Blood and lymphatic vessel invasion as prognostic factors for patients with primary resected nonsmall cell carcinoma of the lung with intrapulmonary metastases

Abstracts/Lung Reduced motility related proiein-I (MRP-IICD9) gene expression as a factor of poor prognosis in non-small cell lung cancer Higashiyama M, Taki T, Ieki Y, Adachi M, Huang C-L, Koh T. Department of l’horacic Surgery, Tazuke Kofikai Med. Research Inst., Kitano Hospital, 13-3 Kamiyama-cho, Kit&u, Osaka 530. Cancer Res 1995;55:6040-4. Motility related protein-l (MRP-1)isatransmembraneglycoprotein that is identical to the CD9 antigen. In previous studies, we showed that various types of cultured tumor cells transfected with MRP-l/CD9 cDNA havelow motilityanddiminishedmetastaticpotential to thelung. More recently we used immunohistochemical procedures, immunoblotting, and reverse transcription-PCR to demonstrate that the level of MRP-l/CD9 expression was inversely related to the clinical stage of a given carcinoma of the breast. In addition, we found that the primary tumors of almost 50% of the patients had higher MRP-l/CD9 levels than their respective metastatic lymph nodes. In consideration of these findings, we have now applied reverse transcription-PCR to determine MRP-l/CD9 gene expression in lung cancer. We analyzed tumor tissues of 109 patients: 49 tumors were stage 1; 15 were stage 11; and 45 were stage III. We found thai 67 patients had MRP-l/CD9positive tumors, and that gene expression was reduced in the tumors of the remaining 42 individuals. The overall rate of survival was strikingly higher among patients with positive tumors than in those whose tumors had reducedgeneexpression (62.3 versus 34.9%; P < 0.001). Thisalso pertained to patients with adenocarcinomas of the lung (55.4 versus 26.0%; P < 0.001). Multivariate analysis with the Cox regression model indicated that MRP-l/CD9 positivity correlated better with overall survival rate than did other variables, except lymph node status. Our data suggest that low MRP- 1/CD9 expression by tumors of the lung may be associated with poor prognosis. It is conceivable that testing for MRP-l/CD9 may identify node-negative lung cancer patients and Jatients with adenocarcinomas who are at high risk for early disease ‘ecurrence.

Post-treatment cancer

management options for patients with lung

Virgo KS, McKirgan LW, Caputo MCA, Mahurin DM, Chao LC, Caputo NA et al. Department of Surgery. St. Louis Univ. Health Sciences Ctr., 3635 Vista Avenue, St. Louis, MO 63110-0250. Ann Surg 1995;222:7OO-10. Objectives: The first objective was to identify variations in patient management practice patterns after potentially curative lung cancer surgery. Patient management practice patterns were expected to range from intensive follow-up to no active surveillance. Thesecond objective was to measure whether intensity of follow-up was related to patient outcomes. Merhodr: An 18-month retrospectiveanalysis wasconducted of 182 patients with low TNM stage (36 IIIA) lung cancer who were surgically treated with curative intent over the I 1-year period from 1982 through 1992 at the St. Louis Department of Veterans Affairs Medical Center. Resulrs: Patients were followed for a mean of 33 years, until death or the end of the study. Analyses of diagnostic test and outpatient visit frequency distributions and cluster analyses facilitated the identificationof62nonintensivelyfollowedpatientsand 120intensively followed patients. Both groups were comparable at baseline, and there were no significant differences in patient outcomes attributable to intensity of follow-up. Intensively followed patients did, however, live an average of 192 days longer than nonintensively followed patients. Conciwions: Significant variations in follow-up practice patterns can exist within a single health care facility. In this analysis, variations in testandvisit frequencydidnotresultinstatisticallysignificantdifferences in patient outcomes, though the survival difference between groups suggests that some benefit might exist. Only well-designed prospective

Gmcer 14 (19%) 377-408 trials are likely to answer the question of what constitutes follow-up after potentially curative lung cancer treatment.

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Splenic metastasis from lung cancer Kinoshita A, Nakano M, Fukuda M, Kasai T, Suyama N, Inoue K et al. Depattment Internal Medicine, Nagawki City Hospital, 6-39 Shinchimachi, Nagasaki 850. Neth J Med 1995;47:219-23. Splenic metastasis from lung cancer is a rare clinical event, most often diagnosed at the time of autopsy. We report 2 cases of splenic metastasis with a primary lung cancer. The first case was a 76-year-old man presenting with a recurrent solitary splenic metastasis 14 months after surgical removal of a squamous cell carcinoma of the lung. The second patient was a R-yearaId woman who had a poorly differentiated carcinoma of the lung and multiple abdominal metastasis. We also investigated 267 autopsy cases of lung cancer from 1975 to 1992. Histologically, there were 73 cases of squamous cell carcinoma, 123 adenocarcinoma, 29 large cell carcinoma, 36 small cell carcinoma, and 7 other miscellaneous hmours. The number of splenic metastasis from lung cancer in these cases was 15 (5.6%). Splenic metastasis from a primary cancer ofthe left lung was more frequent than that from the right lung. Nine of 15 splenic metastases were smaller than 1 cm in size. Splenic metastasis was associated with liver and pancreas metastasis. All 15 autopsy cases with splenic metastasis from lung cancer had other abdominal organ metastasis. Our analysis indicates that a solitary splenic metastasis is rare. Selection of a suitable therapeutic approach is important.

