Contribution of 3H-thymidine labelling index and flow cytometric S-phase in predicting survival of patients with non-Hodgkin's lymphoma

Costa, Alberto; Silvestrini, Rosella; Giardini, Roberto; Messina-Gabrielli, G.; Boracchi, Patrizia; Veneroni, Silvia

doi:10.1038/bjc.1992.337

Cited by 15 publications

(3 citation statements)

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“…In conclusion, Ki-67, MIB-1 or TLI cannot be considered as alternative proliferation indices, as already emerged in the only published comparative analysis of the clinical role of the former two markers (Rudas et al 1994). However, a possible complementarity of the different information provided by the proliferation markers, which already emerged for example for TLI and flow-cytometric S-phase cell fraction in non-Hodgkin's lymphomas (Costa et al 1992), needs to be investigated. Although the biological significance of the exposure of different or of an excess of antigens to microwave treatment of paraffinembedded material remains to be defined, the availability of MIB-1 should allow such comparative studies even on human solid tumours from archival material following formalin fixation, as well as prospective studies on routine material, once the fixation procedures are accurately standardized.…”

Section: Discussionmentioning

confidence: 99%

Immunoreactivity to MIB‐1 in breast cancer: methodological assessment and comparison with other proliferation indices

et al. 1997

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The recent availability of the monoclonal antibody MIB-1 (which is able to detect the human nuclear cell proliferation-associated antigen Ki-67 even on formalin-fixed, paraffin-embedded sections, microwave-treated and routinely processed for immunohistochemistry) could open new avenues for validation of the clinical role of tumour cell proliferation on large, consecutive and unselected series of human tumours. However, the routine use of such a marker requires a methodological standardization as well as the comparative assessment of some technical and biological aspects. The MIB-1 index was determined in parallel samples from 50 consecutive invasive breast carcinomas processed with different fixatives for different times. The median values of MIB-1 indices following 2, 6 and 24 h of formalin fixation were similar (29.4%, 30.6% and 29.7%, respectively) and consistent with those reported in the literature; squared linear regression coefficients were 0.99. The median values of MIB-1 indices were markedly lower in Bouin-fixed, paraffin embedded, and in frozen samples (20.0% and 19.8%, respectively), with a poor correlation coefficient with the values detected following formalin fixation (R2 = 0.456). Moderate and poor correlations were observed between Ki-67 index and MIB-1 detected on frozen (rs, 0.78) or formalin-fixed, paraffin-embedded samples (rs, 0.47) and a minimal concordance was observed between TLI and MIB-1 or Ki-67 (rs, 0.25 and 0.22, respectively). Our results indicate interference of the fixative type on immunoreactivity to MIB-1 and also suggest that Ki-67 and MIB-1 reacted with different epitopes of the same antigen.

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Section: Discussionmentioning

confidence: 99%

Immunoreactivity to MIB‐1 in breast cancer: methodological assessment and comparison with other proliferation indices

et al. 1997

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“…Previous DNA flow cytometric studies in NHL, though relatively scarce, mostly showed that the S-phase fraction (SPF), as an indicator of tumor proliferative activity, is associated with the histopathological grade of NHLs and the clinical outcome. [7][8][9][10][11][12][13][14][15] However, when mutually compared, the relative specific weight of SPF and grading as independent predictors of disease outcome is still controversial. 15 Likewise, the prognostic significance of DNA ploidy in NHL remains unclear.…”

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Flow cytometric S‐phase fraction as a complementary biological parameter for the cytological grading of non‐Hodgkin's lymphoma

