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Small Cell Lung Cancer - October 2000

The following citations were newly added to the CANCERLIT database on the subject of Small Cell Lung Cancer for the month of October 2000.

Nicotine effects on proliferation and the bombesin-like peptide autocrine system in human small cell lung carcinoma SHP77 cells in culture.

Unique Identifier: 20342512

Author: Novak J; Escobedo-Morse A; Kelley K; Boose D; Kautzman-Eades D; Meyer M; Kane MA

Source: Lung Cancer 2000 Jul;29(1):1-10

Address: Section of Medical Oncology, Denver Veterans Affairs Medical Center 111F, University of Colorado Health Sciences Center and University of Colorado Cancer Center, 1055 Clermont St., Denver, CO 80220, USA.

    OBJECTIVES: To determine whether nicotine affects the proliferation and expression of the bombesin-like peptide autocrine system in human small cell lung carcinoma (SCLC) SHP77 cells compared with nonmalignant human bronchial epithelial BEAS 2B cells as non-neuroendocrine controls. METHODS: Human lung cells were cultured in defined serum-free medium with various concentrations of nicotine added for various times. Proliferation was measured by cell counts and colorimetric assay, bombesin-like peptide receptor expression was assayed by specific binding assays and quantitative competitive PCR, and bombesin-like peptides determined by ELISA. RESULTS: Nicotine significantly stimulated the growth of human SCLC SHP77 and NCI-H865 cells, but not BEAS 2B cells. Bombesin-like peptide receptor specific binding and mRNA expression were not affected by nicotine exposure in SHP77 cells or BEAS 2B cells. An increase in SHP77 cellular bombesin-like peptide content was observed. CONCLUSIONS: Human SCLC SHP77 cells express the components of the bombesin-like peptide autocrine system. Increased proliferation in the presence of nicotine may be due in part to increased levels of bombesin-like peptides in SHP77 cultured in nicotine. Nicotine effects on nonmalignant pulmonary neuroendocrine cells may provide additional insight into how nicotine itself may promote lung carcinogenesis.

Immunohistochemical detection of mutant p53 protein in small-cell lung cancer: relationship to treatment outcome.

Unique Identifier: 20342514

Author: Gemba K; Ueoka H; Kiura K; Tabata M; Harada M

Source: Lung Cancer 2000 Jul;29(1):23-31

Address: Second Department of Internal Medicine, Okayama University Medical School, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan.

    We investigated the expression of mutant p53 proteins in small-cell lung cancer (SCLC) immunohistochemically, by identification of stabilized mutant p53 proteins with a much longer half-life than the wild-type protein. Of 103 tumor specimens obtained by transbronchial tumor biopsy for histologic diagnosis, 52 (50%) showed positive staining for p53 protein with a p53 monoclonal antibody, DO-1. Positive staining for p53 protein was not correlated with age, sex, performance status, lifetime cigarette consumption, serum concentration of neuron-specific enolase and extent of disease. Complete response rates in patients with a mutant p53 protein-positive tumor were significantly lower than those in p53-negative patients (25% versus 59%; P=0.0005, by chi-square test). Similarly, survival periods in patients with a mutant p53 protein-positive tumor were significantly shorter than those in mutant p53-protein-negative patients (10.8 months versus 20.6 months; P=0.0001, by generalized Wilcoxon test). Multivariate analysis using Cox's proportional hazards model revealed that the presence of mutant p53 protein is an independent factor associated with differences in overall survival (hazards ratio=2.72; 95% confidence interval, 1.71-4.34; P=0.0001). These observations suggest that the expression of mutant p53 proteins in SCLC may be an important factor predicting poor prognosis.

The inhibitory effect of cisplatin in combination with irradiation on lung tumor cell growth is due to induction of tumor cell apoptosis.

Unique Identifier: 20351764

Author: Fujita M; Fujita T; Kodama T; Tsuchida T; Higashino K

Source: Int J Oncol 2000 Aug;17(2):393-7

Address: Third Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.

