Proliferation and apoptosis in neuroblastoma: subdividing the mitosis-karyorrhexis index

Gestblom, Carolina; Hoehner, JC; Påhlman, Sven

doi:10.1016/0959-8049(95)00006-5

Cited by 24 publications

(22 citation statements)

References 13 publications

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“…No significant differences in Ki67 labelling index were demonstrated in the low vs high MKI subset of NTs, the only difference being confined to the MYCN amplified tumours. A previous report suggested that, since proliferating cells generally outnumbers apoptotic cells, the resulting sum relies most heavily on proliferation and this is the reason why a high MKI correlates with a poor outcome in NTs (Gestblom et al, 1995). This study confirmed that proliferating cells outnumber apoptotic cells but also showed that proliferating cells are equally present in low and high MKI tumours.…”

Section: Discussionsupporting

confidence: 83%

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

et al. 2006

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Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis -karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P ¼ 0.007), neuroblastoma (NB) histological category (P ¼ 0.024), MYCN amplification (Po0.001), and poor outcome (P ¼ 0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-X L , Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.

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Section: Discussionsupporting

confidence: 83%

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

et al. 2006

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“…In contrast to the results that we and others have obtained in thyroid cancer, Bedi et al (1995) found that the transformation of colorectal epithelium to carcinoma was associated with a progressive inhibition of apoptosis, although recently Tatebe et al (1996) have reported that apoptosis occurs more frequently in metastatic foci than in primary lesions of human colorectal carcinomas. In neuroblastoma, Gestblom et al (1995) reported that high density of apoptotic cells indicates favourable outcome in patients. In contrast, a high apoptotic index seems to be associated with features of poor prognosis in endometrial adenocarcinoma (Heatley, 1995).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression

Basolo

Pollina²,

Fontanini³

et al. 1997

Br J Cancer

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Summary The aim of this study was to determine the apoptotic cell death in 92 thyroid carcinomas of different histotypes (42 papillary, PTC; 12 poorly differentiated, PDC; 21 undifferentiated, UC; and 17 medullary, MC) by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labelling (TUNEL). Apoptotic index (Al, evaluated as a percentage of TUNEL-positive cells of neoplastic cells) was calculated in each tumour. The Al was very low in all subtypes of thyroid carcinoma, ranging from a median value of 0.2 in PTC to 1.4 in UC. The proliferative activity was determined by immunohistochemistry using monoclonal antibody, MIB-1. The percentage of proliferating cells was significantly different among the histotypes, increasing with tumour aggressiveness (from the mean value of 3.1 for PTC to 5.6 for PDC and 51.8 for UC). In addition, the ratio between proliferative activity and apoptosis was significantly higher in UC than in the other histotypes. The expression of bcl-2 and p53 protein (important in the modulation of cell death) was correlated (bcl-2, inverse correlation, r2 = 0.1, P= 0.04; p53, direct correlation, r2= 0.11, P= 0.02) with apoptotic index in PTC.Keywords: apoptosis p53; bcl-2; thyroid cancer Cell numbers are regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis, PCD). Until recently, the majority of the studies on oncogenesis have focused on the regulation of cell proliferation. The finding that alterations of negative growth control, including growth arrest and PCD, play a key role in the development of human cancer has been demonstrated by the explosion of reports in this field (Barr and Tomei, 1994; Canman and Kastan, 1995;Katsikis and Leben, 1995;Salomon and Diaz-Cano, 1995; Stauton and Gaffeney, 1995). PCD is an active cellular process involved in a variety of physiological events in which rapid elimination of unwanted cells must occur. Its importance in the turnover of self-renewing tissues, morphogenesis, embryonic development, maturation of cells of the immune system, as well as in the development of cancer and other pathologies, is increasingly being recognized (Chandler et al, 1994; Cotman and Anderson, 1995;Isner et al, 1995;Osborne, 1995). Apoptotic cells can be identified both by nuclear morphology and by techniques that detect fragmentated DNA. The latter methodology could be applied for the in situ visualization of apoptosis by specific labelling of DNA fragmentation. By using Gavrieli's method (Gavrieli et al, 1992), apoptosis can be detected at singlecell level in formalin-fixed, paraffin-embedded tissue sections, thereby allowing the study of retrospective cases.In the present study, we analysed apoptosis in thyroid carcinoma, focusing on its association with the proliferation rate of the tumours themselves. In addition, since apoptosis can be regulated by the p53 tumour-suppressor gene and by bcl-2, we analysed the p53 and bcl-2 expression on the tumour. WHO (Hedinger, 1988) and subsequent updating (Sakamoto et ...

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“…ganglioneuroma, is recognized (Evans et al, 1976b;Nitschke et al, 1988). Our previous work suggests that the extent of apoptosis and proliferation, and the phenotypic mode of tumour cellular differentiation, may be helpful in explaining tumour biology (Gestblom et al, 1995;Hedborg et al, 1995a; Revised 8 October 1996 Accepted 23 October 1996 Correspondence to: S P&hlman, Department of Medicine, Wallenberg Laboratory, Lund University, University Hospital MAS, S-205 02 Malmo, Sweden Hoehner et al, 1995a, b). These characteristics lead us to hypothesize that the disparity in clinical behaviour of different forms of NB may involve differences in the regulation of apoptosis-related genes.…”

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confidence: 99%

Spatial association of apoptosis-related gene expression and cellular death in clinical neuroblastoma

Hoehner

Gestblom²,

Olsen³

et al. 1997

Br J Cancer

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Summary Several unique features of neuroblastoma (NB), including the capacity for spontaneous regression and maturation to benign pathology, suggest that genes that regulate cellular proliferation, survival and differentiation may be involved in directing clinical tumour aggressiveness. The in situ expression of Bcl-2, Rb, p21, p53 and Bax proteins, as well as the proliferation marker proliferating cell nuclear antigen (PCNA) were examined immunocytochemically in a selection of 38 stage-and outcome-identified NB tumours. Apoptotic cells were identified morphologically and by a DNA fragmentation labelling technique (TUNEL). Although the tumour cell density of Bcl-2, p53, Bax, PCNA and TUNEL positivity correlated with patient survival, a spatially organized expression pattern was further recognized in stroma-poor differentiating tumours. Immature tumour cells adjacent to thin fibrovascular stroma are proliferating, as evidenced by PCNA positivity, and often express Bcl-2. At increasing distance from this fibrovascular stroma, intermediately differentiated tumour cells express Rb, while with more advanced differentiation, proliferation ceases and Bcl-2 immunoreactivity is lost. The most differentiated tumour cells, which often express p53, and occasionally p21 and Bax, lie adjacent to TUNEL-positive, morphologically apoptotic cells. This spatial organization in favourable outcome NB tumours suggests that physiological regulation of differentiation and apoptosis may be involved in tumour regression.

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Proliferation and apoptosis in neuroblastoma: subdividing the mitosis-karyorrhexis index

Cited by 24 publications

References 13 publications

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

Apoptosis and proliferation in thyroid carcinoma: correlation with bcl-2 and p53 protein expression

Spatial association of apoptosis-related gene expression and cellular death in clinical neuroblastoma

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