Analysis by TeloView® Technology Predicts the Response of Hodgkin’s Lymphoma to First-Line ABVD Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Patient Information
2.2. Tissue Specimens
2.3. H&E and CD30 IHC
2.4. Quantitative 3D Telomere Co-Immuno-FISH Assay
2.5. 3D Image Acquisition and Processing
2.6. TeloView® Analysis
- (a)
- Nuclear volume: Nuclear volume within one 5 μm thin nuclear section of H-cells or RS-cells is calculated according to the 3D nuclear DAPI staining, as previously described [52]. Contrary to whole cell preparations (cells or cell lines), where the nuclei can be visualized with their entire volumes and z-stack analysis along the z-direction over 15 μm allows the calculation of the entire nuclear volume, in tissue sections the nuclear volume analysis is limited to 5 μm nuclear segments (as used as a standard for histopathologic diagnosis) along the z-direction. Deparaffinized tissue slides of 10 and 15 μm thickness are technically unsatisfactory for Q-FISH analysis. Thus, the nuclear volume represents about 30–50% of the total nuclear volume of H-cells (with a nuclear diameter of about 10–15 μm) and about 15–25% of the total nuclear volume of RS-cells (diameter of two up to several nuclei measures about 20–40 μm).
- (b)
- Telomere number: The sum of all very small, small, mid-sized, and large telomeres and aggregates identified within one 5 μm thin segmental nuclear section of an H-cell or RS-cell.
- (c)
- Telomere intensity: The sum of intensities of all very small, small, mid-sized, and large telomeres and aggregates identified within one 5 μm thin segmental nuclear section of an H-cell or RS-cell (viz. ∑ 2 × 15,000 units > ∑ 7 × 4000 units).
- (d)
- Mean telomere intensity: Mean telomere relative fluorescent intensity (size) of all telomeres within a given segmental volume.
- (e)
- Telomere size: Telomeres with a relative fluorescent intensity (x-axis) ranging from 0 to 5000 units are classified as very small (t-stumps), with an intensity ranging from 5000 to 15,000 units as small, with an intensity from 15,000 to 30,000 units as mid-sized, and with an intensity > 30,000 units as large [45].
- (f)
- Telomere aggregates: Telomere aggregates are defined as clusters of telomeres that are found in close association and cannot be further resolved as separate entities at an optical resolution limit of 200 nm [53].
2.7. Statistical Analysis
3. Results
3.1. Cohort Clinical Data and Outcome
3.2. Target cHL Tumor Cell Identification and Confirmation
3.3. 3D Telomere Profiling of cHL Patients with RR Versus CR for Minimally 5 Years
3.4. Regression Analysis and Predictive Modeling
3.5. Predictive Modeling
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Inclusion Criteria | Exclusion Criteria |
---|---|
First time diagnosed with cHL a | Age < 18 and >80 years old |
Availability of lymph node diagnostic tissue | |
Availability of demographic and clinical follow up data | |
First line treatment with ABVD b |
Gender | Age Groups | Disease Stage (Costwold) | Response to ABVD | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Male | Female | ≥50 Years | <50 Years | I | II | III | IV | Remission ≥5 Years | Refractory or Relapse within 12 Months | |
n = 156 | 79 | 77 | 126 | 30 | 23 | 70 | 32 | 31 | 125 | 31 |
A—Remission > 5 Years (n-125) | B—Refractory/Relapse ≤ 12 Month (n = 31) | <HA + RSA> vs. <HB + RSB> | HA vs. HB | RSA vs. RSB | |||
---|---|---|---|---|---|---|---|
Telomere Parameter | HA | RSA | HB | RSB | p-Value | p-Value | p-Value |
Number of telomeres | 36 (17.8; 0.29) | 55 (36; 0.6) | 31 (14, 0.48) | 47 (31; 1.1) | 0.04 * | 0.000014 * | 0.0007 * |
Number of Aggregates | 4 (2.9; 0.05) | 7 (5.5; 0.09) | 3 (2.5; 0.08) | 6 (4.8; 0.16) | 0.034 * | 0.0026 * | 0.03 * |
Average telomere length | 2926 (1185; 39.5) | 2599 (924; 15.4) | 2788 (1132; 18.9) | 2457 (871; 29) | 0.0029 * | 0.012 * | 0.0003 * |
Nuclear Volume (μ3) | 469.31 (400.81.8; 6.68) | 718.10 (686.11; 11.43) | 440.08 (330.29; 11.00) | 702.00 (574.54; 19.15) | 0.017 * | 0.4 | 0.5 |
A/C Ratio | 3 (1.2; 0.02) | 3.6 (1.5; 0.026) | 2.8 (1.1; 0.04) | 3.4 (1.4; 0.049) | 0.078 | 0.42 | 0.08 |
Distribution of telomeres | 3813 (777; 25.8) | 4876 (1450.7; 24) | 3684 (775; 25.8) | 4740 (1428.4; 47.6) | 0.085 | 0.00016 * | 0.1 |
% of t-stumps | 42 (14; 0.21) | 57 (21, 0.33) | 49 (17; 0.27) | 84 (27; 39) | 0.0012 * | 0.000011 * | 0.000077 * |
Confidence Test | TeloView Parameters Only | TeloView with Clinical Risk Factors |
---|---|---|
Likelihood Ratio | 0.0003 | <0.0001 |
Score | 0.0009 | 0.0003 |
Wald | 0.0024 | 0.0011 |
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Knecht, H.; Johnson, N.; Bienz, M.N.; Brousset, P.; Memeo, L.; Shifrin, Y.; Alikhah, A.; Louis, S.F.; Mai, S. Analysis by TeloView® Technology Predicts the Response of Hodgkin’s Lymphoma to First-Line ABVD Therapy. Cancers 2024, 16, 2816. https://doi.org/10.3390/cancers16162816
Knecht H, Johnson N, Bienz MN, Brousset P, Memeo L, Shifrin Y, Alikhah A, Louis SF, Mai S. Analysis by TeloView® Technology Predicts the Response of Hodgkin’s Lymphoma to First-Line ABVD Therapy. Cancers. 2024; 16(16):2816. https://doi.org/10.3390/cancers16162816
Chicago/Turabian StyleKnecht, Hans, Nathalie Johnson, Marc N. Bienz, Pierre Brousset, Lorenzo Memeo, Yulia Shifrin, Asieh Alikhah, Sherif F. Louis, and Sabine Mai. 2024. "Analysis by TeloView® Technology Predicts the Response of Hodgkin’s Lymphoma to First-Line ABVD Therapy" Cancers 16, no. 16: 2816. https://doi.org/10.3390/cancers16162816