Blood and lymphatic vessel invasion as prognostic factors for patients with primary resected nonsmall cell carcinoma of the lung with intrapulmonary metastases Fujisawa T, Yamaguchi Y, Saitoh Y, Hiroshima K, Ohwada H. Department of Surgery, ht. of Pulmonary Cancer Research, Chiba University School of Medicine, I -8-I) Inohana. Chuo-ku. Chiba 260. Cancer 1995;76:2464-70. Background. Thenew classification of intrapulmonary metastases of lung cancer was proposed by the American Joint Committee on Cancer; however, the prognostic factors are heterogeneous and not yet fully clarified. In this study, theauthors evaluated the prognostic factors for and the possible routes of intrapulmonary metastases. Methods. The factors influencing the prognosis of primary resected nonsmall cell lung carcinomas with intrapulmonary metastasis in the resected specimens were evaluated according to the Cox proportional hazards model using a total of 66 nonsmall cell lung carcinomas. The possible routes of tumor spread via the blood or lymphatic vessels also were evaluated. Results. The overall 5-year survival rate was 26.146, and the statistical analysis of survival curves revealed a significant difference with regard to N classification (P = 0.042). site of intrapulmonary metastasis (P = 0.012), blood vessel invasion (P = 0.0046), and lymphatic vessel invasion (P = 0.0267); there were no significant differences in relation to age, sex, histology, differentiation, T classification, tumor size, stage, number of intrapulmonary metastases, or size of intrapulmonary metastasis. Multivariate analysis according to the Cox proportional hazards model identified a significant correlation between survival and blood vessel invasion (P = 0.044) and lymphatic vessel invasion (P = 0.042). suggesting independent prognostic significance. The correlation between site of intrapulmonary metastasis and the ratio of blood or lymphatic vessel invasion showed a significantly lower ratio of blood vessel invasion in cases with intrapulmonary metastases at sites central to the primary lesion or in different segment(s) compared with those in cases with intrapulmonary m&stases at sites peripheral to the primary lesion or in ipsilateral different lobe(s), suggesting a possible lymphatic vessel route of tumor spread. Conclusion. Blood vessel and lymphatic

Abstracts/Lung

Comer I4 (1596) 377-408

vessel invasion are important clinical factors in evaluating prognosis and the route of tumor spread in primary resected nonsmall cell carcinoma with intrapulmonary metastasis.

Prognostic significance of ~53 and ras p21 expression in nonsmall cell lung cancer Fujino M, Dosaka-Akita H, Harada M, Hiroumi H, Kinoshita I, Akie K et al. First Depanment of Medicine, Hokkaido Univ. School of Medicine, North 15, West 7, Kira-ku, Sapporo 060. Cancer 1995;76:2457-63. Background. Alterationsofthep53 geneareoneofthemostcommon genetic changes in various types of cancer, including lung cancer. Abnormalities in the ras genes, including point mutations and overexpression, are another common feature in the molecular biology of lung cancer and are associated with a poorer prognosis. The authors’ purpose was to determine expression of the mutated p53 gene in nonsmall cell lung cancer (NSCLC) specimens that were studied for expression of res ~21 and to document whether altered p53 expression was also an important factor for survival. Methods. Ninety-six patients with NSCLC underwent surgical resection between 1977 and 1985,63 of whom received postoperative combination chemotherapy. None received radiation therapy. Tumor specimens were analyzed for altered ~53 expression by immunohistochemistry. Univariate and multivariate analyses were performed toassess theassociation betweenp53 expression and survival. Results. Fifty- six (58 W) of 96 tumor specimens showed altered ~53 expression, and 91 patients were analyzed for survival. Altered ~53 expression did not correlate with clinicopathologic characteristics except for postsurgical pathologic tumor (pT) classification. The patients with altered ~53 expression survived for a significantly shorter period after surgery than those without ~53 expression, including all patients whounderwent resectionandpotentially curative resection (P = 0.02 and P = 0.046, respectively, generalized Wilcoxon test). Multivariate analysis showed independent prognostic significance for altered ~53 expression (hazard ratio [HR] = 1.72, P = 0.04) and surgical cure (HR = 4.69, P < 0.001). The combined analysis of mutated ~53 and ras p21 expression in the same tumor specimens revealed that patients with p53- and res p21-negative tumors survived the longest among thosewith different ~53 and ras p21 features (P = 0.005, generalized Wilcoxon test). Conclusion. Altered ~53 expression is a significant and independent negative prognostic factor for patients with surgically resected NSCLC. Combined immunohistochemical analysis of mutated ~53 and ras p21 expression can divide patients with NSCLC into more accurate prognostic groups. If the current fmdingscanbeconfirmedin largerprospectivestudies, combined immunohistochemical analysis of mutated ~53 and res p21 expression can be a useful clinical tool for stratifying patients with NSCLC into accurate prognostic groups and for identifying the population with a different risk of recurrence.