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et al. 2003

Diagnostic Cytopathology

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Fine-needle aspiration cytology (FNAC) is a technique that can overcome tissue-sampling disaggregation problems related to DNA flow cytometry analysis. The aim of this study, with long-term follow-up (median, 72 mo), was to investigate the prognostic value of DNA ploidy and S-phase fraction (SPF) in patients with non-Hodgkin's lymphoma (NHL), and additionally, the relevance of SPF in the grading of NHLs, using FNAC. The series comprised 76 patients with NHL (32 indolent and 44 aggressive tumors, including 14 Burkitt lymphomas) and 30 patients with reactive lymph node enlargement used as a control group. DNA flow cytometry was performed on fresh samples obtained by FNAC. NHL grading was done according to the updated Kiel classification. The 5-yr overall survival of patients with NHL was determined using the Kaplan-Meier method. All samples of the control group and 81.6% of the NHLs showed a DNA diploid pattern. Fourteen cases (18.4%) were DNA aneuploid with bimodal distribution: slight hyperdiploidy and near-tetraploidy. Despite the higher incidence of aneuploidy in aggressive than in indolent tumors (22.7% vs. 12.5%), no correlation between DNA ploidy and NHL grading was observed. In contrast, SPF revealed a strong correlation with grading (P=0.0001). The mean SPF values varied from 6.5% in indolent NHLs, to 20.4% in aggressive not-otherwise-specified (NOS) NHLs, and to 35.3% in Burkitt lymphomas. Nearly all aggressive NHLs had an SPF >15%, while the vast majority of indolent NHLs showed an SPF <10%. The mean SPF value in the reactive node group was 6.6%. NHL grading significantly was correlated to survival (P=0.004) only if the Burkitt lymphomas, which showed the best prognosis, were analyzed as an independent group. There was a trend that did not reach statistical significance (P=0.072) for a worse clinical outcome of patients with aneuploid tumors. When mean SPF values were used as cutoff points to divide both indolent NHLs and aggressive NOS NHLs into two proliferative subgroups, no differences in relation to survival were found (P=0.763 and P=0.994, respectively). Also, no proliferative difference was verified between indolent NHLs and the reactive lymph node group (P=0.223). These results show that flow cytometric SPF is a valuable complementary parameter for grading NHLs on FNAC samples, but it appears to give no additional prognostic information on subset analyses.

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“…The prognostic role of S-phase cell fraction, determined by flow cytometry (FCM-S) or by autoradiography ([3H]dT LI), has been consistently evidenced in several studies on a series of patients including all histologies (Roos et al 1985, Lenner et al 1987, Griffin et al 1988, Silvestrini et al 1989b, Grierson et al 1990, Joensuu, Klemi & Jolkanen 1990, Rehn et al 1990, Costa et al 1992 (Table 3). The relevance of the S-phase cell fraction has also been maintained in multivariate analyses including morphology, symptoms, tumour stage and patient's age.…”

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confidence: 97%

Cell kinetics: prognostic and therapeutic implications in human tumours

Silvestrini

1994

Cell Proliferation

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Clinical evidence has shown the limitation of pathological staging to give accurate prognostic information and its inability to predict clinical response to specific treatments. It therefore has been considered of utmost importance to integrate pathological stage with biological variables of consolidated predictive relevance to improve prognostic accuracy and possibly to identify indicators of response to different treatments.With regard to the first point, successive generations of prognostic factors have been proposed (Table 1): a first generation of pathological factors including tumour size, stage and morphology; a second generation including biochemical markers, steroid and growth factor receptors, cell kinetics and ploidy; and a third generation including oncogenes and oncosuppressor genes, proteases, extra-cellular matrix-related antigens and angiogenesis markers. For some tumour types, biological markers have been increasingly used to complement clinicopathological findings for a more accurate definition of individual patient prognosis and for helping clinicians in treatment decision making. PROGNOSTIC RELEVANCEThere has been considerable interest in proliferative activity for several years. Preliminary results showing the relevance of proliferative status as an indicator of biological and clinical aggressiveness have led to the proposal of several approaches based on dilferent rationales, with the main purpose to have efficient, inexpensive, highly feasible techniques without compromising the reliability of the results (Quinn & Wright 1990). The two most intensively investigated indicators first used to obtain information on cell proliferation are the fraction of cells in the S-phase, quantified on the basis of nucleic acid precursor incorporation ( [3H]-thymidine labelling index, [3H]dT LI, bromodeoxyuridine labelling index, BrdUrd LI) or of DNA-synthetic content (FCM-S), and more recently, the entire fraction of proliferating cells, hypothetically quantified by the expression of a nuclear antigen detected by Ki-67 monoclonal antibody. Available data on the prognostic relevance of these cell proliferation markers, generally determined at a single point during the clinical life of a tumour, were derived from a large series of patients with solid and systemic diseases. The clinical endpoints considered were relapse-free and overall survival for the former (possibly subjected to local-regional therapy), and overall survival for the latter diseases (subjected to systemic treatments). However, basic and clinical results do not support the Correspondence: Professor R. Silvestrini, Oncologia Sperimentale C, Istituto Nazionale Tumori,

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Contribution of 3H-thymidine labelling index and flow cytometric S-phase in predicting survival of patients with non-Hodgkin's lymphoma

Cited by 15 publications

References 23 publications

Immunoreactivity to MIB‐1 in breast cancer: methodological assessment and comparison with other proliferation indices

Immunoreactivity to MIB‐1 in breast cancer: methodological assessment and comparison with other proliferation indices

Flow cytometric S‐phase fraction as a complementary biological parameter for the cytological grading of non‐Hodgkin's lymphoma

Cell kinetics: prognostic and therapeutic implications in human tumours

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