S288 ,&tracts Not Presented/Novel Therapies

q 60 Correlation between overall survival and some characteristics of long survivors with advanced non small cell lung cancer (NSCLC) stages (IIIB and IV), a retrospective study

Alexandru Calin Griqorescul, Claudia Bala2, loan Popa3, Nicolae Gutulescu4. ’ IASLC, Bucharest, Romania; 2 ESMO, Bucharest, Romania; 3 Public Health, Bucharest, Romania; 4 ASCO, Bucharest, Romania

Backgound: The overall S-year survival rate of 14% for NSCLC is tow because the staae of luna cancer is often advanced at the time of diagnosis, some char- acteristics of the patients (Pts) have important prognostic significantion.

Aims: This study tries to find some characteristics of the Pt. with advanced NSCLC which could olav a role in the oroonosis and outcome of treatment.

Material and method: 37 Pts. with NSCLC stage 1116 (24 Pts.) and lV(t3 Pts.) and more then one year overal suvival, were selected from 1999 Pts.with advanced NSCLC treated by chemotherapy atone or radiotherapy and chemotherapy in secvential administration betveen I 996 since 2009. The main characteristic of Pts.were mean age 54 years (34-73) 31 males and 8 women, ECOG performance status 1 or 2. The chemotherapy was: cispfatin/atoposid for 20 Pts, carboplatin/gemcitabine for 15 Pts, cispaltin/taxoter for 2Pts. 5 Pts received chemotheraov onlv. 32Pts received cemoradiotherapy in secventialad- ministration, The an&ed ;tsc factors were: age, sex, stageperformance sta- tus, smoking, blood biochemistry at baseline [alkaline phosphatase (PA), creati- nine (Cr). alicemia (G). aamma olutamiltransbeotidaze (GGTP) Transaminases (ALT ‘and AST)], stress: Statistical analises ‘was due by odd ratio calculation and multiple regresion in order to estabish the potential role of this parameters in survival.

Results: At the moment of analises there were IO survivors (27%) 25 death (67.6%) and 2 lost of evidence (5.4%) Odd ratio was statisticaly significant in decreasing range for: PA:2.84, smoking2.67, ALTand AST:2.25, stress:1 56, GGTP: 1.26. Multiple regresion releve the association with approximativelY the some factors with the rise of death (stress, sax, smoking). Other factors analtsed were not significant for the rise of death.

Conclusion: In the analises of the rise for death the folowig factors could Play an important rOl: PA, smoking, sex, ALT, AST, stress, GGTP. An ample analise of a large population of long survivors with advanced NSCLC must be dona in order to confirm the most important prognostic factors,

161( Metastatic site is a prognostic factor in patients with stage IV non-small cell cancer

SUnq Soo Jung’, Hee Sun Park’, Ju Ock Kim”, Sun Young Kim3. ‘Da@. of Internal Medicine. Chunanam National University Hospital, Daejon, Korea; * Department of /kerna/-Medicine, Chungnam I\iatjona/ Ukversity Hospital, Daeion, Korea; 3 Cancer Research Institute, Chungnam National UnivSrsitY Ho&ital, Daejon, South Korea

Background: The patients with stage IV non-small cell lung cancer wars known to have poor prognosis, but literature implying sense of prognosis in Patients with stage IV lung cancer is rare. This study was performed to elucidate the prOgnOStic factors for survival in patients with stage IV non-small cell lung can- cer.

Materials and method: From January 1997 to December 2001,211 patients who confirmed stage IV non-small cell lung cancer were reviewed retrospac- tively. Prongnosis were analysed by cell type performance, number Of metas- tasis, site of metastasis, age, initial LDH level at the time of diagnosis, and by either receiving active anti-cancer treatment or not, etc.

ResUltS: Median overall survival is 289 days, There was a poor Survival for patients with low performance (ECOG performance z-4) old age (285 Years old), low serum albumin level (<3g/dl), weight loss (>fO% in recent 3 months), not taken active anti-cancer therapy, 2 or more sites of metastasis, metastasis to liver, or Anemia (Hb <lOg/dL) on univariate analysis. Patients with metastasas to lUno. or brain onlv were sliahtlv better survival than those with metastasis to another site. Among the metastatic sites, single brain metastasis shows best survival. In the multivariate analysis, better survival were still in patients with ECOG performance O-l (relative risk of death [RR]: 0.563), given active anti- cancer treatment (RR: 0.483), normal serum albumin level (RR: 0.638).