Brain metastases from lung and breast cancer. Differences in patterns of spread and irognosis Nieder C, Niewald M, Hagen T. Abteilung fur Strahlentherapie, Radiologische Vniversitatsklinik, D-66421 Homburg/Saar. Radiologe 1995;35:816-21. Evaluation of 135 cases with brain metastases from non-small-cell lung cancer (group 1) compared with 51 cases from small-cell lung cancer (group 2) and 56 cases from breast cancer (group 3) showed that the frequency of solitary metastaaes was significantly higher in group 1 and 3. However, in group 2 lesions without surrounding edema occurred more frequently. The rate of patients with extracerebral metastases was significantly higher in groups 2 and 3. The longest median interval between primary tumor and brain metastases was observed in breast cancer patients. The highest local remission rate was seen in small-cell

lung cancer if patients who received whole-brain irradiation of 30 Gy alone were compared (63 96 vs 45 96 in group 1 and 52 96 in group 3). However, with regard to clinical course no significant differences were recorded Survival of lung cancer cases was similar, whereas breast cancer cases survived significantly longer, both after radiotherapy alone and after surgery plus radiotherapy. This might be caused by differences in the natural course of the two diseases as well as adjuvant treatment modalities like hormone and chemotherapy. In conclusion, because long-term survivors were observed only in the breast cancer group, these patients probably have the highest chance of profiting from a locally aggressive treatment approach.

Comparison between serum levels ofcarcinoembryonicantigen, sialic acid and phosphohexose isomerase in lung cancer Pate1 PS, Raval GN, Rawal RM, Pate1 GH, Balar DB, Shah PM et al. Biochemistry Division, Department of Cancer Biology, Gujarat Cancer and Research Inst., Asarwa, Ahmedabad 380 016. Neoplasma 1995;42:271-4. The identification and application of quantifiable tumor markers as adjuncts to clinical care is a story ofboth success and failure. The present study compared serum levels of carcinoembryonic antigen (CEA) with totalsialicacid/totalpmtein(TSAfIP)mtioandphosphohexoseisomerase (PHI) in 192 untreated lung cancer patients as well as 80 age and sex matched controls (44 non-smokers and 36 smokers). CEA values were significantly raised (p < 0.001) in smokers as compared to the nonsmokers; whereas,TSA/TP and PHI values were comparable between the hvo groups of the controls. All the biomarkers were significantly elevated (p < 0.001) in untreated lung cancer patients as compared to the controls. Receiver operating characteristic curve analysis revealed higher sensitivities of TSA/TP and PHI as compared to CEA at different specificity levels between 60 96 and 95 96. Mean values of CEA, TSAl TP and PHI were higher in non-responders compared to the responders. The results indicate that TSA/TP and PHI are superior tumor markers than CEA for lung cancer patients.

Pulmonary function changes in lung-cancer patients treated with radiation with or without carboplatin Green HJM, Van der Mark TW, Van der Leest AHD, De Vries EGE, Mulder NH. Depanment of Pulmonary Diseases. University Hospital Groningen, OostersingelS9, 9713 IZ Groningen. Am J Respir Crit Care Med 1995;152:2044-8. In order to examine changes in pulmonary function in patients with locally advanced non-small-cell lung cancer (NSCLC) before, during, and after standard radiotherapy or combined chemoradiotherapy, we conducted a prospective study involving patients with such cancer, who were treated with radiation alone or with concurrent radiation and carboplatin from October 1992 to February 1994 at the University Hospital in Gromngen, the Netherlands. Thirty-five patients were treated Two patientswereexcluded becauseofpulmonary emphysema. Pretreatment values of TLC, VC, the gas- transfer coefficient (KCO), thepulmonarydiffusingmembranefactor(Dm), andpulmonarycapillary blood volume (Vcap) were lower than in normal subjects and patients with chemotherapy-naive germ-cell carcinoma who had a similar pulmonary tumor load as the result of hematogenous metastases. The NSCLC patients’ reduced KC0 was explained by a decrease in Dm, a measure of alveolar-capillary membrane disturbance, and a similar decrease in Vcap. Pretreatment TLC did not correlate with Vcap or Dm, indicating extra- rather than intrapulmonary vascular and lymphatic obstruction as an explanation for the reduced Vcap and Dm. Locally advanced NSCLC was treated with radiation (n = 16) or combined continuous carboplatin infusion and radiation (n = 17). No changes in TLC, VC, KCO, Dm, or Vcap were observed during and 2 wk after the