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• W3103455821 abstract "Mycosis fungoides (MF) is the commonest cutaneous T-cell lymphoma (CTCL). MF is a lifelong, slow-growing CD4+ neoplasm, which may evolve over years from skin patches to plaques and tumors (Swerdlow et al., 2016Swerdlow S.H. Campo E. Pileri S.A. Harris N.L. Stein H. Siebert R. et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood. 2016; 127: 2375-2390Crossref PubMed Scopus (4071) Google Scholar; Willemze et al., 2019Willemze R. Cerroni L. Kempf W. Berti E. Facchetti F. Swerdlow S.H. et al.The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.Blood. 2019; 133: 1703-1714Crossref PubMed Scopus (215) Google Scholar). Outcomes are good in the early stages of the disease with a survival comparable with that of an age-matched cohort (Agar et al., 2010Agar N.S. Wedgeworth E. Crichton S. Mitchell T.J. Cox M. Ferreira S. et al.Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.J Clin Oncol. 2010; 28: 4730-4739Crossref PubMed Scopus (543) Google Scholar). In later stages, defined as tumors and extracutaneous dissemination, the prognosis is poor owing to organ involvement and immune suppression. Sézary syndrome (SS) is defined by the triad of erythroderma, generalized lymphadenopathy, and a circulating clone of T cells with cerebriform nuclei (Sézary cells). SS accounts for <5% of CTCLs. It is closely related to MF; however, they are considered as separate entities on the basis of clinical presentation, behavior, and the cell of origin. The 5-year overall survival rate for SS is <30% (Swerdlow et al., 2016Swerdlow S.H. Campo E. Pileri S.A. Harris N.L. Stein H. Siebert R. et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood. 2016; 127: 2375-2390Crossref PubMed Scopus (4071) Google Scholar). Research on factors that lead MF cells to become more aggressive to transform into leukemic Sézary cells has shown that cytokines such as IL-15 and mutations involving oncogenic signaling pathways (MYC, PTEN, Jak-3/signal transducer and activator of transcription, and p53) play a role in CTCL pathogenesis (Agar et al., 2010Agar N.S. Wedgeworth E. Crichton S. Mitchell T.J. Cox M. Ferreira S. et al.Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.J Clin Oncol. 2010; 28: 4730-4739Crossref PubMed Scopus (543) Google Scholar; Zhao and Tao, 2018Zhao X. Tao J. BRD4: epigenetic origin and target of CTCL.Blood. 2018; 131: 712-713Crossref PubMed Scopus (2) Google Scholar). Biomarkers of clinical aggressiveness in T-cell proliferations are the lymphoid activation marker CD30 (Zain, 2019Zain J.M. Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and management.Am J Hematol. 2019; 94: 929-946Crossref PubMed Scopus (30) Google Scholar) and shorter telomeres (Chevret et al., 2014Chevret E. Andrique L. Prochazkova-Carlotti M. Ferrer J. Cappellen D. Laharanne E. et al.Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma.Blood. 2014; 123: 1850-1859Crossref PubMed Scopus (16) Google Scholar). On the basis of these findings, we hypothesized that the three-dimensional (3D) spatial telomere organization and dynamics might correlate with clinical tumor aggressiveness and CD30 expression (Knecht et al., 2012Knecht H. Kongruttanachok N. Sawan B. Brossard J. Prévost S. Turcotte E. et al.Three-dimensional telomere signatures of Hodgkin- and Reed-Sternberg cells at diagnosis identify patients with poor response to conventional chemotherapy.Transl Oncol. 2012; 5: 269-277Crossref PubMed Scopus (29) Google Scholar; Vermolen et al., 2005Vermolen B.J. Garini Y. Mai S. Mougey V. Fest T. Chuang T.C. et al.Characterizing the three-dimensional organization of telomeres.Cytometry A. 2005; 67: 144-150Crossref PubMed Scopus (78) Google Scholar). Although strong CD30 expression is almost invariably associated with large cell transformation and severe disease, CD30-negative large cell transformation of MF does exist. It would be interesting to see whether CD30-negative transformation behaved as aggressive as CD30 positive and whether they were different with respect to telomere kinetics and loss. For these experiments, institutional approval and written informed consent of patients were obtained. Our pilot study of 10 samples (Supplementary Table S1) revealed that 3D telomere analysis combined with clinical staging and CD30 expression represents an innovative approach to MF and/or SS diagnosis. We have used both clinical stage and CD30 expression as markers of more advanced disease. The choice of these parameters is based on published data. There is substantial evidence that clinical stage is one of the best prognostic tools in CTCL (Kim et al., 2003Kim Y.H. Liu H.L. Mraz-Gernhard S. Varghese A. Hoppe R.T. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.Arch Dermatol. 2003; 139: 857-866Crossref PubMed Scopus (533) Google Scholar; Olsen et al., 2007Olsen E. Vonderheid E. Pimpinelli N. Willemze R. Kim Y. Knobler R. et al.Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (933) Google Scholar; Swerdlow et al., 2016Swerdlow S.H. Campo E. Pileri S.A. Harris N.L. Stein H. Siebert R. et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood. 2016; 127: 2375-2390Crossref PubMed Scopus (4071) Google Scholar). High CD30 expression by immunohistochemistry has been shown to be an independent poor prognostic marker in nontransformed MF and to be a frequent finding in transformed MF (Edinger et al., 2009Edinger J.T. Clark B.Z. Pucevich B.E. Geskin L.J. Swerdlow S.H. CD30 expression and proliferative fraction in nontransformed mycosis fungoides.Am J Surg Pathol. 2009; 33: 1860-1868Crossref PubMed Scopus (85) Google Scholar). We are aware that our approach has limitations. For example, telomere loss may also be complemented by a mechanism termed alternative telomere lengthening not analyzed in this study owing to limited material (Sobinoff and Pickett, 2017Sobinoff A.P. Pickett H.A. Alternative lengthening of telomeres: DNA repair pathways converge.Trends Genet TIG. 2017; 33: 921-932Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). The choice of controls in MF is confounded by the localization of MF to the skin. The use of keratinocytes is limited by their programmed cell death, which may alter their telomere dynamics, and circulating T lymphocytes show a significant variation in age-associated telomere attrition (Lin et al., 2015Lin Y. Damjanovic A. Metter E.J. Nguyen H. Truong T. Najarro K. et al.Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions.Clin Sci (Lond). 2015; 128: 367-377Crossref PubMed Scopus (75) Google Scholar). Circulating CD4+ T lymphocytes in MF show already shortened telomeres compared with CD4+ circulating lymphocytes of healthy donors (Wu and Hansen, 2001Wu K.D. Hansen E.R. Shortened telomere length is demonstrated in T-cell subsets together with a pronounced increased telomerase activity in CD4 positive T cells from blood of patients with mycosis fungoides and parapsoriasis.Exp Dermatol. 2001; 10: 329-336Crossref PubMed Scopus (0) Google Scholar). Therefore, the use of nonmalignant, lymph node tissue‒residing CD4+, CD30‒ lymphocytes from treatment-naive patients with Hodgkin lymphoma was considered the best alternative control. Of note, in Hodgkin lymphoma, the tumor cells make up for only 1–5% of the lymph node cells, the bulk thereof being made of benign, mainly CD4+ lymphocytes. 3D Telomeric quantitative FISH enabled us to perform an in-depth analysis of the 3D telomeric configuration and organization of MF tumor cells. An important parameter pertaining to telomeric signal intensity is the proportion of abnormal telomeres of low intensity (TLIs), the so-called ultrashort telomeres or t-stumps (Baird et al., 2003Baird D.M. Rowson J. Wynford-Thomas D. Kipling D. Extensive allelic variation and ultrashort telomeres in senescent human cells.Nat Genet. 2003; 33: 203-207Crossref PubMed Scopus (392) Google Scholar; Xu and Blackburn, 2007Xu L. Blackburn E.H. Human cancer cells harbor T-stumps, a distinct class of extremely short telomeres.Mol Cell. 2007; 28: 315-327Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) (Figure 1). Table 1 summarizes the main findings of this analysis pertaining to the number and intensity of telomeric signals, the proportion of TLIs and aggregate formation, and the nuclear volume. Importantly, TLIs represented 26.6% of the malignant lymphocytes’ telomeric signals and 17.7% of those of control lymphocytes (P < 0.0001). The proportion of telomeric aggregates was similar when comparing malignant lymphocytes