Conclusion: Performance status and anticancer therapy were independent better prognostic factors as well known. Also, the survival of stage IV non-small cell lung cancer was different according to the metastatic organs. Among the metastatic sites, patients with metastasis to lung, or brain showed better sur- vival than that of other sites.

Molecular Biology 2

cl 62 Tumour Necrosis Factor-alpha Cell Signalling Events in Human Bronchoepithelial Cells

William A. Swain, Kenneth J. O’Byrne. University of Leicester, Leicester, UK

Recent experimental evidence indicates that chronic immune activation, asso- ciated with anaioaenesis. suppression of cell mediated immunity and inhibition

I I

of apoptosis, plays a central’ role in the development of malignant disease. In particular the interplay between cell death and survival/proliferation is crucial in the early stages of carcinogenesis. On a molecular level, the activation and integration of cell signalling pathways influence how this balance is set. Central to the instigation and propagation of a chronic immune response is the cytokine TNF-c(, which can exert a number of effects depending on cell type and con- text. The studies outlined here were designed to investigate if TNF-or activates sianallina oathwavs in a bronchoepithelial cell line (BEASPB) that could facil- -0

itate ent;y’into the multistage carctnogenesis paradigm. In particular we have focused upon possible crosstalk with the EGFRIPl3WAkt pathway, which is in- tegral in cell survival under conditions that would normally eliminate damaged cells. Furthermore, this pathway is known to be constitutively active in a variety of human tumours and as such represents a valid target for future pharmacolog- ical theraoies. TNF-a induces increased expression and tyrosine phosphoryla- tion of EGFR over a range of time points, most notably at 8 hrs. In addition these conditions resulted in increased phosphorylation of Akt at Ser’$73, with the peak induction also at 8 hrs. Moreover, activation of Akt by TNF-or was shown to be dependent upon oxidative stress as preincubation with N-acetyl cysteine atten- uated this effect, In contrast, treatment with EGF or H202 resulted in transient activation of EGFWAkt, which peaked at 15 mins. These results demonstrate for the first time that TNF-ol can transactivate EGFR in this cell line. Further- more, exposure to this cytokine activates Akt in an oxidative stress dependent manner. Together, these events may contribute to cell survival under inflamma- tory conditions designed to eliminate cells in the early stages of carcinogenesis. Therefore, therapies designed to interfere with these processes may prove to be beneficial in the chemoprevention of lung cancer in the future.

Novel Therapies

q Combined chemogene treatment of cyclinD1 antisense ORN (W-22) and vinorelbine eradicates by PCD chemoresistant aneupioid NSCLC overexpressing K-Ras and HER-2lneu after their DNA pattern changes to diploid

John N. Giannios’, Emmanuel Michailakise. ’ Dept.of Clinical OncologyGSHA, Filothei, Greece; ‘State Hospital of Athens, Athens, Greece

Overexoression of oncoorotein cvclin Dl has been associated with poor clinical -.-.- I

prognosis in NSCLC. Oncogenes such as K-Ras and HERP/neu send signals through the cyclin Dl protein. Activation of these oncogenes causes potent chemoresistance due to inhibition of PCD. Cyclin Dl overexpression has been associated with DNA ploidy. We obtain NSCLC cells from a chemoresistant pt. lmmunohistochemistry exhibits overexpression of K-Ras,HER-2/neu and cyclin Di. Flow cytometry has detected aneuploid DNA of NSCLC which was corre- lated with high proliferation index using as marker the Ki-67 nuclear antigen. In this studv. we aim to eradicate NSCLC cells by induction of PCD with antimitotic agent vinorelbine after we have circumvented chemoresistance by downregu- lating oncogenes K-Ras and HER-2/neu. To achieve thiswe treated NSCLC with antisense oligoribonucleotides (ORNs) called (SV-22) which repressed the translation of specific cyclin Di mRNA transcripts into protein. Thus, cyclin Dl protein levels were depleted downregulating and inactivating the HER-2/neu - K-Ras pathway. This allowed antimitotic vinorelbine to induce irreversible D2 apoptotic stage with subsequent bystander killing effect after polymerization of tumoural cytoskeleton microtubules according to morhological results obtained hv electron microscoov. In the mean t ime.DNA flow cytometry has exhibited that -I--- I

aneuploid NSCLC has changed to a diploid pattern which correlated with a low oroliferation index according to Ki-67 and BrdU. Concluding, we have achieved to eradicate aneuploid NSCLC with antimitotic vinorelbine after circumvention of the antiapoptotic HER-2/neu - K-Ras pathway by suppressing cyclin Dl with antisense oligoribonucleotides.