Abstracts/Lung Cancer II f1994J 323-344 321

and poor prognoses for ad,juvant therapy subsequent to complete surgtcal resecllon.

Fetal isoform of human retinoic acid receptor R expressed in small cell lung Uncer line5 HOI& B, Prllel~er hi. Wu J. Goodyer C, Bradley WEC. lnsrirur du cancer de Momreal. Hopiral Notre-Dome, 1560 Sherbrooke Enrr. Monrreccl. Que. H2L 4MI. Cancer Res 1994;54:365-9.

The retinoic acid receptor type I! (RARE) complementary DNA from a small cell tumor hne was amplified. sequenced, and found to be homologous to the munne RARn I. Seventeen lung tumor lines were analyzed. Five of seven small cell lung carcinoma lines expressc?d RARE 1, hut only one other line (epldermoid) expressed tbe isoform. and this was at trace levels. Two other epidermoid lines, ps well as three adenocarcinoma. two adenosquamous, and two large cell-derived lines did not express RARRI, Nineadult human tissues, including lung, were analyzed. and m contrast to what has been reported for the IIU)U% undetectable or harely drtstahle levels were ohserved. On the other hand, a total of I3 different fetal tissues. at three different developmental stages. all expressed RARBI. RARRI may he a master developmental gene in humans. and the remarkably spacitic association with small cell lung carcinoma suggests a molecular link between this typeofcancer and development.

Genes of laminin Bl chain, al (IV) chain of type IV collagen,

and 72-kd type IV collagenase are mainly expressed by the stromal cells of lung carcinomas Soini Y, Paakko P. Autio-Harmainen H. Depanment of Porhology, Uniwrsiry of 0~1~. Kajaonintie 52 D. SF-90220 Oulu. Am J Path01 1993;142:1622-30.

lnthisstudy, weanalyladtheexpressionof mmaenger(m)RNAs for laminin Bl chain. al (IV) chain of type IV collagen. and 72-kd type IV collagenase in 15 primary lung carcinomas and in two m&static adenocarcinomss to the lung. The results show that the mRNA synthesis for these proteins mainly occurs in the stromal tibroblasts acd endothelial cells. In a proportiw of Nmors. mRNAs for laminin Bl chain and 72- kd type IV collagenase could also be observed in carcinoma cells, but the amount of mRNAs was considerably lower in them than in the stromal cells. There were no convincing signals for the p-ce of the a I (IV) chain of type IV collagen mRNA in any of the carcinoma cells. A simullaneous expression or lack of expression of signals for laminin Bl chain and 72-kd type IV collagenase mRNAs could be observed in carcinoma cells of 12 cases. suggesting that the activation of these two genes may be somehow connected. There was no association between the mRNA expression and the differentiation degree or the size of the tumors. The occurrence of the mRNA synthesis for the 72-kd type IV collagenase in stromal fibrohlasts and endothrlial cells indicates that the stromal cells of tumors have a more pronounced impact on the spread of the neoplastic disease than previously thought. The results further show that in their ability to synthesize these proteins the stromal cells of tumors re.semhle those of developing embryonic tissues. This resemblance is probably connected with the constant remodeling of

extracellularmatrix in responsetotheproliferativeactivityofcarcinorna cells.

In vitro and in vivo exprmions of transforming growth factor-a and tyrosine kinase receptors in human non-small- cell lung carcinomas Liu C, Tslo M-S. DeponmemofPathology. Momreal~~ralHospiral, 1650 Cedar Avenue, UonIrenl. Que. H3G IA4. Am J Pathol 1993;142: 1155-62.

The mRNA expression of transforming growth fectora (TGF- a), epiderrnal growth factor recqtor (EGFR), c+bB-2 and c-met proto-oncogenes in eight newly established cell lines and 29 primary tumors of human non-smrll~ll lung carcinoma (NSCLC) have been investigated. In vitro, the expressions of TGF-u, c-erbB-2, and c-met were consistently high in adenocarcinomas, while EGFR wsr expressed highest in a squamous cell carcinoma cell line. There was linear correlation between the levels of expression of TGFa and EGFR or c- erbB-2, and between EGFR and c-erbB-2. The c-met expression WBS also correlated with those of TGFa. EGFR, and cerbB-2. In viva. the mean mRNA levels of TGFa. EGFR. and c-met, but not c-erbB-2, were higher in carcinomas than in normal lung tissues (2.8, 1.7. and 3.0 times, respectively); however, only adenocarcinonvs expressed a significantly higher level of cerbB-2 than their corresponding normal tissues (2.2 times). In 20 patients whose paired normal and tumor tissue were examined, the percentages of cpses with greater than twofold increase in expression in carcinom than normal were 55% for both TGFa and EGFR. 30% forcerbB-2. and 47% fort- met. Among the histologicalsubtypesofNSCLC,ahigherpercentageofadenocarcinomas than squamous cell carcinomas over-expressed these genes, especially c-&B-2 and c-met Overexpression is rarely the result of gene ampli- ticntion. The results suggest a differential expression of growth factor and receptorgenes among the various histological .subtypesofNSCLCs.