with control lymphocytes. Among the malignant lymphocytes, the CD30-high group (lesions with 5–30% and more CD30+ cells) was associated with 8.4 ± 7.1% aggregates compared with 7.2 ± 7.5% in the CD30-low group (lesions with ≤5% CD30+ cells; P = 0.10). However, a significant difference with a higher proportion of telomeric aggregates in the advanced-stage group (IIb–IV) was found between the advanced-stage group and the early-stage group (I–IIa) (8.5 ± 7.6% vs. 7.1 ± 7.1%, P = 0.04).Table 1Telomeric and Nuclear ParametersParametersControls (n = 4)MF Lymphocytes (n = 10)P-valueTotal intensity sum (rfu)420,220 ± 134,430151,411 ± 73,448<0.0001Average signal intensity (rfu)20,632 ± 6,87812,952 ± 4,855<0.0001Total signals (telomeres per cell)19.9 ± 2.1812.9 ± 7.3<0.0001Proportion of TLI (%)17.7 ± 6.326.6 ± 8.7<0.0001Proportion of aggregates (%)8.3 ± 1.77.6 ± 7.4NSNuclear volume (μm3)351.9 ± 114.3217.2 ± 96.4<0.0001Abbreviations: MF, mycosis fungoides; NS, nonsignificant; TLI, telomere of low intensity.rfu indicates relative fluorescence units. Data are presented as a proportion (%) or mean ± SD. Categorical variables were analyzed using the chi-square statistic. Continuous variables were analyzed using ANOVA followed by the least-squares means statistic. Open table in a new tab Abbreviations: MF, mycosis fungoides; NS, nonsignificant; TLI, telomere of low intensity. rfu indicates relative fluorescence units. Data are presented as a proportion (%) or mean ± SD. Categorical variables were analyzed using the chi-square statistic. Continuous variables were analyzed using ANOVA followed by the least-squares means statistic. The total and average telomere signal intensities stratified for CD30 expression and clinical stage are shown in Supplementary Figure S1a and b. Lymphocytes from CD30-high lesions had lower average signal intensity (CD30 high = 11,318 ± 4,387 relative fluorescence units vs. CD30 low = 13,729 ± 4,881 relative fluorescence units, P < 0.0001), and both CD30-high and advanced-stage lymphocytes had a significantly higher number of telomeres per cell. The numbers of telomeric signals per cell based on CD30 expression and clinical stage are presented in Supplementary Figure S1c and d. High CD30 expression and advanced clinical stage had significantly more telomeric signals than early-stage and low CD30 expression. Moreover, among malignant lymphocytes, the CD30-high group had significantly more TLIs than the CD30-low group (34.0 ± 2.2% vs. 22.1 ± 7.4%, respectively, P < 0.0001). The same observation applied when comparing the advanced-stage group with the early-stage group (30.2 ± 10.5% vs. 23.9 ± 7.9%, respectively, P < 0.0001) (Supplementary Figure S1e and f). The 3D dynamics of telomere shortening and loss occurring during the progression of a normal CD4+ lymphocyte to a histologically malignant tumor cell are shown in Supplementary Figure S2. 3D imaging of nucleus and telomeres is advantageous because it enables the accurate determination of the length (size), number, and positioning of the telomeres as well as the volume of the nucleus (Mai and Garini, 2006Mai S. Garini Y. The significance of telomeric aggregates in the interphase nuclei of tumor cells.J Cell Biochem. 2006; 97: 904-915Crossref PubMed Scopus (70) Google Scholar). In this study, we show that the proportion of TLIs, called ultrashort telomeres (Baird et al., 2003Baird D.M. Rowson J. Wynford-Thomas D. Kipling D. Extensive allelic variation and ultrashort telomeres in senescent human cells.Nat Genet. 2003; 33: 203-207Crossref PubMed Scopus (392) Google Scholar), is significantly higher in MF than in nonmalignant control lymphocytes. In cancer cells (lung carcinoma, bladder carcinoma, fibrosarcoma), such ultrashort telomeres or t-stumps were identified as a hallmark of malignancy (Xu and Blackburn, 2007Xu L. Blackburn E.H. Human cancer cells harbor T-stumps, a distinct class of extremely short telomeres.Mol Cell. 2007; 28: 315-327Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Of note, in Hodgkin lymphoma, a very high percentage of TLIs in the Hodgkin cells of diagnostic biopsies predicted a poor response to ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) chemotherapy (Knecht et al., 2012Knecht H. Kongruttanachok N. Sawan B. Brossard J. Prévost S. Turcotte E. et al.Three-dimensional telomere signatures of Hodgkin- and Reed-Sternberg cells at diagnosis identify patients with poor response to conventional chemotherapy.Transl Oncol. 