Miliary never-smoking adenocarcinoma of the lung: strong association with epidermal growth factor receptor exon 19 deletion.

Miliary pattern of pulmonary metastases is a rarity in patients with lung cancer. We report five cases of patients with a never-smoking adenocarcinoma of the lung with such a pattern of metastases. In the tumor cells of all five patients, epidermal growth factor receptor (EGFR) mutation gene sequencing identified a deletion in exon 19 of the EGFR gene, and all five patients had a dramatic response to EGFR tyrosine kinase inhibitors. No echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) translocation was detected. We believe that the miliary never-soking adenocarcinoma of the lung is a distinct clinically relevant subgroup of the never-smoking non-small cell lung cancer. Physician should recognize this subgroup of patients with lung cancer when facing a picture of miliary pulmonary metastases in chest x-ray or computed tomography scan in patients with a history of never smoking and consider upfront therapy with EGFR tyrosine kinase inhibitors.

Elevated pretreatment serum concentration of YKL-40-An independent prognostic biomarker for poor survival in patients with metastatic nonsmall cell lung cancer.

BACKGROUND: The glycoprotein YKL-40 is synthesized both by cancer cells and by tumor-associated macrophages and plays a functional role in tumor progression. Consequently, high serum YKL-40 levels have been associated with a poor prognosis in patients with several cancer types. However, the role of YKL-40 has not been established in nonsmall cell lung cancer (NSCLC). METHODS: Pretreatment serum levels of YKL-40 were determined in 189 patients with NSCLC (143 men and 46 women; median age, 62 years;, age range, 41-76 years). Twelve percent of patients had stage IIIB disease, and 88% had stage IV disease. Ninety-eight patients received combined gemcitabine and vinorelbine, and 91 received combined gemcitabine, vinorelbine, and cisplatin as first-line chemotherapy. The median overall survival was 37 weeks. RESULTS: Patients had a median serum YKL-40 level of 209 ng/mL (range, 19-2153 ng/mL). No correlation was observed between overall survival and the type of chemotherapy regimen used, tumor stage, sex, or histologic types. Patients with high serum YKL-40 levels (greater than the median level for all patients [209 ng/mL]) had a significantly shorter survival than patients with serum YKL-40 levels below the median (median survival, 32 weeks vs 41 weeks; P = .007). In multivariate analysis, the serum YKL-40 level, the presence of bone lesions, and the serum lactate dehydrogenase level were independent, statistically significant prognostic factors. CONCLUSIONS: The pretreatment serum YKL-40 level was identified as a new, independent prognostic biomarker in patients with metastatic NSCLC and may help to determine the individual prognosis of these patients.

Single-center management of 136 patients with cancer of unknown primary site (CUP syndrome) over a period of 10 years.

BACKGROUND: Cancer of unknown primary site (CUP syndrome) is a particular challenge in oncology which occurs in about 5-10% of cancer patients. Here, we investigated clinicopathological and prognostic factors in patients with CUP syndrome in a retrospective analysis. PATIENTS AND METHODS: 136 patients with CUP syndrome who were treated in our Department of Oncology and Hematology were analyzed over a period of 10 years. Clinical and histopathological characteristics, response to chemotherapy, survival and prognostic factors were investigated in a retrospective analysis. RESULTS: 83 of the patients (61%) received first-line chemotherapy, which induced an overall response rate of 19%. Altogether 37 different chemotherapy regimens were used. Median overall survival of all patients was 7.9 months. In multivariate Cox regression analysis, gender, Karnofsky performance status, treatment modality and extent of disease were identified as independent prognostic factors. CONCLUSIONS: Our analysis showed a poor prognosis for patients with CUP syndrome. The response rate to chemotherapy was low with no significant benefit for any of the investigated cytotoxic agents. Newer diagnostic and therapeutical approaches might contribute to an improvement of prognosis, and their value is currently investigated in prospective studies.

Expression of CEACAM-1 in pulmonary adenocarcinomas and their metastases.

BACKGROUND: CEACAM-1 is involved in intercellular adhesion and is expressed in a variety of human tissues. In cases of malignant transformation, a down-regulation or loss of CEACAM-1 has been shown. In contrast, CEACAM-1 is not expressed in normal lung tissue or melanocytes. It has been demonstrated that an expression in these tissues is associated with the development of metastatic disease. The aim of the present investigation was to analyze a possible association between the expression of CEACAM-1 in pulmonary adenocarcinomas and their lymph node and hematogenous metastatic cells. PATIENTS AND METHODS: CEACAM-1 expression was immunhistochemically evaluated in primary tumors, lymph nodes and distant metastases of 96 patients with metastatic pulmonary adenocarcinoma who had undergone surgery between 1999 and 2002. RESULTS: Expression of CEACAM-1 was shown in 78 out of 96 primary tumors (81.3%). A significant positive correlation was found between CEACAM-1 expression on cells of the primary tumor, lymph node metastases (p < 0.005) and hematogenous metastases (p = 0.03). CEACAM-1 expression did not correlate with stage, gender, grading or patients' age. Compared to patients with tumors not expressing CEACAM-1, patients with a CEACAM-1-expressing tumor had a shorter median overall survival (21 vs. 28 months) and progression-free survival (11.7 vs. 16.3 months). CONCLUSION: CEACAM-1 is expressed in most primary pulmonary adenocarcinomas. This investigation demonstrates that its expression is preserved in lymph node and hematogenous metastases, indicating that its expression is of functional significance for both metastatic sites. These results support the prognostic relevance of the expression of CEACAM-1 in pulmonary adenocarcinoma.