    Chemoradiation is becoming an important method of treatment of advanced lung cancer. Although many studies have demonstrated the efficacy of chemoradiation against lung tumors, the mechanism of its effect is still poorly understood. In this study, we analyzed the combined effect of cisplatin (CDDP) and irradiation on human lung cancer cell lines (PC-9 and Lu 134A) in vitro using MTT assay and isobologram analysis. To study whether the combined effect is due to induction of tumor cell apoptosis, we further quantified the nuclear fragmentation of tumor cells by flow cytometric analysis. Our study revealed that a combination of cisplatin and irradiation had an additive inhibitory effect on both PC-9 (adenocarcinoma) and Lu 134A (small cell carcinoma) tumor cell growth. Cisplatin improved the sensitivity of tumor cells to irradiation. The use of both cisplatin and irradiation doses could be reduced without decreasing the inhibitory effect. The additive inhibitory effect was correlated positively with the levels of tumor cell nuclear fragmentation. We concluded that combination treatment with cisplatin and irradiation is effective against lung tumors, not only small cell carcinoma but also non-small cell carcinoma, and the inhibitory effect was due to induction of tumor cell apoptosis.

A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma.

Unique Identifier: 20273357

Author: Eerola AK; Soini Y; Paakko P

Source: Clin Cancer Res 2000 May;6(5):1875-81

Address: Department of Pathology, University of Oulu, Finland.

    Tumor-infiltrating lymphocytes, apoptosis, and angiogenesis have a pivotal role in tumor growth control. This study was undertaken to analyze the associations of these factors and their role in the prognosis, defined as survival time, of 56 patients operated on for small cell lung carcinoma (SCLC). Immunohistochemically detected T cells and macrophages were the most abundant tumor-infiltrating lymphocytes in SCLC, whereas the number of B cells was small. There was a trend in the number of intratumoral cytotoxic/suppressor CD8 cells that were associated with the extent of apoptotic bodies in SCLC, as measured by in situ 3'-end labeling of apoptotic DNA. A high number of intratumoral T cells and CD8 cells were associated significantly with a low tumor size (<3 cm) and low tumor stage (stages I-II). A high number of intratumoral macrophages were associated with a low tumor stage and angiogenesis, as measured by microvessel density. A high number of T cells, CD8 cells, and macrophages and a low tumor size (<3 cm) were prognostic markers predicting favorable survival time of the patients with SCLC.

Serum HDL cholesterol concentration in patients with squamous cell and small cell lung cancer.

Unique Identifier: 20394242

Author: Siemianowicz K; Gminski J; Stajszczyk M; Wojakowski W; Goss M; Machalski M; Telega A; Brulinski K; Magiera-Molendowska H

Source: Int J Mol Med 2000 Sep;6(3):307-11

Address: Department of Experimental and Clinical Biochemistry, Silesian Medical Academy, 40-752 Katowice, Poland.

    Cancer patients often present altered serum lipid profile including changes of HDL cholesterol level. The aim of our work was to evaluate serum level of HDL cholesterol in patients with squamous cell and small cell lung cancer and its dependence on histological type and clinical stage of lung cancer. Fasting serum level of HDL cholesterol was analysed in 135 patients with newly diagnosed lung cancer and compared to a control group of healthy men. All lung cancer patients, as well as subgroups of squamous cell and small cell lung cancer had statistically significantly lower HDL cholesterol concentration than controls. There were no statistically significant differences of HDL cholesterol level between the histological types or between clinical stages of each histological type of lung cancer.

Opioid analgesic-induced apoptosis and caspase-independent cell death in human lung carcinoma A549 cells.

Unique Identifier: 20394247

Author: Yoshida A; Tokuyama S; Iwamura T; Ueda H

Source: Int J Mol Med 2000 Sep;6(3):329-35

Address: Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki 852-8521, Japan.

