1
Abstracts/Lung Cancer IS (19%) 139-157 (25/53, 47 46). as assessed by immunostaining using a monoclonal antibody. In 22125 cases, cyclin D 1 was localised in the cytoplasm, but some (7125) had simultaneous nuclear staining. This result is in marked contrast to that reported in breast, hepatocellular and colorectal carcinoma studies where immunostaining was invariably nuclear. Examination of a restriction fragment length polymorphic (RFLP) site within the 3’untranslated region of the cDNA following reverse transcriptase (RT)-PCR (29153 informative cases) showed a strong association between cytoplasmic staining and imbalance in allele-specific message levels. Cyclin Dl overexpression was associated with a poorly differentiated histology (P = 0.04). less lymphocytic infiltration of the tumour (P = 0.02) and a reduction in local relapse rate (P = 0.01). The relative risk of local relapse was 9.1 in tumours without cyclin Dl overexpression (P=O.Ol, Cox regression analysis). We conclude that genetic alterationofcyclinD1 isakey abnormality in hmgcarcinogensis and may have diagnostic and prognostic importance in the treatment of resectable NSCLC. Frequency and prognostic evaluation of 3~21-22 allelic losses in non-small-cell lung cancer Thiberville L, Bourguignon J, Metayer I, Bost F, Diarra-Mehrpour M. Bignon J et al. CliniquePneumologiqute, Hopiral Charles Nicolle, 1, rue de Getmont, 76031 Rouen Ceder. Int J Cancer 199.5;64:371-7. Previous loss of heterozygosity (LOH) studies of chromosome 3p loci have displayed a 60% deletion frequency in non-small-cell lung cancers (NSCLC), as opposed to small-cell lung cancers, in which the 3p deletion is consistently found. However, the high stromal-cell admixture found in NSCLC and the use of thesouthern blot method lead to under-evaluation of this frequency. In this study, we used a very precise microdissection technique followed by PCR ampIitication of 6 3~2 l-22 polymorphic genotnic sequences to analyze LOH in 86 NSCLC and in normal adjacent tissue. We found the sensitivity of the microdissection-PCR-based LOH technique higher than the sensitivity of the Southern-blot technique: 87% of the squamous-cell carcinomas and 84% of the large-cell undifferentiated carcinomas showed a clear LOH for a 3~21-22 locus. All doubly informative cases but 4 showed concordantdeletionatall3p21-22loci. Theanalysisof3p microsatellite sequences displayed only 2 cases of genomic instability, one of them also displaying features of tumoral heterogeneity as regards the instability genotype. Four carcinomas in situ adjacent to these NSCLC showed the same all&c profile as the invasive tumors. The only prognostic factors in this study were the disease stage and histology. The 3~21-22 deletion was not related to the stage of the disease and did not appear to be a significant prognostic factor of survival. 3~2 1 loss appears, so far, to be the most frequent and the earliest genetic alteration described in NSCLC, but does not seem to carry significant prognostic information in invasive tumors. ~53 protein accumulation and the presence of human papillomavirus DNA in bronchiole-alveolar carcinoma correlate with poor prognosis Nuorva K, Soini Y, Kamel D, Pollanen R, Bloigu R, Vahakangas K et al. Department of Pathology. University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu. Int J Cancer 1995;64:424-9. Accumulation of the tumour suppressor gene p53 product due to a gene mutation is frequently seen in human carcinomas, including lung carcinoma. Another indirect mechanism involving p53 in malignant growth relates to the E6 protein of the human papillomavirus (HPV), which is able to bind and degradewild-type ~53 protein, thus eliminating its tumour suppressor activities. Bronchiole-alveolar carcinoma (BAC) is a rare type of lung carcinoma. The aim of our study was to examine the occurrence of p53 accumulation and the presence of HPV DNA in BAC. Sections of 22 BACs were immunohistochemically stained using ap53antibody, CM-I. ThepresenceofHPVDNAin BACswasverified by in situ hybridisation for HPV types 6, 11, 16, 18, 31 and 33 and confirmed by PCR. Thirty-six percent of the tumours showed abnormal ~53 nuclear accumulation, and HPV DNA, revealed by in situ hybridisation, was found in 36 96. Unexpectedly, only 13 % of the type 1 BACS were positive for ~53, whereas 45% of the type 2 BACs were positive. Duringa follow-upof 12-176 months, only 10% ofthepatients withBACsnegativeforbothp53 andHPV diedofthedisease, compared with 42% of the patients with either ~53 or HPV positivity. No inverse relationship between abnormal p.53 protein accumulation and the presence of HPV DNA was found. Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: Improvement of tumour uptake by internalisation Kwa HB, Wesseling J, Verhoeven AHM, Van Zandwijk N, Hilkens J. Department of Pulmonology. OLVG Hospital, le Oosterparkstraat 279, 1091 HM Amsterdam. Br J Cancer 1996;73:439-46. The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLC) xenografts was studied in a Balblc nulnu mouse model. These MAbs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with ‘251, the highest uptakeintumourtissuewasobtained withMAb 123C3. Sevendaysafter administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour to tissue ratios ranged from 3.97 for blood to 3 1.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%). although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for a11three MAbs. These results may be explained by the differences in the interaction between theMAbsand thetumourcells. MAb 123C3 isinternalised into tumour cells, whereas both other anti-NCAM MAbs are not. lntemalisation into NC1 H69 cells was demonstrated in vitro by a radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalized fraction of MAb 123C3 was 22.3 46 after 24 h, whereas this fraction was only 7.5% for MAb 123A8. Although the intemalised radiolabelled MAbs are usually degraded and dehalogenated intracellularly. the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequentsecretionofradioactiveiodinedidnotpreventtheaccumulation of intracellular radioactivity. In conclusion, accumulation and retention ofradioactivityinthetumourtissue, duetointemalisationofradiolabeIIed MAbs, may improve the results of immunoscintigraphy. Rne tuning of epitopic dominance induced by lung cancer on the IgC response to bovine betalactoglobulin: Towards a paraneoplastic immune marker Michils A, Lambert JP, Yemault J-C, Fabry V, Gossart B. Duchateau J. Chest Department, Erasme University Hospitrrl. 808Routede Lennik. 1070 Brussels. Cancer 1996;77:657-64. Background. Investigating the humoral immune response to mucosal antigens in patients with lung cancer, wehave documentedapreferential immunoglobulin G (IgG) binding to cryptic epitopes unmasked by the proteolysis of bovine R-Iactoglobulin (BLG). In contrast. IgG from healthy controls and patients with chronic bronchitis (COPD) bind preferentially to continuous epitopes presented on both native (n) and

