs 14%; median CD68 - 10% vs 7%; median CD163- 8% vs 3,5%; р &lt;0,05). Conclusion.A comprehensive analysis of expression of CD68, CD163, LAG-3, TIGIT, CTLA4, TIM-3, PD-1 was performed in patients with r/r cHL before and after treatment with nivolumab. Significant association was found between the expression of CD163 and CTLA4. The results of the study indicate inferior PFS among patients with low expression (&lt;9%) of CD163 in lymph node samples before immunotherapy. Biopsies taken after treatment with nivolumab showed a statistically significant increase in the number of PD-1+ and TIGIT+ cells and a decrease in the number of CD68+ and CD163+ cells compared with data from primary biopsies. The results of the study may contribute to our knowledge regarding biology of classical Hodgkin lymphoma and the mechanisms of resistance to therapy with immune checkpoints inhibitors. This study was supported by BMS research grant CA209-8EG Disclosures Ionova: Takeda:Other: principal investigator of the observational studies sponsored by Takeda;BMS:Other: principal investigator of the observational studies sponsored by BMS.

scholarly journals MicroRNA signatures and treatment response in patients with advanced classical Hodgkin lymphoma

2013 ◽  
Vol 162 (3) ◽  
pp. 336-347 ◽  
Author(s):  
Beatriz Sánchez-Espiridión ◽  
Ana M. Martín-Moreno ◽  
Carlos Montalbán ◽  
Vianihuini Figueroa ◽  
Francisco Vega ◽  
...  
Keyword(s):  
Treatment Response ◽  
Hodgkin Lymphoma ◽  
Classical Hodgkin Lymphoma

scholarly journals The Multi-biomarker Disease Activity test for assessing response to treatment strategies using methotrexate with or without prednisone in the CAMERA-II Trial

2020 ◽  
Author(s):  
Maud Jurgens ◽  
Mary Safy-Khan ◽  
Maria de Hair ◽  
Johannes Bijlsma ◽  
Paco Welsing ◽  
...  
Keyword(s):  
Disease Activity ◽  
Treatment Response ◽  
Treatment Strategies ◽  
Response To Treatment ◽  
Rank Test ◽  
Treat To Target ◽  
Similar Response ◽  
Gradual Improvement ◽  
Signed Rank Test ◽  
Response Profiles

Abstract ObjectivesThe CAMERA-II trial compared two tight-control, treat-to-target strategies, initiating methotrexate with prednisone (MTX+pred) or MTX with placebo (MTX+plac), in early RA-patients. The multi-biomarker disease activity (MBDA) blood test objectively measures RA disease activity with a score of 1−100. In CAMERA-II, response profiles of the MBDA score, its individual biomarkers and DAS28 were assessed.MethodsWe evaluated 92 patients from CAMERA-II of whom clinical data and serum for MBDA testing at baseline and ≥1 timepoint from months 1, 2, 3, 4, 5, 6, 9 or 12 were available. Changes (∆) from baseline for DAS28 and MBDA score and comparisons of ∆DAS28 and ∆MBDA score over time within the MTX+pred versus the MTX+plac strategy, were tested for significance with t-tests. Changes in biomarker concentration from baseline to months 1−5 were tested with Wilcoxon signed rank test and tested for difference between treatment arms by Mann-Whitney U test. ResultsMBDA and DAS28 showed similar response profiles, with gradual improvement over the first 6 months in the MTX+plac group, and in the MTX+pred group faster improvement during month 1, followed by gradual improvement. The 12 MBDA biomarkers could be grouped into 4 categories of response profiles, with significant responses for 4 biomarkers during the MTX+plac strategy and 9 biomarkers during the MTX+pred strategy.ConclusionsMBDA tracked treatment response in CAMERA-II similarly to DAS28. More individual MBDA biomarkers tracked treatment response of MTX+pred than of MTX+plac. Four response profiles could be observed.

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