2012; 5: 269-277Crossref PubMed Scopus (29) Google Scholar). Recently, Chevret et al., 2014Chevret E. Andrique L. Prochazkova-Carlotti M. Ferrer J. Cappellen D. Laharanne E. et al.Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma.Blood. 2014; 123: 1850-1859Crossref PubMed Scopus (16) Google Scholar using interphase quantitative FISH demonstrated that telomere length in fresh-frozen tissue and cell lines of aggressive subtypes of CTCL, such as transformed MF and SS, were shorter than in nonmalignant controls and in a more indolent CTCL subtype, primary cutaneous anaplastic large cell lymphoma. They also elegantly demonstrated that telomerase activity played a key role in ensuring cell survival in SS cell lines. Our results complement the findings of Chevret et al., 2014Chevret E. Andrique L. Prochazkova-Carlotti M. Ferrer J. Cappellen D. Laharanne E. et al.Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma.Blood. 2014; 123: 1850-1859Crossref PubMed Scopus (16) Google Scholar by demonstrating that telomere length is a key feature of MF at the early stages of the disease when compared with that in nonmalignant CD4+ control lymphocytes and that the proportion of ultrashort telomeres or t-stumps is higher in more advanced clinical stage or higher CD30 expression (Supplementary Figure S2) than in early-stage MF. Thus, besides clinical staging, TLIs might present a prognostic marker in MF. Such findings are to our knowledge previously unreported. Telomeric aggregates, 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, are well-studied features of telomeric dysfunction in tumor cells (Mai and Garini, 2006Mai S. Garini Y. The significance of telomeric aggregates in the interphase nuclei of tumor cells.J Cell Biochem. 2006; 97: 904-915Crossref PubMed Scopus (70) Google Scholar). Although this difference was not statistically significant between control lymphocytes and MF lymphocytes, it might be worth asking the same question in a larger study, in relation to disease progression. In conclusion, we show that 3D telomeric quantitative FISH is feasible in skin-residing MF lymphocytes and that such tumor lymphocytes show striking differences compared with normal tissue-residing CD4+ lymphocytes with respect to 3D telomere dynamics, nuclear volume, and configuration. Our study shows that in MF the increasing number of ultrashort telomeres correlates with clinical progression and appears parallel to CD30 expression. Marc N. Bienz: http://orcid.org/0000-0002-6683-5348 Tina Petrogiannis-Haliotis: http://orcid.org/0000-0002-7675-906X Kevin Pehr: http://orcid.org/0000-0002-2950-4603 Naciba Benlimame: http://orcid.org/0000-0001-6456-1737 Sabine Mai: http://orcid.org/0000-0002-5797-2201 Hans Knecht: http://orcid.org/0000-0002-7909-7866 SM is the chair of the clinical and scientific advisory board of Telo Genomics. HK is a member of the clinical and scientific advisory board of Telo Genomics. Telo Genomics had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. This research was funded by private donations to HK for trainee research. Three-dimensional imaging was performed at the Genomic Centre for Cancer Research and Diagnosis (Winnipeg, Manitoba, Canada). TeloView was used under a Research Use Only License granted by Telo Genomics to SM. The authors thank Mary Cheang for her statistical expertise and Daniel Lichtensztejn for his technical support with three-dimensional imaging. Conceptualization: HK, SM; Formal Analysis: MNB, SM, HK; Funding Acquisition: HK; Methodology: MNB, TPH, KP, NB, SM, HK; Project Administration: SM, HK; Resources: MNB, TPH, KP, NB, SM, HK; Software: MNB, SM, HK; Supervision: SM, HK; Validation: HK, SM; Writing - Original Draft Preparation: MNB; Writing - Review and Editing, TPH, KP, SM, HK Our pilot cohort was composed of nine patients and four controls. Three cases, initially selected, had to be excluded because of insufficient material for additional serial sections. Nine samples were collected from patients diagnosed with mycosis fungoides. Two of those samples were