p53 protein accumulation and the presence of human papillomavirus DNA in bronchiolo-alveolar carcinoma correlate with poor prognosis

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Page 1: p53 protein accumulation and the presence of human papillomavirus DNA in bronchiolo-alveolar carcinoma correlate with poor prognosis

Abstracts/Lung Cancer IS (19%) 139-157

(25/53, 47 46). as assessed by immunostaining using a monoclonal antibody. In 22125 cases, cyclin D 1 was localised in the cytoplasm, but some (7125) had simultaneous nuclear staining. This result is in marked contrast to that reported in breast, hepatocellular and colorectal carcinoma studies where immunostaining was invariably nuclear. Examination of a restriction fragment length polymorphic (RFLP) site within the 3’untranslated region of the cDNA following reverse transcriptase (RT)-PCR (29153 informative cases) showed a strong association between cytoplasmic staining and imbalance in allele-specific message levels. Cyclin Dl overexpression was associated with a poorly differentiated histology (P = 0.04). less lymphocytic infiltration of the tumour (P = 0.02) and a reduction in local relapse rate (P = 0.01). The relative risk of local relapse was 9.1 in tumours without cyclin Dl overexpression (P=O.Ol, Cox regression analysis). We conclude that genetic alterationofcyclinD1 isakey abnormality in hmgcarcinogensis and may have diagnostic and prognostic importance in the treatment of resectable NSCLC.

Frequency and prognostic evaluation of 3~21-22 allelic losses in non-small-cell lung cancer Thiberville L, Bourguignon J, Metayer I, Bost F, Diarra-Mehrpour M. Bignon J et al. CliniquePneumologiqute, Hopiral Charles Nicolle, 1, rue de Getmont, 76031 Rouen Ceder. Int J Cancer 199.5;64:371-7.