    We characterized anticancer effects of opioid analgesics that are clinically used for cancer patients for pain relief. Treatment with 100 microM buprenorphine, a representative analgesic, induced cell death of human carcinomas, such as A549 (squamous epithelial cell of lung cancer), MCF-7 (breast cancer) and N417 (small cell of lung cancer), but not in KATO III (gastric cancer) cells as evaluated by alamar blue assay. Among 18 clinically utilized and related analgesics, buprenorphine and loperamide showed potent inhibition of cell viability. However, these anti-cancer effects were not affected by opioid receptor antagonists nor by pertussis toxin. Buprenorphine-induced cell death occurred as early as 1 h after the addition, and its T1/2 of cell viability inhibition was 3 h. The cell death manifested the characteristics of apoptosis, such as DNA-laddering and nuclear fragmentation, which were sensitive to a caspase inhibitor, Z-Asp-CH2-DCB. The nuclear fragmentation was independent of cell cycle phase specificity. The activity of caspase-3-like protease which is known to be closely related to apoptotic DNA laddering was markedly enhanced by buprenorphine. However, the inhibition of cell viability by buprenorphine was not affected by the caspase inhibitor. These findings suggest that some opioid analgesics induce typical apoptotic features sensitive to the caspase inhibitor, while also inhibition of cell viability insensitive to the inhibitor.

Gene product immunophenotyping of neuroendocrine lung tumors. No linking evidence between carcinoids and small-cell lung carcinomas suggested by multivariate statistical analysis.

Unique Identifier: 20392730

Author: Sampietro G; Tomasic G; Collini P; Biganzoli E; Boracchi P; Bidoli P; Pilotti S

Source: Appl Immunohistochem Molecul Morphol 2000 Mar;8(1):49-56

Address: Division of Anatomical Pathology, Istituto Nazionale Tumori, Milan, Italy.

    Fifty-three neuroendocrine lung tumors (24 carcinoids, one atypical carcinoid, five large-cell neuroendocrine carcinomas, and 23 small-cell lung carcinomas) were investigated for immunocytochemical expression of several gene products, i.e., p53, Rb, bcl-2, c-kit, mdm-2, cdk-4, p21 proteins, and proliferation index as assessed by MIB-1. The goal of the study was to explore the relationships between histotypes in light of their own gene product-based immunophenotypical profiles. To this aim we applied the multiple correspondence analysis, which is an exploratory statistical multivariate technique that converts a data matrix into a particular type of graphic display in which the rows and columns are depicted as points. Such statistical analysis displayed that some categories of the gene product-based immunophenotyping variables are grouped in the plot identifying three groups: the first group related to carcinoids, the second to small-cell carcinomas, and the third to large-cell neuroendocrine carcinomas. These data support the evidence that carcinoids and small-cell carcinomas are two distinct, apparently immunogenotypically unrelated entities among neuroendocrine lung tumors and that atypical carcinoids and large-cell neuroendocrine carcinomas seem not to represent intermediate steps between them.

[Northern blot analysis of nm23 gene expression in human lung cancer]

Unique Identifier: 20376440

Author: Liu L; Qin Y; Zhou Q

Source: Chung Hua Chung Liu Tsa Chih 1998 Sep;20(5):342-4

Address: Department of Thoracocardiac Surgery, First University Hospital, West China University of Medical Sciences, Chengdu.

    OBJECTIVE: To investigate the role of nm23 gene expression in lung cancer. METHODS: Forty human lung cancer tissues and 19 non-cancerous pulmonary tissues were studied for their nm23-H1 and nm23-H2 mRNA expression with nonradioactive Northern blot hybridization. Correlation of nm23 mRNA expression with clinical features of lung cancer was analyzed. RESULTS: The mRNA expression of nm23-H2 gene in poorly differentiated squamous-cell carcinoma was significantly decreased compared to that in moderately differentiated squamous-cell carcinoma. The mRNA expression of nm23-H1 and nm23-H2 genes in small cell lung cancer was decreased compared to that in squamous-cell carcinoma. No significant difference in nm23 mRNA expression was observed in lung cancers with and without lymph node metastasis, nor was there significant difference in patients with lung cancers in different stages. CONCLUSION: The mRNA expression of nm23 gene is correlated with the degree of differentiation of lung cancer, but there is no evidence of metastasis suppression effect by nm23 gene.

Increasing use of bronchoscopic needle aspiration to diagnose small cell lung cancer.

Unique Identifier: 20398929

Author: Chin R Jr; Cappellari JO; McCain TW; Case LD; Haponik EF

Source: Mayo Clin Proc 2000 Aug;75(8):796-801

Address: Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC 27157, USA.