biopsied on the same patient but at a 6-year interval. One sample was collected from a patient with Sézary syndrome. For controls, we used nonmalignant CD4+ lymphocytes of four Caucasians (two males, aged 29 and 55 years, and two female, aged 25 and 85 years) with enough biopsy material to assess CD4+ purity of >70% (the remaining <30% being CD8+ NK cells and rare CD20+ lymphocytes) by both flow cytometry and immunohistology in three controls and immunohistochemistry alone in one control, diagnosed with classic Hodgkin lymphoma from diagnostic lymph node biopsy cell suspensions and immunohistologic slides (Knecht et al., 2017Knecht H. Johnson N.A. Haliotis T. Lichtensztejn D. Mai S. Disruption of direct 3D telomere-TRF2 interaction through two molecularly disparate mechanisms is a hallmark of primary Hodgkin and Reed-Sternberg cells.Lab Invest. 2017; 97: 772-781Crossref PubMed Scopus (11) Google Scholar). The lymphocytes of all the four controls were negative for CD30 expression, assessed by immunohistochemistry. These lymphocytes were considered suitable controls because they were established healthy T lymphocytes that are tissue-residing, similar to CTCL lymphocytes. CD4+ circulating lymphocytes of patients with mycosis fungoides were not suitable because of already shortened telomeres (Wu and Hansen, 2001Wu K.D. Hansen E.R. Shortened telomere length is demonstrated in T-cell subsets together with a pronounced increased telomerase activity in CD4 positive T cells from blood of patients with mycosis fungoides and parapsoriasis.Exp Dermatol. 2001; 10: 329-336Crossref PubMed Scopus (14) Google Scholar), and normal peripheral blood T lymphocytes show telomere shortening in only 27% and no telomere length change in 63% but show increased telomere length in 10% over a 5-year observation period (Lin et al., 2015Lin Y. Damjanovic A. Metter E.J. Nguyen H. Truong T. Najarro K. et al.Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions.Clin Sci (Lond). 2015; 128: 367-377Crossref PubMed Scopus (88) Google Scholar). The diagnosis was made by trained hematopathologists and staging by trained dermatologists and hematologists according to the revised World Health Organization‒European Organisation for Research and Treatment of Cancer staging criteria (Willemze et al., 2019Willemze R. Cerroni L. Kempf W. Berti E. Facchetti F. Swerdlow S.H. et al.The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.Blood. 2019; 133: 1703-1714Crossref PubMed Scopus (443) Google Scholar). Data from patients’ demographics, cytology reports including diagnosis, subtype (patch, plaque, tumor, Sézary syndrome), clinical stage, and CD30 expression were retrospectively collected using the Jewish General Hospital (Montreal, Quebec, Canada) electronic chart system. Patients’ demographics and cytological data are detailed in Supplementary Table S1. This study was approved by the local Ethics Committee, and signed consent was provided by each patient. Investigations were conducted in accordance with the Declaration of Helsinki. Skin biopsies were formalin-fixed, paraffin-embedded, and serially cut in 5 μm sections. As per standard procedure, several slides were analyzed in cytology and stained for immunohistochemistry purposes. Of the remaining tissue used for the study, the first slide was stained with H&E, the second was stained against CD4 using immunohistochemistry, and the subsequent underwent telomeric three-dimensional (3D) quantitative FISH. All slides of unstained paraffin-embedded tissue underwent 3D telomeric quantitative FISH using our recently published detailed protocol (Knecht and Mai, 2017Knecht H. Mai S. The Use of 3D Telomere FISH for the Characterization of the nuclear architecture in EBV-positive Hodgkin's lymphoma.Methods Mol Biol. 2017; 1532: 93-104Crossref PubMed Scopus (5) Google Scholar). A peptide-nucleic acid-telomere probe (Dako, Glostrup, Denmark) was used for telomeric hybridization. DAPI was used for nuclear staining. Slides were mounted with Vectashield (Vector Laboratories, Burlingame, CA). Imaging of interphases after 3D telomere quantitative FISH was performed using a Zeiss Axiomanager Z2 (Zeiss, Toronto, Ontario, Canada) with a cooled AxioCam HR B&W (Zeiss), DAPI (nuclear DNA), and Cy3 (telomere) filters (Zeiss) in combination with a Planapo ×63/1.4 oil (Zeiss) objective lens. Images were acquired using AXIOVISION 4.8 (Carl Zeiss AG, Oberkochen, Germany) in a multichannel mode followed by constraint iterative deconvolution as specified later. For both nuclear DAPI and telomeric fluorochromes, an initial two-dimensional image of the slide was acquired. Cells were compared with the patient’s H&E- and CD4-stained preceding tissue slides. Malignant lymphocytes of interest were identified by their nuclear shape and position within infiltrative lymphocytic collections in the upper dermis and epidermal Pautrier’s microabscesses. A minimum of 30 lymphocytes per patient was identified and processed using the Axiovision 4.8 program (Zeiss) with deconvolution and rendering modules. During this step, 50 images of the identified cells of interest were acquired in the z-axis at a sampling distance of 200 nm and deconvoluted using the constrained iterative algorithm (Schaefer et al., 2001Schaefer L.H. Schuster D. Herz H. Generalized approach for accelerated maximum likelihood based image restoration applied to three-dimensional fluorescence microscopy.J Microsc. 2001; 204: 99-107Crossref PubMed Scopus (90) Google Scholar) to create a 3D image of the nucleus and telomeres (Knecht et al., 2017Knecht H. Johnson N.A. Haliotis T. Lichtensztejn D. Mai S. Disruption of direct 3D telomere-TRF2 interaction through two molecularly disparate mechanisms is a hallmark of primary Hodgkin and Reed-Sternberg cells.Lab Invest. 2017; 97: 772-781Crossref PubMed Scopus (11) Google Scholar). Analysis of telomeric signals was done with TeloView (Vermolen et al., 2005Vermolen B.J. Garini Y. Mai S. Mougey V. Fest T. Chuang T.C. et al.Characterizing the three-dimensional organization of telomeres.Cytometry A. 2005; 67: 144-150Crossref PubMed Scopus (83) Google Scholar). The program is proprietary to Telo Genomics (Toronto, Ontario, Canada) and was used with the company’s permission. Using validated calculations, we collected data on multiple variables pertaining to telomeric signal intensity, number of signals, and nuclear volume. Telomeric signal intensities have been shown to correlate with telomere length and are expressed as units (Knecht et al., 2017Knecht H. Johnson N.A. Haliotis T. Lichtensztejn D. Mai S. Disruption of direct 3D telomere-TRF2 interaction through two molecularly disparate mechanisms is a hallmark of primary Hodgkin and Reed-Sternberg cells.Lab Invest. 2017; 97: 772-781Crossref PubMed Scopus (11) Google Scholar). The sum of telomeric intensity, termed telomeric volume, and the average of telomeric signal intensities were measured. The total number of telomeric signals is the average absolute number of telomeres per cell. On the basis of signal intensity, telomere size can be grouped into large (>30,000 units), medium (>15,000–30,000 units), short (>5,000–15,000 units), and very short (≤5,000 units) telomeres (Knecht et al., 2017Knecht H. Johnson N.A. Haliotis T. Lichtensztejn D. Mai S. Disruption of direct 3D telomere-TRF2 interaction through two molecularly disparate mechanisms is a hallmark of primary Hodgkin and Reed-Sternberg cells.Lab Invest. 2017; 97: 772-781Crossref PubMed Scopus (11) Google Scholar). Those ultrashort telomeres or telomeres of low intensity are also called t-stumps and are considered a hallmark of tumor cells (Figure 1c) (Xu and Blackburn, 2007Xu L. Blackburn E.H. Human cancer cells harbor T-stumps, a distinct class of extremely short telomeres.Mol cell. 2007; 28: 315-327Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Aggregates are defined as clusters of telomeric signals in close association (within 200-nm distance) and cannot be further resolved as separate entities at an optical resolution limit of 200 nm. Aggregates have been shown to be features of tumor cells in some cancers (Mai and Garini, 2006Mai S. Garini Y. The significance of telomeric aggregates in the interphase nuclei of tumor cells. Journal of cellular biochemistry.J Cell Biochem. 2006; 97: 904-915Crossref PubMed Scopus (74) Google Scholar). Nuclear volume is quantified according to the DAPI staining described earlier (Mai and Garini, 2006Mai S. Garini Y. The significance of telomeric aggregates in the interphase nuclei of tumor cells. Journal of cellular biochemistry.J Cell Biochem. 