Debrisoquin oxidation genotype and susceptibility to lung cancer Agunder JAG, Martinez C, Lndero JM. Led-ma MC. Ramos JM. Martin R et al. Departamemo de Farmacologia. Facvltadde Uedicina, Uniwrsidad de Extmnadura. Awia. de Elwu s/n. 06071 Badajoz. Clin Pharmacol Ther 1994;55: 10-4.

The association between the polymorphism of the cytochrome P450 debrisoquin hydroxylase (CUpsilonP2D6) and lung cancer is controversial. Previous reports suggested a link between CYP2D6 phenotype and lung cancer, with poor metsbolizers having reduced susceptibility. Nevertheless. negative bindings haveaLs, been published. By using allele-specific amplification. we have studied the frequency of four CUpsilonFXI6 (wild type and mutant) alleles in 89 patients with histologically proved bronchogenic carcinoma and in 98 healthy volunteers. Our findings confirm that poor metabolizers are under- presentedamong patients with lungcancerbttcauseofadifferent genetic hackground. Our findings also reveal that the rare CUpsilonP2Db(C) mutant allele is sixfold more frequent among patients with lung cancer (pCO.0005). This suggcFLs that the CUpsilonPZW(C) allele could be considered asanadditional risk factorbecausecarrierscouldhave higher susceptibility to the development of lung cancer.

Scintigraphic detection of neuralcellderived small-cell lung cancer wing glioma-specific antibody Kobayashi H. Sakahara H, Hosono M. Shinto M, Koodo S, Miyatake S-I et al. Depanmenr of Nuclear Medicine, Faculty of Medicine, Kyoro Uniwrsiiy. 54 Kawahara-rho, Shogoin. Sakyo-b. Kyoro 606. J Cancer Res Clin Oncol 1994;120:259-62.

Radiolabeled GA-17. a murine monoclonal antibody that reacts specitically with gliomacetls. bound to a small-cell lung cancer (SCLC) cell line NCI-H69 derived from neural cells, both in vitro and in viva. The affinity constant of GA-17 F (ab’), fragment binding to NCI-H69 was 1.02x10)/M while that to the glioma cell line U87MG was 1.22xl@/M. Iodine-125-labeled GA-17 F(ab’), fragmentsinjected i.v. localized well in NCI-H69 cells xenografted in nuce mice. The percentage

of the injected dose per gram accumulated in the xenografted tumor was 6.87f l.34%g I (-*SD, n=S) 24 h after injection. On the other hand, control monoclonal F (Ab’), fragments accumulated in the

328 Abstracts/Lung Cancer I I (1994) 323-344

XmlOgnfted tomof at 0.75f0.3096g”. The tumor-to-blood ratio wps I.EforNCI-H69,whilethatofcontrol F(Ab’),was0.60. Inconclusion, the radiolabeled GA-17 (ab’), fragment is expected to be useful clinically to visualize the small-cell lung cancer and in radioimmunotherapy.

Alteraths ol K-ras, pS3, and erbB-2/neu in human lung adenocardnomas BongiomoPF,WltyteRI,LesserEJ,MooreJH,OrringerMB,Bee.rDG etd. lJniversityofMi&igan,BarM86. AnnArbor. Ml4B109. JThorac Cudiovasc Surg 1994;107:590-5.

The development of human denocarcinonu of the. lung involves multiple genetic changes including activation of oncogenes and loss of tumor suppressor genes. Patients whose lung tumors contain K-ras oocogene mutation, wumulrtion of the protein product of the tumor suppressor gene ~53, or erbB-2lneu oocoproteia overexpression have been shown tohaveaworscpmgnosis. Weexaminedthese threegenetic indicators in 29 lung adenocarcinomas to determine whether these markers are present in the same tumors or if they represent moleculnr changes that define different subsets of patients. P53 nuclear protein accumulation and erbEd/neu protein overexpression were determined byimmunohistochemicalanalysisofcryostatsectionsoftumorspecimms and corresponding normal lung tissue. K-rasmutationsweredetected by radiolabeled oligonucleotide probes, specific for the various twelfth codon mutations, hybridized to exon I of K-ras, which was amplified by the polymerase chain reaction. Increased nuclear accumulation of pS3 protein was found in I I adenocarcinom (38%). All of the ~53 positive tumors werefound to show high level staining and homogeneous expression of erbB-2/neu protein. K-ras mutations were detected in seven tumors (24%). all of which overexpressed erbB-tlneu. The presence of P K-ras mutation did not correlate with ~53 accumulation. In total, 93 96 of the tumors were found to overexpress erbB-2/neu. the highest being in one tumor with erbB-2/neu gene amplification. The presence of K-ras twelfth codon mutation was associated with increased cigarette smoking. In conclusion. erbB-2/neu overexpression is a common event in lung sdenocarcinomas. Furthermore, the presence of K-ras mutation and pS3 protein accumulation define separate groups of patients. The mzchanisms hy which these genetic alterations interact or adversely affect prognosis is unknown.