    OBJECTIVE: To review pathology reports to determine whether a temporal change in diagnostic procedures that included bronchoscopic needle aspiration (BNA) in evaluation of small cell lung cancer (SCLC) had occurred. METHODS: A retrospective review of the computerized pathology database of the Wake Forest University Baptist Medical Center from 1990 to 1998 was performed. All pathology reports of patients newly diagnosed with SCLC were reviewed and abstracted. RESULTS: The number of patients newly diagnosed with SCLC during the 9-year study period totaled 277. Of these, 173 underwent bronchoscopy. From January 1990 to December 1991, 32% (8/25) of bronchoscopies done in patients with SCLC included BNA compared with 81% (120/148) (P < .001) from January 1992 to December 1998. In addition to the increased use of BNA in patients with SCLC undergoing bronchoscopy, the overall diagnostic yield for BNA in SCLC significantly increased over the 9-year study period from 50% (4/8) in 1990 and 1991 to 88% (106/120) thereafter (P = .001). Overall sensitivity of BNA during bronchoscopy was 86% for SCLC with only a small increase in sensitivity with use of all procedures (including BNA) to 91%. The use of forceps biopsy and bronchial brushings decreased over this period. CONCLUSION: With progressive experience with BNA, the frequency of its performance and its diagnostic yield in patients with SCLC increased markedly. The SCLC yield may be a worthwhile marker of BNA program development.

[Pilot study of dose intensive weekly chemotherapy followed by cisplatin plus etoposide with concurrent thoracic irradiation for limited-disease small-cell lung cancer. West Japan Thoracic Oncology Group]

Unique Identifier: 20401298

Author: Isobe T; Fukuoka M; Negoro S; Sugiura T; Kawahara M; Kudoh S; Araki J; Nakagawa K; Yokozaki M; Yamakido M; Ariyoshi Y

Source: Gan To Kagaku Ryoho 2000 Jul;27(8):1091-6

Address: Second Dept. of Internal Medicine, Hiroshima Unversity Faculty of Medicine.

    It was reported from a previous randomized trial (NEJM 329: 1848, 1993) that a moderate increase in the initial dose of cyclophosphamide and cisplatin improves the survival of patients with LDSCLC. Rapid administration of several active agents over a short treatment period, such as the CODE regimen, is a potentially usefully strategy for increasing the initial dose intensity. Based on these findings, we conducted a pilot study of CODE (C: 25 mg/m2, day 1, weeks 1-4, O: 1 mg/m2, day 1, weeks 2, 4, D: 40 mg/m2, day 1, weeks 1, 3, E: 80 mg/m2, days 1-3, weeks 1, 3) chemotherapy for the first 4 weeks followed by PE therapy (P: 80 mg/m2, day 1, E: 100 mg/m2, days 1-3, for 3 cycles) with concurrent TRT (1.5 Gy bid x 30 fr., total 45 Gy) to treat LDSCLC. From June 1996 through September 1996, 23 patients (pts) were enrolled, among whom 22 were eligible. The patients' characteristics were as follows: median age 65; M/F, 15/7; PS, 0/1/2,9/9/4; Stage II/IIIA/IIIB, 3/8/11. The relative dose intensities in the CODE phase for patients who received this treatment were 107% for P and 156% for E, compared with standard PE therapy. No treatment related death occurred in this series. Myelosuppression was the most frequent toxicity in both treatments. Grade 3 and 4 leukopenia and neutropenia occurred in 73% and 86% of patients in the CODE phase, and in 83% and 91% in the PE phase, respectively. Thrombocytopenia occurred in 14% of the patients in the CODE phase and in 37% in the cisplatin-etoposide phase. Other non-hematological toxicities were mild. There was no severe esophagitis or pneumonitis following radiation therapy. CR was observed in 13 (59%) of the 22 patients, and 9 (41%) patients showed PR, giving an overall response rate of 100%. A median survival time has not yet been ascertained. Our preliminary results indicate that CODE therapy followed by PE therapy with concurrent TRT has very high activity with acceptable toxicities. This treatment regimen should be compared with PE therapy and concurrent TRT in a randomized trial.

[Combination of irinotecan hydrochloride and etoposide for treatment of refractory or relapsed small-cell lung cancer]

Unique Identifier: 20401300

Author: Negoro S; Masuda N

Source: Gan To Kagaku Ryoho 2000 Jul;27(8):1105-8

Address: Dept. of Respiratory Disease, Osaka City General Hospital.

    We used a combination of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor as a support therapy for refractory or relapsed small-cell lung cancer (SCLC). This combination regimen was active against refractory or relapsed SCLC as gauged by a response rate of 71% and a median survival time of 271 days. Further studies of this combination regimen in refractory or relapsed SCLC are warranted.

[Treatment of lung cancer--state of the art in 2000]

Unique Identifier: 20401320

Author: Nakanishi Y; Inoue K; Hara N

Source: Gan To Kagaku Ryoho 2000 Jul;27(8):1247-52

Address: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University.

    Small-cell lung cancer (SCLC) is, in general, sensitive to anti-cancer chemotherapy and radiotherapy. Standard therapies for extensive SCLC are combination chemotherapies with cyclophosphamide, adriamycin and vincristine (CAV), with cisplatin and etoposide (PE), as well as an alternating CAV/PE program. On the other hand, the standard therapy for limited SCLC is chemoradiotherapy, especially PE and concurrent accelerated hyperfractionated radiotherapy. Based on the therapy, the current state of treatment of small cell lung disease is a median survival time of 10 months and a 3-year survival in 10% of patients with extensive disease, and a median survival time of 30 months and a 3-year survival in 30% of patients with limited disease. Promising trials under investigation including those for dose-intensive chemotherapy, multimodality treatment and combination chemotherapy adopting new drugs are introduced. The standard therapy for inoperable stage III non-small cell lung cancer is a multimodality therapy employing chemotherapy and radiotherapy. However, neither the timing of the radiotherapy nor the optimal combination of anti-cancer agents has yet been established. Nowadays, the combination of cisplatin-based chemotherapy and radiotherapy is expected to bring a median survival time of 15 months and a 3-year survival in 25% of patients. For stage IV non-small cell lung cancer, chemotherapy prolongs survival time by a modest but statistically significant amount of time. For the treatment of inoperable lung cancer, the survival benefit from the use of newly developed drugs with or without platinum is under investigation.

Combination chemotherapy with tamoxifen, ifosfamide, epirubicin and cisplatin in extensive-disease small-cell lung cancer.

Unique Identifier: 20425539

Author: Chen YM; Perng RP; Yang KY; Wu HW; Lin WC; Liu JM; Tsai CM; Whang-Peng J

Source: Chung Hua I Hsueh Tsa Chih (Taipei) 2000 Aug;63(8):605-11

Address: Chest Department, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan, ROC.

    BACKGROUND: A study of tamoxifen, ifosfamide, epirubicin and cisplatin (TIEP) chemotherapy was conducted in patients with extensive-disease, small-cell lung cancer (SCLC) to assess response and toxicity. METHODS: From November, 1997, to February, 1999, 11 patients were treated, including six chemo-naive patients and five patients previously treated with cisplatin plus etoposide (EP). The treatment regimen included tamoxifen 60 mg twice daily orally on days 1 to 3, ifosfamide 3 g/m2 intravenous (i.v.) infusion for 60 minutes with mesna on day 2, epirubicin 50 mg/m2 i.v. bolus on day 2 and cisplatin 60 mg/m2 i.v. for 60 minutes on day 2, every 4 weeks for up to six cycles. RESULTS: All patients were evaluated for toxicity and response rate. As expected, the major toxicity was myelosuppression. Grade 3 or 4 leukopenia or neutropenia occurred in all patients during treatment. Two patients (18.2%) experienced fever in association with the neutropenia, one of whom died of sepsis. Grade 3 anemia occurred in two patients (18.2%) during treatment. Toxicities other than neutropenia and anemia were limited. After two cycles of treatment, five of six chemo-naive patients (83%), and one of five previously treated patients (20%) attained a partial response (overall 54.5%, 95% confidence interval 25%-83.9%). Median survival time was 8.5 and 6 months in chemo-naive and previously EP-treated patients, respectively. The response rate and median survival time in chemo-naive patients did not improve compared with a previous study of ifosfamide plus etoposide undertaken 4 years earlier. CONCLUSIONS: Although TIEP is an active combination regimen with an acceptable toxicity profile in Chinese patients with extensive-disease SCLC, it showed no remarkable benefit compared with other regimens used in chemo-naive patients. The 20% response rate and median survival of 6 months in EP-treated patients deserve further study.

Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of radiation therapy oncology group trial 93-12.

Unique Identifier: 20402473

Author: Glisson B; Scott C; Komaki R; Movsas B; Wagner H

Source: J Clin Oncol 2000 Aug;18(16):2990-5

Address: University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

    PURPOSE: The combination of cisplatin, ifosfamide, and oral etoposide (PIEo) given concurrently with accelerated hyperfractionated thoracic radiation was studied in patients with limited small-cell lung cancer in a phase II trial to assess response, survival, and toxicity. PATIENTS AND METHODS: Sixty-seven patients were accrued between March 1994 and April 1996. Chemotherapy doses were cisplatin 20 mg/m(2) and ifosfamide 1,200 mg/m(2) on days 1 to 3 and etoposide 40 mg/m(2) administered orally days 1 through 14. Radiation consisted of accelerated hyperfractionated thoracic radiation (AHTRT) 1.5 Gy bid x 30 fractions (total 45 Gy) days 1 through 19, concurrent with cycle 1 of chemotherapy. Three additional cycles of chemotherapy were given every 4 weeks after completion of chemoradiation. Prophylactic cranial radiation (25 Gy in 10 fractions) was offered to patients for whom complete response (CR) after completion of chemotherapy was achieved. RESULTS: An overall objective response rate of 78% (41 CRs [67%] and seven partial responses [11%]) was seen in 61 patients whose disease response could be evaluated. Median progression-free and overall survival estimates were 12.7 and 23.7 months, respectively. Two- and 3-year survival rates were estimated at 50% and 39%, respectively. Major toxic effects included grade 4 granulocytopenia in 34 (55%), grade 4 thrombocytopenia in 16 (26%), grade 3 to 5 fever/infection in six (10%; with one death resulting from sepsis), and grade 3/4 esophagitis in 27 patients (43%). Other nonhematologic toxic greater than grade 2 occurred in 11 patients (18%). CONCLUSION: Relative to conventional etoposide/cisplatin and concurrent AHTRT, chemoradiation with PIEo produced similar median and 2-year survival rates and a higher rate of acute esophageal toxicity. However, the locoregional control rate with a minimum follow-up of 2 years is excellent at 80%. It is conceivable that longer follow-up will prove this regimen more promising. Research efforts should focus on other methods to improve disease control in all potential sites of recurrence.

Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas.

Unique Identifier: 20431207

Author: Ordonez NG

Source: Am J Surg Pathol 2000 Sep;24(9):1217-23

Address: University of Texas M.D. Anderson Cancer Research Center, Houston, 77030, USA.

    The distinction between small cell lung carcinoma (SCLC) and small cell carcinomas of other sites is difficult by routine histology. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is selectively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has also been demonstrated in adenocarcinomas of the thyroid and lung, and SCLC. However, the value of TTF-1 immunostaining in discriminating between SCLC and nonpulmonary small cell carcinomas has not been investigated. In the present study using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1 and cytokeratin 20 (CK20), a marker that has previously been demonstrated in small cell carcinomas of the skin (Merkel cell carcinomas), in 82 small cell carcinomas from a wide variety of sites (28 lung, 18 skin, 12 gastrointestinal tract, 8 sinonasal, 5 bladder, 3 prostate, 3 uterine cervix, 2 thyroid, 2 salivary gland, and 1 pancreas). Twenty-seven (96%) of the 28 SCLCs were positive for TTF-1. Among the nonpulmonary small cell carcinomas, two tumors of the gastrointestinal tract, one of the bladder, and one of the uterine cervix exhibited TTF-1 positivity. Sixteen (89%) of the 18 Merkel cell carcinomas and one SCLC were CK20-positive. All other small cell carcinomas were negative for this marker. These results indicate that although TTF-1 is not a specific marker for SCLC, it may assist in distinguishing SCLC from some nonpulmonary small cell carcinomas, particularly Merkel cell carcinoma, especially when it is used in conjunction with CK20.

Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas.

Unique Identifier: 20404015

Author: Virmani AK; Rathi A; Zochbauer-Muller S; Sacchi N; Fukuyama Y; Bryant D; Maitra A; Heda S; Fong KM; Thunnissen F; Minna JD; Gazdar AF

Source: J Natl Cancer Inst 2000 Aug 16;92(16):1303-7

Address: Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75390-8593, USA.

    BACKGROUND: Retinoic acid plays an important role in lung development and differentiation, acting primarily via nuclear receptors encoded by the retinoic acid receptor-beta (RARbeta) gene. Because receptor isoforms RARbeta2 and RARbeta4 are repressed in human lung cancers, we investigated whether methylation of their promoter, P2, might lead to silencing of the RARbeta gene in human lung tumors and cell lines. METHODS: Methylation of the P2 promoter from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines and tumor samples was analyzed by the methylation-specific polymerase chain reaction (PCR). Expression of RARbeta2 and RARbeta4 was analyzed by reverse transcription-PCR. Loss of heterozygosity (LOH) was analyzed by PCR amplification followed by electrophoretic separation of PCR products. Statistical differences were analyzed by Fisher's exact test with continuity correction. RESULTS: The P2 promoter was methylated in 72% (63 of 87) of SCLC and in 41% (52 of 127) of NSCLC tumors and cell lines, and the difference was statistically significant (two-sided P:<.001). By contrast, in 57 of 58 control samples, we observed only the unmethylated form of the gene. Four tumor cell lines with unmethylated promoter regions expressed both RARbeta2 and RARbeta4. Four tumor lines with methylated promoter regions lacked expression of these isoforms, but demethylation by exposure to 5-aza-2'-deoxycytidine restored their expression. LOH at chromosome 3p24 was observed in 100% (13 of 13) of SCLC lines and 67% (12 of 18) of NSCLC cell lines, and the difference was statistically significant (two-sided P: =.028). CONCLUSIONS: Methylation of the RARbeta P2 promoter is one mechanism that silences RARbeta2 and RARbeta4 expression in many lung cancers, particularly SCLC. Chemical demethylation is a potential approach to lung cancer therapy.

Lenograstim as support for ACE chemotherapy of small-cell lung cancer: a phase III, multicenter, randomized study.

Unique Identifier: 20410838

Author: Gatzemeier U; Kleisbauer JP; Drings P; Kaukel E; Samaras N; Melo MJ; Cardenal F; Robinet G; Snijder RJ; von Pawel J; Palisses R

Source: Am J Clin Oncol 2000 Aug;23(4):393-400

Address: Krankenhaus Grosshansdorf, Pneumology/Oncology, Germany.

    This phase III study was conducted to evaluate the usefulness of lenograstim as support for ACE (doxorubicin, cyclophosphamide, and etoposide) chemotherapy in previously untreated patients with small-cell lung cancer. Patients were randomized to receive up to six 3-week cycles of either ACE alone (n = 139) or ACE with lenograstim support (150 microg/m2/day subcutaneously, days 4-13, n = 141). Compared with the chemotherapy-alone group, the lenograstim support group was more likely to achieve neutrophil recovery (absolute neutrophil count, > or =1.5 x 10(9) cells/l) by day 14 (95.8-100% vs. 14.3-24.1% across the cycles) and less likely to experience at least one infectious episode (36.7 vs. 54.0%; p = 0.004), chemotherapy delay (51.8 vs. 56.2%; NS), or dose reduction (17.3 vs. 27.7%; p = 0.037). Objective response and event-free and overall survival rates were similar. Lenograstim was well tolerated. Lenograstim may allow the interval between cycles of ACE to be reduced to 2 weeks; such dose intensification may lead to more favorable objective response and survival rates.

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