Abstracts/Lung Cancer 12 (1995) 265-329

to bc a relatively early genetic event in the development and progression of lung CIL~CC~ and to be maintained in the process of metastasis: abnormal p53 expression was found in both the early and late clinical stages, and identical ~53 expression was detected consistently among primary and met&&c lesions from the same patients. Furthnmorc, an observed association between abnormal p53 expression and the patients’ smoking history suggests that the p53 gent could bc B common met of tobacco-associated carcinogenesis in lung cancer.

Tbemkdplatekt~~factorpmdacdonbyhnccr-ressociated macropbagcs ia tumor stromaformatioa ia lung cancer Vignaud J-M, Marie B, Klein N, Plenat F, Pech M, Bomlly J et al. Deporfemenl d %tatomie Patfwlogique, Universile de Nancy, BP 184.54505 Vondoeuvre-/es- Nancy. CanwrRes 1994;54:545543.

Lung cancer is the most common cause of death by cancer in developed countries. Since a tumor cannot develop without the parallel expansion of a tumor stroma, a better understanding of its formation could lead to new therapeutical approaches. In this respect, since platelet-derived growth- factor (PDGF) is a chemotactic and growth factor for mcsenchymal and eodothclisl cells, lung tumors of patients undergoing surgery for non-smell cell lung cancer were evaluated for their replication rate using iododcoxyuridinc incorporation, and for the expression of PDGF genes and the presence of PDGF A and B chains and of PDGF receptor 6 and 8 subunits. This observation demonstrates that: (a) tumor cells and stroma mcsenchymal cells, but not tomor-associated macmphagcs, display a high replication rate; (b) I of 3 tumors are characterized by cancer cells expressing the genes for PDGF A and/or B chains, while I of 2 tumors are composed of tumor cells presenting PDGF receptors 6 and I3 subunits on their surface, and in only 1 of 6 tumors, tumor cells -press PDGF and its receptor; (c) in almost all tumors, tumor-associated macrophagcs express PDGF A and/or B chain genes; (d) mesenchymal cells, as well as endothelisl cells, do not express PDGF A and B chain genes but do express PDGF receptor 0 and 8 subunits; and (e) an ongoing active process was suggested in the periphery of the tumor by the simultaneous strong expression of PDGF A and B chain genes by tumor- associated mawophages and the high replication rate of mcsenchymal and cndothelial cells in the same area. Thus, PDGF is likely to have a limited autocrine role in honor cell replication but is B potential player, in a paracrine fashion, in tumor stmma development.

Cytogeactic analysis of 63 non-small cell lung carcinomas: Rccarrent chmmommealten&nsamidfquentandwidcspmad~cupheaval Test8 JR, Siegfried JM, Liu 2, Hunt JD, Feder MM, Litwin S et al. Section o/ Molecular Cylogenetics, Fox Chose Cancer Cente,: 7701 Burholme Avenue, Philadelphia, PA 19111. Genes Chromosomes Cancer 1994;ll: 178-94.

A detailed cytogenetic analysis of 63 non-small cell lung carcinomas (NSCLCs) was carried out for identification of recurrent chromosomsl alterations. Most specimens displayed very complex kayotypes with multiple numerical and stroctoml changes (median number, 31). Losses of chromosomes 9 (65% of cases) and 13 (71%) wcm the most frequent numerical changes. Loss of the Y was oflen observed in tumors from males. Gain of chromosome 7 was also frequent (41%). Chromosome arms lp, Iq, 3p, 3q, 6q, 7q, 8q, Pp, Ilq, 17p, and IPq were particularly prone to rearrangement. The chromosome arm most often contributing to losses was Pp (79%). Other arms that were frequently lost included 3p, 6q, 8p, Pq, l3q, 17~. 18q, IPp, 2lq, 22q, and the short arm of each acroccntric chromosome. The percentage of cases with loss of 3p was significantly higher in squamous cell carcinomas (94%) than in adenocarcinomas (60%). There was also a statistically significant increase in the proportion of cases with gains of Iq, 7p, and I lq in adenocarcinomas compared to squamous cell carcinomas. Several recurrent isochromosomes and unbalanced exchanges were found. Among these was i(5p). which was observed in nine tomors, eight of which displayed adenomatous features. An i(8q) was identified in six cases, including five adenocarcinomas. Double minutes and/or homogeneously staining regions were seen in ~evcn specimens. These data indicate that numerous chromosome alterations contribute to the pathogencsis of NSCLC and that, amid this widespread genomic disarray, recurrent abnormalities exist that could have biological and clinical implications.