Pathology

Cytometric validation of immunocytochemical observations in developing lung cancer Tockman MS, Gu~ta PK. Pressman NJ, Mulshine JL. Entironmentol Health Sciences Dept., School of Hygiene and Public Health. Johns Hopkins Univcrsiry, 615 N Wore Street, Baltimore, MD 21205. Dingn Cytopathol 1993;9:6 15-22.

Videodanced optical microscopy objectively confirms that immunocytochemiul biomarker supplementation of mutine cytology permits separation of (I) ‘pm’-cancer epithelirl cells from JHLP screened individuals who subsequently developed lung cancer from (2) similarly atypical epithelial cells t?om JHLP participants who did not. The establishment of a benk of sputum cytology specimens along with a data respository of 5-yr follow-up and clinical outcome had permitted banked specimens to be immunostained and scored against a gold standard of subsequent histologic lung cancer. A highly skilled cytopatbologist, interpretingimmunostnined5zreeningsputumspecimens and blinded to the clinical outcome, originally was able to correctly predict clinical outcome with 88.7% accuracy compared to this ‘gold standard’ (Tockman et al.. J Clin Oncol 1988;6: 1685-1693). Thisstudy

pmsentsan indepndmt confirmation ot that eariier immunocytochemical classification through feature extraction of digitally recorded. transmission optical microscope video images of immunostained, moderately atypical sputum cells from the original slides.

Clinical Assessment

Malignant epithelial mesothelioma presenting as cardiac tomponade Meysman M, Noppen M, Demeyer G, Vinckeo W. Respiratory Divi- sion, Academic Hospital, Vniwsity of BruweLc (AZVUB). Laarbeek- laan 101, B-1090 Brtusels. Eur Heart J 1993;14:1576-7.

A tare case of malignant mtsothelioma of the mediastinal pleura with mediastinal lymph nodes and pericardial involvement, presenting 0s cardiac &e, is presented.

Interest of C-reactive protein assay in small cell lung cancer Arpin D, Trillet-Renoir V, l-asset C, Souquet PJ, Riou R, Yoanidis I et al. SerGe de Pnewnologie. Hopital Louis-Prtuiel. 28 Rue du Doyen- Lepine, 69394 Lyon. Bull Cancer 1993;80: 1063-8.

A prospective analysis of serum levels of C-reactive protein (CRP) has been conducted on a series of 39 small cell lung umcer (SCLC) patients during the first course of chemotherapy in order to evaluate the predictive value of this marker on tumonl extension at diagnosis and response to therapy. Serum levels of CRP were measured before chemotherapy (day 0) and during the first two days of treatment (day I. day 2). Twenty-three of 32 evrluable patients (71%) had extensivedisease. The mean pm-treatment CRP level was significantly higher in this group than in the group of patients with limited disease (52.3 mgll vs 15.8 mgll, P = 0.02). Twenty-three patients responded to treatment and ninedid not. Theevolution of serum CRP levels in both groups was compared between day 0 and day 2. A more than two-fold increase of initial CRP levels showed a 100% predictive value for response. On the other hand, a decrease by more then 50% of initial serum levels was associated with P negative predictive value of 75 96 for response. We conclude that the follow-up of CRP levels during initial chemotherapy of SCLC might be useful in the initial evaluation of tumoral extension and in the early prediction of response to therapy.

Cerebral met&stases in pleural mesothelioma: Case report und review nf the literature Wronski M, Butt M. ‘Ihorncic Setvim, Uemorinl Slonn-Kettering Cnacer Ctr., 1275 York Awwue. New York. NY 10021. J Neuro-Oncol 1993;17:21-6.

A case of malignant mesothelioma m&static to the brain is described. A 52-year-old woman, with no known exposure to asbestos. presentad with a biphuic mesothrlioma of Ihe left pa&al pleura. Following rcftrtion. the thorax was imdiatal with 4000 cCy, and all symptoms subsided. Three months later, P left temporal lobe tumor was diagnosedandsu~uently rewted. Despiteneurological improvement, she died IO dnys postoperatively from constrictive pericardial disease. The authors have reviewal the 54 reported c&w of brain metastases from rnesolhrlioma and have noted that the histologic appearance of bnin metas1avs from mesothelioma may be similar to gliohlastoma multiforme. Because brain metastasis from mesothelioma is rare, procedurr?s 10 clarify the nature of the turnOr should be Performed.

Transthoracic needle biopsy We&rod GL. DepartmentofRadiology, Uniursityof Toronto, Toronto Hospital, Toronto, Ont. MSG 2C4. World J Surg 1993;17:705-I 1.