A pilot study of docetaxel and trofosfamide as second-line 'metronomic' chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: The aim of this pilot study was to evaluate the efficacy and safety of a chemotherapy containing docetaxel and oral trofosfamide as a 'metronomic' secondline treatment of patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 21 patients with stage IV disease NSCLC who had progressed under first-line chemotherapy were enrolled. Previous chemotherapy was platinum-based in 15 patients (71.4%), whereas 6 patients (28.6%) had received platinum-free combination chemotherapy. Patients received docetaxel 25 mg/m(2) on days 1, 8, and 15 every 4 weeks plus trofosfamide 50 mg per day. RESULTS: A total of 62 chemotherapy cycles were administered. The median number of cycles per patient was 3. The overall response rate to chemotherapy was 19%, median overall survival was 6.9 months, the median progression-free survival 2.9 months, the 1-year survival rate 28.6%, and the 2-year survival rate 7.1%. No grade IV toxicity was observed. CONCLUSIONS: Our results suggest that the combination of docetaxel and trofosfamide in a metronomic schedule is active and well tolerable as second-line therapy in patients with metastatic NSCLC. The concept of metronomic chemotherapy promises to be a valuable addition to the existing treatment options in NSCLC and warrants further investigation in phase III studies.

A phase II study of irinotecan (CPT-11) and carboplatin in patients with limited disease small cell lung cancer (SCLC).

PURPOSE: The aim of this phase II trial was to evaluate the efficacy and safety of a combination chemotherapy containing irinotecan (CPT-11) and carboplatin as first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: From December 2002 to May 2004 61 patients with limited disease (IASLC classification) were enrolled who were not suitable for concurrent chemo-radiotherapy. Eighteen of the 61 patients (29.5%) had malignant pleural or pericardial effusion and 4 patients (6.6%) had involved supra- or infraclavicular lymph nodes. Patients received irinotecan 50mg/m(2) on days 1, 8 and 15 and carboplatin AUC 5 on day 1, every 4 weeks. RESULTS: A total of 233 chemotherapy cycles were administered. The median number of cycles per patient was 4. The overall response rate to chemotherapy on an intention-to-treat basis was 64%. The median overall survival was 13.8 months, the median disease-free survival 8.0 months, the 1-year survival rate 53.5%, and the 2-year survival rate 17.9%. Haematological and non-hematogical toxicities were low (CTC-grade 3 neutropenia 14.8%, grade 3 thrombocytopenia 5.2%, grade 3/4 anemia 5.1%, grade 3 nausea/vomiting 5.1%, grade 3 diarrhea 3.6%, grade 3 alopecia 3.6% of pts). CONCLUSION: The results suggest that the combination of irinotecan (CPT-11) and carboplatin is active and well tolerable in patients with limited disease SCLC who were not suitable for concurrent chemotherapy.

Lectin histochemistry of metastatic adenocarcinomas of the lung.

BACKGROUND: Several clinical studies indicate that primary tumour cells with high metastatic potential often show aberrant glycosylation as detected by lectin histochemistry. However, it is unclear whether aberrant glycosylation is still present in metastatic deposits. The aim of the present investigation was thus to analyse a possible association between the presence of lectin binding sites of pulmonary adenocarcinoma cells and their lymph node and haematogenous metastatic cells. METHODS: For this purpose, the expression of HPA, PHA-L and UEA-I was assessed in primary tumours, lymph node metastases and haematogenous metastases of 96 patients with metastatic adenocarcinomas of the lung that underwent surgery between 1999 and 2002. Besides, lectin-binding data and other known prognostic factors were correlated with survival. RESULTS: We found a significant positive correlation between the binding of the lectins HPA (p=0.002), PHA-L (p<0.00001) and UEA-I (p<0.00001) to the cells of the primary tumour and to their lymph node metastases. There was a positive correlation between the binding of HPA to the cells of the primary tumour and the haematogenous metastases as well. Patients with tumours which did not show HPA binding sites had a median overall survival of 27.9 months (95%-CI 7.7-infinity months). Patients with a HPA binding tumour had a median overall survival of 20.9 months (95%-CI 18.5-28.7 months). CONCLUSION: This is the first investigation to demonstrate a positive correlation between the binding of the lectins HPA, PHA-L and UEA-I to the cells of the primary tumour and to their lymph node metastases. Expression of HPA binding sites is also preserved in the haematogenous metastases. In summary, our results support the hypothesis that altered glycosylation of the membrane-bound glycoproteins of the tumour cells is associated with, but not sufficient for promotion of lymphogenic and haematogenous metastasis.