Proliferating cell nuclear antigen and Ki-67 in lung carcinoma: Cormlath with DNA flow cytometric aaalysis Kawai T, Suzuki M. Kono S, Shinomiya N, Rokutanda M, Takagi K et al. Department of Pathology, Nalionol Defense Medical College, 3-2 Namiki, Tokorozawa 359. Cancer 1994;74:2468-75.

Background. To study the prognosis of patients with lung carcinomas, the ctlicacy of proliferating cell nuclear antigen (PCNA) in ensuring both the pmlifemtive activity defined using Ki-67 labeling and the cell cycle data obtained using flow cytometry was determined. Methods. The authors used immunostaining to study frozen and paraffin embedded sections of 165 surgically reacted lung carcinomas [squamous cell carcinoma, n = 84; adenocarcinoma, n = 62, large cell carcinoma, n = IS; small cell carcinoma, n = 41 for the presence of PCNA and Ki-67 antibodies. Also studied were hvo parameter flow cytometric analysis of fluorescein isothiocyanatc conjugated PCNA/propidium iodide for 165 fresh frozen tissues. Clinicopathologic data (sex, age. tumor stage, survival period, histologic type, degree of cell differentiation, and cellularity) were evaluated using the Statistical Analysis System. Results. The percentages of PCNA positive cells per 1000 nuclei were 52% of squamous cell carcinoma; 49% in adenocarcinomas; 76% of large cell carcinoma; and 63% of small cell carcinoma. Positive PCNA staining was significantly correlated with stage, cellularity, and DNA index. Calculation of logistic regression coeff~cicnts indicated an association behvecn overall survivals and tumor ccllul.wity (P c 0.0003), percentage of cells stained with PCNA antibody @’ c 0.02). DNA pattern (ancuploid versus diploid) (P < 0.009), DNA index (P < 0.009). and percentage of cells in S- phase (P < 0.04). Both cellularity @’ = 0.03) and DNA (p = 0.08) retained its indepcodent level of signiticaocc by multivariate analysis. Conclusions. In addition to clinical stage and histologic differentiation, both cellularity and DNA content may help predict the coarse of lung carcinomas.

Genetic alterations in p53 and K-Pas in lung cancer in relation to Ctopathology dthe turner and smoking history oftbe patient Ridanpaa M, Karjalaincn A, Anttila S, Vainio H, Husgafvel-Pursisinen K. Inslifute of Occupational Health, Dept. of Industr Hygiene/Toxicology, Topeliuksenkahrm 41 a4. F7N-00250 Helsinki. Int J Oncol 1994;5: 1109-17.

The inactivation of the p53 suppressor gene and the activation of the ras proto-oncogenes .are frequent events in non-small cell lung cancer as well as in many other solid neoplasms in man. Somatic mutations in axons 5-8 of the ~53 gene were detected in 59% (3015 I) of the squamous cell carcinoma and in 38% (14137) of the adenocarcinoma tumors using GC-clamped, non-radioactive denahoing gradient gel clatmphoresis (DGGE). The mutations in the cxons 5 and 8 npmsented larger proportion of the alterations in squamous cell carcinoma tumors (p=O.O4; Fisher’s exact test, hvo-tailed), in the adenocarcinoma tumors, mutations were most common in the exon 7 of ~53. Most of the identified mutations (25139; 64%) arc predicted to cause an amino acid substitution. Mutations leading to the premature termination of translation were more frequent in adamcarcinoma (604) than in squamous cell carcinoma (3130) tumors (p=O.O2). In adcnocarcinoma, also base substitutions in the K-m gene were detected more ot?en (18137; 49%) than in squamous cell carcinoma (p<o.Ol). However, a mutation both in p53 and Kms was detected in only 4% of the lung tumors which does not support importance of w-operation between the genes in viva. Mutations in p53 and K-Pas did not correlate with tumor differentiation in either histological type. In squamous cell carcinoma, mutations in p53 showed relation to pack years smoked whereas in adcnocaminoma, mutations in the K- res gene were associated with cigarette consumption. G to T tramversion was the most common type of base substitution in both genes (31% in p53 and 53% in K-ms).

Therapeutic effect of a retroviral wild-type ~53 expression vector in an orthotopk lung cwaar model Fujiwara T, De Wci Cai Georgcs RN, Mukhopadhyay T, Grimm EA, Roth JA. Thoracic/CardiovoJcrrlor Surg. Dept., Universily of Texas. M. D. Anderson Cancer Cenfec I515 Holcombe Bhd, Hmukm. TX 77030. J Nat1 Cancer Inst 1994;86:145842.

Background: Mutations in the p53 tumor suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung