235

were Confirmed. In conuast to previously published ~53 mutations in other human tumors, the ~53 gent mutatmns in NSCLC were diverse with regard to the locauon and nature of Ihc mumlions. The region corresponding to codons 144.166, which is outside Ihc evohmonarily conservedregions, wasafrequcntsiteofp53genemuta~onsinNSCLC. The presence of a ~53 gene mutation was not associated wth age. sex, hlsmloglcal types, culture site, treaunent intent, presence of prior cymtoxic ueatmem, neuroendocrine differentiation, median culrure time or patient survival. The prevalence of p53 mutations in cell lines with ras mutations did not differ from Ihat in cell hncs without ras muwons. However, ~53 gene mutations in NSCLC cell hnes with ras mutatmns tended to cluskx in exon 8, suggesting the presence of a functmnal domain of the ~53 gene relating to imcracuon with the ra.s gene. We conclude that ~53 and ras mutaalions are frequent and appar- ently mdepcndcnt geneuc alieratmns whxh play different roles in the pathogenesis, progression and prognosis of NSCLC.

~53 Mutations in non-small cell lung cancer in Japan: Association

behveen mutalions and smoking

Suzuki H, Takahashi T, Kuroislx T, Suyama M, Ariyoshi Y, Takahashi T et al. Laboratory of Chemotherapy. Aichi Cancer Center Research Instttute, Chikusa-ku, Nagoya 464. Cancer Res 1992;52:134-6.

The ~53 gene has been implicated as a tumor suppressor gene involved in the pathogenesls of lung cancer. Our previous study revealed that the pS3 gene is frequently mutated with a dwinct nucleo- tide subsdumon pattern in small cell lung cancer specimens in Japanese patlents. In this study. we examined 30 primary, resected non-small cell lung cancer samples in Japanese patients using complementary DNA- polymerasechainreactionandsequencing. Mulationschangmgthcp53 codmg sequence were found m 14 of 30 tumor samples (47%), while G:C Lo T:A uansversions which are uncommon in other cancers such as colon cancer were Ihe most frequently observed mutauons, in agrcc- ment with an earlier report on non-small cell lung cancer in American pauents. Furthermore, the present study shows for the first lime that in univariale and multivariakz analyses, the presence of ~53 mu(ations is closely assoclaled with hfetime cigaretrc consumption.

Energy-dependent processes involved in reduced drug accumula-

tion in multidrug-resistant human lung cancer cell lines without P-

glycoprotein expression

Versanwoon CHM, Broxterman HJ, Pinedo HM, De Vries EGE, Feller N, Kuiper CM et al. Department ofMedical Oncology, Free University Hospital, i3R 232, De Boelelaan I1 17. 1081 HV Amsterdam. Cancer Res 1992;52:17-23.

Mechanisms contihuting to reduced cytotoxic drug accumulation were studied in two multidrug-reswant (MDR) human lung cancer cell lines wllhout P-glycoprotein expression. In these (non-small cell) SW- 1573RRl20 and (small cell) GLC4/ADR MDR cells, the steady-state accumulation of [“Qlaunorubicin was 30 and 124, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced accumulation of daunorubicin in the SW-1573/2Rl20 and GLC4/ADR cells was accompanied by a lower Initial Qmin) uplakerateofthlsdrug. Nodifference in initialeffluxrate of daunorubicin from preloaded cells could be detected between sensi- tiveand resistant SW-1573 cells. However,daunorubicin wasextruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy mecabohsm inhibitors sodium azide and deox- yglucose, Ihe reduced daunorubicm accumulations in the SW-1573/ 2Rl20 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on drug uptake were already apparent durmg the earliest rnezwred time points (~15 s). Also, the enhanced efflux of daunorubicin from GLC4/ADR cells was inhibited. In ATP- depleted cells. the intracellular pH was lowered by -0.3 units in resistant as well as in sensitive cells. The lower intracellular pH, however, could not accouru for the increase in daunorubicin accumulation in the

resistant cells. Also, for vincristine and etoposlde, the Increases in drug accumulationunderenergy-deprivedconditionsweremorepronounced in the resistant SW-1573/2Rl20cells than in the parent SW-1573 cells. These resuks suggest that accumulation of drugs in the non-P-glycoprotein MDR human lung carcinoma cell lines SW-1573/2Rl20 and GLCV ADR is reduced by an energy-dependent drug expon mechanism which prevents efficient transport of drug to the target. Since P-glycoprotein expression in lung tumors is generally low, these MDR lung cancer cell lines can be used as a model to study alternative mechanisms leadmg 10 mukidmg resistance in this tumor type.

Correlation of L-myc RFLP with metastasis, prognosis and mul-

tiple cancer in lung-cancer patients Kawashima K, Nomura S, Hirai H, Fukushi S, Kambe T. Takeuchi K et al. Btology Division, Namnnl Cancer Cenler Research Institute, To- kyo. Int J Cancer 1992;50:557-561.

For further study of the correlation of L-myc restriction-fragment- length polymorphism (RFLP) and metastasis of lung cancer to lymph nodes or other organs at the time of surgery, L-myc RFLP was analyzed in 252 Japanese lung-cancer patients. A close correlation between L- myc RFLP and metastasis was confirmed m this large number of patients (p = 0.01). The correlation was particularly pronounced in cases of adenocarcinoma and squamous-cell carcinoma. Poor prognosis (additional metastases after surgery) was observed in lung-cancer patients with L-S (identified as long and short bands produced with EcoRl) and S-S type L-myc RFLP. In addition, Ihe death rate of lung- cancer patients with the L-S and S-S types was greater than that of those with the L-L type. Lung-cancer patients of the L-S and S-S types had almost 4 times higher incidence of multiple cancer in the lung, pharynx and other organs than those with the L-L type. Our results indicate that, in patients wlh lung cancer, genetic disposition with respect to the L- myc gene influences the extent of metastasis, the incidence of multiple cancers and prognosis.

Pathology Spindle cell carcinoma of the lung. A clinicopathologic study of

three cases

Matsui K, Kitagawa M. Department ofPathology, Faculty ofMedrctne, Toyama Medical and Pharmaceutical Universiry, 2.630 Sugitani. Toyann 930-01 Toyama. Cancer 1991: 67~2361.7.

Two cases of monophasic spindle cell carcinomas and one case of adenosquamous carcinoma with the spindle cell component located in the lower respiratory tract are presented. In the biphaw tumor, arcas of transition from carcinoma to sarcomalow spindle cells were clearly found. The two monophasic tumors and Ihe spmdle ccl1 componem of the biphaslc tumor were histologically characterized by sheets of spindle cells. However, by electron microscopic and immunohisto- chemical study, several features of squamous epithelial differentiation were found in the spindle cell areas of all cases. Keraun and vimentin were, in various degrees, coexpressed in all the cases. Thercforc. it is supposed that the spmdle cell component displays a spectrum of phenotypes originating from squamous cell carcinoma, and monopha- sic spmdle cell carcinoma is considered as a kmd of the extreme phenotype of squamous cell carcinoma pretending mesenchymal dif-

fercnGauon.

Does malignant small round cell tumor of the thoracopulmonary

region (Askin tumor) constitute a clinicopathologic entity? An

analysis of 30 cases with immunohistochemical and electron-mic-

roscopic support treated at the Institute Gustave Roussy

Conlesso G. Llombart-Bosch A, Terrier P, Peydro-Olaya A, Henry- Amar M, Oberlin 0 et al. Departamento de Patologia, Facultad de Medicina. Avemda Blasco lbanez 17, 46010 Valencia. Cancer 1992:69:1012-20.

236

The morphology and clinical outcome of 30 patients with malignant small round cell tumors located in the thoracopulmonary region (Askin tumor) are reported. Histologically, all tumors had similar patterns, with small round- to-oval cells and a lobulated stroma. Immunohisto- chemical analysis always resulted in positive staining for one or several neural markers. No significant differences were found compared with the immunomarkers in 26 typical Ewing’s sarcomas located outside the thoracic wall. In three specimens, electron microscopy confirmed the presence of membrane-bound neurosecretory granules. It was con- firmed that there is a remarkable similarity among all malignant small roundcell tumors, including Askin tumor and Ewing’s sarcoma. Over- all survival waspoorwitha2-yearrateof38% anda6-yearrateof 14%.

An evaluation of the prognostic significance of alpha-1-antitrypsin expression in adenocarcinomas of the lung: An immunohistnehemical analysis Higashiyama M. Doi 0. Kodama K, Yokouchi H, Tateishi R. Depart- ment of Thoracic Surgery, The Center for Adult Diseases, Osaka. 3 Nakzmichi I-chome, Hig&imri-hx, Osaka 537. Br 1 Cancer 1992;65:3@ 2.

Expression of alpha-l-antitrypsin (AAT) in tumour cells of I02 surgically resected lung adenocarcinomas was examined by immu- nohistochemical method using anti-AAT antiserum. While only 13 cases (13%) were negative for AAT expression, 89 cases (87%) con- tained AAT at varying degrees. The degree of AAT-positive tumour cells was significantly higher in advanced cases than in early cases. Clinical follow-up study of the patients, particularly in stage 1, showed that strongly AAT-positive cases have poor prognosis than weak-to- moderately AAT-positive or AAT-negative cases, Thus, AAT expres- sion status in tumour cells of lung adenocarcinoma may be a biological marker of prognostic significance in regard to tumour growth.

Malignant granular cell tumor Uzoaru I, Fiifer 6, Ray V, Hubbard-Shepard M, Rhee H. Department of Pathology, Hektoen Institute of Medical Research, Cook County Hos- pitol, 627 S Wood SI., Chicago, IL 60612. Arch Pathol Lab Med 1992;116:206-8.