Long-term survival after second-line therapy with docetaxel and carboplatin and monthly pamidronic acid in a woman with metastatic non-small cell lung cancer.

BACKGROUND: In patients with metastatic non-small cell lung cancer (NSCLC), second-line chemotherapy induces response rates of less than 20% and median survival times between 5 and 8 months. CASE REPORT: In the case described here, a patient with metastatic NSCLC responded with complete remission of the primary tumor and the involved lymph nodes as well as partial remission of bone metastases to a second-line chemotherapy with docetaxel and carboplatin. Since April 2003 (33 months), no tumor progression has been observed. Until present, the patient received monthly infusions of pamidronic acid. CONCLUSION: Our case report indicates that in certain patients with metastatic NSCLC who did not respond to first-line regimens, second-line chemotherapy can induce outstanding tumor response and significantly improve survival. It also indicates that the role of bisphosphonates in the treatment of NSCLC should be further investigated in large clinical trials.

Docetaxel and cisplatin as first-line treatment for patients with metastatic esophageal cancer: a pilot study.

BACKGROUND: We investigated the combination of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic esophageal cancer. PATIENTS AND METHODS: 16 chemotherapy-naïve patients with distant metastases were included in the study (15 male, 1 female; median age: 58.5 years (range 37-69); median ECOG performance status: 1). 11 patients (69%) had esophageal cancer, and 5 patients (31%) had cancer of the gastroesophageal junction. Patients received docetaxel 75 mg/m2 and cisplatin 80 mg/m2 on day 1 every 3 weeks. A total of 55 chemotherapy cycles was administered. The median number of cycles was 3 (range 1-6). RESULTS: The overall response rate was 31.3%. 4 out of 10 patients (40%) with squamous cell carcinoma and 1 out of 5 patients (20%) with adenocarcinoma responded to chemotherapy. The median overall survival was 29.6 weeks, and the median progression-free survival was 18.6 weeks. Hematological and non-hematological toxicities were moderate (neutropenia WHO grade III/IV: 42.9%, alopecia grade II/III: 64.3%, nausea/vomiting grade II/III: 57.2%, neurotoxicity grade II: 14.3%). CONCLUSION: The combination of docetaxel and cisplatin is an active regimen with moderate toxicity in the treatment of patients with metastatic esophageal cancer. This pilot study demonstrates the feasibility of a combination treatment containing a taxane and cisplatin in metastatic esophageal cancer.

Pretreatment vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) serum levels in patients with metastatic non-small cell lung cancer (NSCLC).

PURPOSE: In the present study, we investigated the prognostic value of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 serum levels in patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From September 1999 to June 2001, pretreatment serum levels of VEGF and MMP-9 were analysed in 194 patients of a randomized phase III trial with enzyme-linked immunoassays. RESULTS: Patients with a VEGF serum level higher than the median serum level (10,995 pg/ml) had a significantly shorter overall survival than those with a lower serum level (P=0.04). The MMP-9 serum level did not correlate with survival. In a multivariate Cox regression analysis, only the pretreatment serum level of VEGF, the Karnofsky performance status, and the presence of bone metastases were identified as independent prognostic factors. CONCLUSIONS: The pretreatment VEGF serum level was identified as independent prognostic factor in this study and may help to assess individual risk and treatment profiles in patients with metastatic NSCLC.

The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas.

Members of the Fos family of AP-1 transcription factors (c-Fos, FosB, FosB2, Fra-1 and Fra-2) are able to form dimers with Jun proteins which bind to the regulatory sequences of target genes. As many proteases involved in tumor invasion are AP-1-regulated, we assumed that Fos family members might be important for invasion of mammary carcinomas. Therefore, we performed transient transfections with expression vectors for c-Fos, FosB, FosB2, Fra-1 and Fra-2, followed by matrigel invasion assays. Fra-1 transfection resulted in a 2-4-fold increase of invasive cells in both cell lines. In a less degree, the invasive potential of MDA-MB231 cells was stimulated by Fra-2, whereas MCF7 invasion was enhanced by c-Fos and FosB. By double-labelling immunocytochemistry, PAI-1 up-regulation was observed in cells transfected with c-Fos, Fra-1 and Fra-2 expression vectors, whereas MMP1 and MMP9 expression was not affected. Results of cotransfection with a MMP9 promoter construct and AP-1 expression vectors do not indicate a direct up-regulation of MMP9 expression by Fos proteins except a positive effect of c-Fos in MCF7 cells. In parallel, expression of Fos family members as determined by Western Blot analysis in 75 mammary carcinomas was correlated with MMP1, MMP9, PAI-1 and uPAR protein levels in the tumors. Interestingly, high FosB levels were significantly associated with MMP1 overexpression, whereas expression of c-Fos and phosphorylated Fra-1 correlated with MMP9 protein levels. Strong Fra-2 expression correlated with high levels of MMP9, PAI-1, the uPA/PAI-1 complex and early recurrence. These data indicate that Fos proteins, especially Fra-1, c-Fos and Fra-2, might be involved in invasion of breast cancer cells.