Previous loss of heterozygosity (LOH) studies of chromosome 3p loci have displayed a 60% deletion frequency in non-small-cell lung cancers (NSCLC), as opposed to small-cell lung cancers, in which the 3p deletion is consistently found. However, the high stromal-cell admixture found in NSCLC and the use of thesouthern blot method lead to under-evaluation of this frequency. In this study, we used a very precise microdissection technique followed by PCR ampIitication of 6 3~2 l-22 polymorphic genotnic sequences to analyze LOH in 86 NSCLC and in normal adjacent tissue. We found the sensitivity of the microdissection-PCR-based LOH technique higher than the sensitivity of the Southern-blot technique: 87% of the squamous-cell carcinomas and 84% of the large-cell undifferentiated carcinomas showed a clear LOH for a 3~21-22 locus. All doubly informative cases but 4 showed concordantdeletionatall3p21-22loci. Theanalysisof3p microsatellite sequences displayed only 2 cases of genomic instability, one of them also displaying features of tumoral heterogeneity as regards the instability genotype. Four carcinomas in situ adjacent to these NSCLC showed the same all&c profile as the invasive tumors. The only prognostic factors in this study were the disease stage and histology. The 3~21-22 deletion was not related to the stage of the disease and did not appear to be a significant prognostic factor of survival. 3~2 1 loss appears, so far, to be the most frequent and the earliest genetic alteration described in NSCLC, but does not seem to carry significant prognostic information in invasive tumors.

~53 protein accumulation and the presence of human papillomavirus DNA in bronchiole-alveolar carcinoma

correlate with poor prognosis Nuorva K, Soini Y, Kamel D, Pollanen R, Bloigu R, Vahakangas K et al. Department of Pathology. University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu. Int J Cancer 1995;64:424-9.

Accumulation of the tumour suppressor gene p53 product due to a gene mutation is frequently seen in human carcinomas, including lung carcinoma. Another indirect mechanism involving p53 in malignant growth relates to the E6 protein of the human papillomavirus (HPV), which is able to bind and degradewild-type ~53 protein, thus eliminating its tumour suppressor activities. Bronchiole-alveolar carcinoma (BAC) is a rare type of lung carcinoma. The aim of our study was to examine

the occurrence of p53 accumulation and the presence of HPV DNA in BAC. Sections of 22 BACs were immunohistochemically stained using ap53antibody, CM-I. ThepresenceofHPVDNAin BACswasverified by in situ hybridisation for HPV types 6, 11, 16, 18, 31 and 33 and confirmed by PCR. Thirty-six percent of the tumours showed abnormal ~53 nuclear accumulation, and HPV DNA, revealed by in situ hybridisation, was found in 36 96. Unexpectedly, only 13 % of the type 1 BACS were positive for ~53, whereas 45% of the type 2 BACs were positive. Duringa follow-upof 12-176 months, only 10% ofthepatients withBACsnegativeforbothp53 andHPV diedofthedisease, compared with 42% of the patients with either ~53 or HPV positivity. No inverse relationship between abnormal p.53 protein accumulation and the presence of HPV DNA was found.

Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: Improvement of tumour uptake by internalisation Kwa HB, Wesseling J, Verhoeven AHM, Van Zandwijk N, Hilkens J. Department of Pulmonology. OLVG Hospital, le Oosterparkstraat 279, 1091 HM Amsterdam. Br J Cancer 1996;73:439-46.

The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLC) xenografts was studied in a Balblc nulnu mouse model. These MAbs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with ‘251, the highest uptakeintumourtissuewasobtained withMAb 123C3. Sevendaysafter administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour to tissue ratios ranged from 3.97 for blood to 3 1.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%). although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for a11 three MAbs. These results may be explained by the differences in the interaction between theMAbsand thetumourcells. MAb 123C3 isinternalised into tumour cells, whereas both other anti-NCAM MAbs are not. lntemalisation into NC1 H69 cells was demonstrated in vitro by a radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalized fraction of MAb 123C3 was 22.3 46 after 24 h, whereas this fraction was only 7.5% for MAb 123A8. Although the intemalised radiolabelled MAbs are usually degraded and dehalogenated intracellularly. the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequentsecretionofradioactiveiodinedidnotpreventtheaccumulation of intracellular radioactivity. In conclusion, accumulation and retention ofradioactivityinthetumourtissue, duetointemalisationofradiolabeIIed MAbs, may improve the results of immunoscintigraphy.

Rne tuning of epitopic dominance induced by lung cancer on the IgC response to bovine betalactoglobulin: Towards a paraneoplastic immune marker Michils A, Lambert JP, Yemault J-C, Fabry V, Gossart B. Duchateau J. Chest Department, Erasme University Hospitrrl. 808Routede Lennik. 1070 Brussels. Cancer 1996;77:657-64.

Background. Investigating the humoral immune response to mucosal antigens in patients with lung cancer, wehave documentedapreferential immunoglobulin G (IgG) binding to cryptic epitopes unmasked by the proteolysis of bovine R-Iactoglobulin (BLG). In contrast. IgG from healthy controls and patients with chronic bronchitis (COPD) bind preferentially to continuous epitopes presented on both native (n) and