We report a case of malignant granular cell tumor of the chest wall that recurred in the right breast with axillary lymph node metastases. The recurrent tumor clinically and grossly mimicked a breast carci- noma.Electronmicroscopyandimmunohis~hemicaltechniqueswere used to confirm the cytologic and histologic diagnosis of granular cell tumor. The importance of true metastases in the diagnosis of malignant granular cell tumor and their differential diagnosis are discussed.

Clinical assessment A comparative trial of LC9018 plus doxorubicin and doxorubicin alone for the treatment of malignant pleural effusion secondary to lung cancer Masuno T, Kishimoto S, Ogura T, Honma T, Niitani H, Fukuoka M et al. Department ofMedicine HI. Osaka Untversity MedicalSchool. I-50 Fuktuhima. l-chrome, Fukmhim-ku. Osaka553. Cancer 1991:68:1495- 1500.

The efficacy and safety of intrapleural LC9018 (Yakult Co. Ltd., Tokyo, Japan) with or without doxorubicin (Adriamycin; Adria Labc- ratories, Columbus, OH) were evaluated in a randomized, controlled trial performed in 95 patients with malignant pleural effusions secon- dary to lung cancer. Seventy-six patients were eligible for the assess- ment of efficacy. The response rate for treatment with intrapleural doxorubicin plus LC9018 (38 patients) was 73.7%. which was signifi- cantly higher than the response rate of 39.5% for the control group treated with doxorubicin alone (38 patients) (P < 0.01). The LC9018 group also showed a significantly greater improvement in performance status (PS) and symptoms (chest pain, chest discomfort, and anorexia)

than the control group (P < 0.05). A significant prolongation of survival was noticed in the LC9018 group (P < 0.05). The main side effects of LC9018 were fever and transient hepadc dysfunction, but there were no serious adverse reactions. These results suggest that the irmapleural instillation of LC9018 can be recommended for the treatment of malignant pleural effusions.

Resting energy expenditure in patients with non-small cell lung cancer Fredrix EWHM, Wouters EFM, Soeters PB, Van der Aalst ACJM, KesterADM,VonMeyenfeldtMFetal.DeparfmentofHumanBiology. University of Limburg, P.O. Box 616. 6200 MD Maastricht. Cancer 1991;68:1616-21.

Resting energy expenditure (REE) was determined in 30 patients with newly detected non-small cell lung cancer. Measured values were compared with the values predicted by the Harris-Benedict (HB) formula. MeanREEwas20% higherthanpredicted. Sixtypercentofthe patients (18 patients) had an elevated REE (greater than or equal to 115%) compared with this formula. The prevalcncc of hypermetab- olism in a group of patients with gastric and colorectal cancer was only 13%(13of 104patients). Whencorrectedforfat-freemass(FFM),REE was still significantly higher (P less than 0.001) in the lung cancer group compared with the gastric andcolorectal cancer group. Whereas weight loss in healthy men leads to an adaptational decrease in energy expen- diture (EE), weight loss in the patients with lung cancer was accompa- nied by an increase in REE. Tumor stage, tumor localization, pulmo- nary function, or smoking behavior could not explain the observed increase in REE in patients with lung cancer. Therefore, these mcta- bolic alterations appear to be tumor mediated.

ParaneoplasticCushing’ssyndromeasanadversepr~nosticfactor in patients who die early with small cell lung cancer Dimopoulos MA, Femandez JF, Samaan NA, Holoye PY, Vassilo- poulou-Sellin R. Section of Endocrinology, M. D. Anderson Cancer Center, University of Texas, Box IS, 1515 Holcombe Boulevard, Houston, TX 77030. Cancer 1992;69:66-71.

The potential role of paraneoplastic Cushing’s syndrome (CS) was assessed on the clinical course of patients with small cell lung cancer. A retrospective comparison was done of complications and survival rates according to the presence or absence of CS in patients with small cell lung cancer who died within 90 days of initial administration of chemotherapy. The setting was a comprehensive cancer center. Eleven patients with clinical and/or biochemical features ofCS were identified from among 90 patients who presented between 1979 and 1989 with previously untreated small cell lung cancer. The group with CS and the control patients were compared in terms of clinicopathologic prognos- tic factors, treatment, and outcome. Patients with CS were comparable to the control patients in all prognostic factors, including tumor stage and cancer treatment. Eighty-two percent of patients with CS (nine of 11) died within 14 days of initiation of chemotherapy compared with 25% of the control patients (19 of 77). The median survival from initi- ation of chemotherapy was 12 days for the 1 I patients with CS and 27 days for the 77 control patients. In 45% of the patients with CS (five of 11). death was attributed to opportunistic fungal or protozoa1 infectron compared with 8% of control patients (six of 77). Paraneoplastic CS is a previously unrecognized adverse prognostic factor for patients with small cell lung cancer. Those with both small cell lung cancer and CS have severe opportunistic infections soon after the initiation of chemo- therapy, leading to clinical deterioration and death before antineoplas- tic benefit from chemotherapy can be achieved. Biochemical control of CS for at least 1 to 2 weeks before initiation of chemotherapy may ameliorate the poor prognosis.