2006; 97: 904-915Crossref PubMed Scopus (74) Google Scholar). We compared the telomeric and nuclear parameters between malignant lymphocytes and control lymphocytes. The malignant group was further stratified on the basis of the frequency of CD30+ cells as defined on the immunohistology reports in a CD30-low group (absent or rare CD30+ lymphocytes, n = 7) and a CD30-high group (moderate to high proportion of CD30+ lymphocytes, n = 3) and on the basis of clinical stage in an early-stage group (stage I–IIA, n = 6) and an advanced-stage group (stages IIB–IV, n = 4) using the revised World Health Organization‒European Organisation for Research and Treatment of Cancer staging classification (Willemze et al., 2019Willemze R. Cerroni L. Kempf W. Berti E. Facchetti F. Swerdlow S.H. et al.The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.Blood. 2019; 133: 1703-1714Crossref PubMed Scopus (443) Google Scholar). Categorical variables were analyzed using the chi-square statistic. Continuous variables are presented as a mean ± SD and compared using the ANOVA followed by the least-squares means statistic for multiple comparisons. Significance level was set at α = 0.05. Analyses were carried out using the SAS, version 9.4, program. Datasets related to this article can be found at https://doi.org/10.17632/2m2t5d6drg.1, hosted at Mendeley Data (Bienz et al., 2020Bienz M.N. Mai S. Knecht H. 3D Telomeric fingerprint of advanced cutaneous T-cell lymphoma: a pilot study. Mendeley Data, 2020Google Scholar).Supplementary Figure S2Telomere distribution according to size in a control patient (dotted), a CD30-low patient (stripped), and a CD30-high patient (black). Telomeres with an intensity of ≤5,000 units are ultrashort or t-stumps. There is a visible skewing of the curve toward a larger number of small telomeres in the CD30-low patient and even more so in the CD30-high patient.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Table S1Demographic, Clinical, and Pathological ParametersSampleDiagnosisSexAgeStageSubtypeCD30 Expression, %Evolution1MFMale422BTumorAbsent or rare, <5Progressed2MFFemale222APlaqueAbsent or rare, <5Progressed3MFFemale221APatchAbsent or rare, <5Improved4SSMale78IVASSModerate, 5–30Improved5MFFemale511APlaqueModerate, 5–30Improved6MFMale442BTumorAbsent or rare, <5Progressed71Samples 7 and 10 were from the same patient biopsied at a 6-year interval.MFFemale741BPlaqueAbsent or rare, <5Progressed8MFMale752BTumorSignificant, >30Progressed9MFFemale621BPlaqueAbsent or rare, <5Improved101Samples 7 and 10 were from the same patient biopsied at a 6-year interval.MFFemale802APlaqueAbsent or rare, <5ProgressedAbbreviations: EORTC, European Organisation for Research and Treatment of Cancer; ISCL, International Society for Cutaneous Lymphomas; MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumor-node-metastasis-blood.Staging is defined as per the TNMB revised ISCL/EORTC staging criteria (Olsen et al., 2007Olsen E. Vonderheid E. Pimpinelli N. Willemze R. Kim Y. Knobler R. et al.Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1049) Google Scholar). Evolution is defined as improved if the clinical stage has regressed or remains stable on therapy with good control of symptoms and as progressed if the clinical stage has evolved despite therapy or in the case of transformation of disease.1 Samples 7 and 10 were from the same patient biopsied at a 6-year interval. Open table in a new tab Abbreviations: EORTC, European Organisation for Research and Treatment of Cancer; ISCL, International Society for Cutaneous Lymphomas; MF, mycosis fungoides; SS, Sézary syndrome; TNMB, tumor-node-metastasis-blood. Staging is defined as per the TNMB revised ISCL/EORTC staging criteria (Olsen et al., 2007Olsen E. Vonderheid E. Pimpinelli N. Willemze R. Kim Y. Knobler R. et al.Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1049) Google Scholar). Evolution is defined as improved if the clinical stage has regressed or remains stable on therapy with good control of symptoms and as progressed if the clinical stage has evolved despite therapy or in the case of transformation of disease." @default.
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