A. Semeraro

High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients

BACKGROUND Insulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I-III NSCLC patients. PATIENTS AND METHODS Tumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS IGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P = 0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, chi(2) = 9.8, P = 0.001). IGFR-1 protein expression was associated with EGFR protein expression (P = 0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P = 0.01). CONCLUSION A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.

Plasma DNA, microsatellite alterations, and p53 tumor mutations are associated with disease-free survival in radically resected non-small cell lung cancer patients: a study of the perugia multidisciplinary team for thoracic oncology.

Introduction: This prospective study examined association between circulating plasma DNA, microsatellite alterations (MA), p53 mutations with time to relapse and survival in surgically treated non-small cell lung cancer (NSCLC) patients (pts). Methods: Plasma samples, adjacent lung tissue, and lung tumor tissue specimens were collected from consecutive patients with stage I–III NSCLC. Blood samples of 66 matched healthy donors with positive smoking history were collected as controls. The plasma DNA amount was determined by real-time PCR. The analysis of MA at loci D3S1300, D3S1289, D3S1266, and D3S2338 on chromosome 3p was performed by radiolabeled PCR. p53 Mutations (exons 5, 6, 7, and 8) were detected by PCR-single-strand conformational polymorphism assay. Results: There were 76 patients, 65 men; median age was 68 years (range, 42–86), 20 had stage I, 40 stage II, and 16 stage III, the majority of pts (48.7%) had squamous-cell histology. Sixty-nine (91%) were smokers and most had good Eastern Cooperative Oncology Group performance status (0/1:72/4). Mean circulating DNA of all pts was 60 ng/ml versus 5 ng/ml in smoker-matched controls (p < 0.0001). In pts without recurrence, mean circulating DNA was 48.5 ng/ml at baseline, 32.8 ng/ml at 3rd month, and 20.6 ng/ml at 12th month after surgery. In pts with recurrence, mean circulating DNA at baseline was 97.1 ng/ml. At 3rd month after surgery, mean DNA concentration was significantly lower in disease-free pts than in patients with recurrent disease (32.8 versus 292.7 ng/ml; p = 0.0016). MA in at least one locus was found in 39.5% of NSCLC tumors. p53 Genomic mutations were observed in 54.0% of tumor samples. Statistically significant associations were observed between MA and squamous-cell histotype (p = 0.007) and between p53 mutations and lymph node involvement (p = 0.012). MA and p53 mutations were found to be significantly associated with recurrence of disease (p = 0.033 and 0.026, respectively). Conclusion: Our results suggest that MA and p53 mutations in tumor DNA have a potential prognostic role for disease recurrence in NSCLC patients, and elevated levels of plasma circulating DNA identify patients with possible systemic disease at diagnosis. This might be proposed as an early detection test of disease recurrence.

Tumorlets, Multicentric Carcinoids, Lymph-Nodal Metastases, and Long-Term Behavior in Bronchial Carcinoids

Background: The clinical significance of lymph-node metastases, multicentric forms, and tumorlets in bronchial carcinoids is still a matter of debate. Aim of this study was to analyze their prevalence and clinical significance in a series of 123 bronchial carcinoids. Patients and Methods: Nodal dissection and serial sections of resected lung parenchima for research of multicentric forms and tumorlets were performed in most patients. Survival curve was produced using the Kaplan-Meyer method and multivariate analysis by the Cox proportional hazard model. Results: Lymph-node involvement was present in 14% of typical (14 of 100) and 13.04% of atypical carcinoids (3 of 23). Multicentric forms (syncronous carcinoids or tumorlets) were found in 11.3% of the total with a negative impact on survival (p = 0.021). Multiple tumorlets were found in 7.3% of all cases at the standard pathologic examination, but whenever accurate palpation and serial sections of the surgical specimen were performed, the percentage reached 24% of the cases. Overall survival was 98.2%, 95.8%, and 83.9% for typical and 71.6%, 57.3%, and 24% for atypical carcinoid respectively at 5, 10, and 15 years. Time from surgery was significantly directly correlated with recurrences (p < 0.0001) and disease related death (p = 0.0002). Conclusions: A high prevalence of tumorlets, multiple carcinoids, and lymph-nodal involvement was found in our series. On the basis of these observations bronchial carcinoids always require major surgical procedures with systematic nodal dissection, and a careful search for multifocal lesions should always be performed. Follow-up should always be accurate and protracted, due to the frequency of very long-term relapses (often more than 10 years after surgery).

Biological markers and DNA flow cytometric analysis in radically resected patients with non-small cell lung cancer. A study of the Perugia Multidisciplinary Team for Thoracic Tumors.

Aims and Background The aim of this study was to evaluate the relationship between a panel of biological markers (p53, Bcl-2, HER-2, Ki67, DNA ploidy and S-phase fraction) and clinical-pathological parameters and its impact on outcome in non-small cell lung cancer (NSCLC). Methods and Study Design Tumor tissue specimens obtained after surgical resection were collected from consecutive patients with NSCLC. We used an immunocytochemical technique for p53, Bcl-2, HER-2 and Ki67 analysis in fine-needle aspirates obtained from surgical samples that were also evaluated by flow cytometric DNA analysis using a FACScan flow cytometer. Results From April 2000 to December 2005, 136 patients with radically resected NSCLC were recruited. Median age was 66 years (range, 31–84 years), male/female ratio 117/19, ECOG performance status 0/1 127/4, stage I/II/III 76/25/35, squamous/adenocarcinoma/large-cell/mixed histology 62/49/17/8, smokers yes/no 121/11. Positivity of p53, Bcl-2, HER-2 and Ki67 was detected in 51.4%, 27.9%, 25.0% and 55.8% of the samples, respectively; 82.9% of the cases revealed aneuploid DNA histograms and 56.7% presented an S-phase fraction of more than 12%. Statistically significant associations between high Ki67 and poorly differentiated tumors (P = 0.016) and a smoking history (P = 0.053); p53 positivity and high Ki67 (P = 0.002); HER-2 positivity and adenocarcinoma subtype (P = 0.015) and presence of lymph node involvement (P = 0.006); and Bcl-2 positivity and squamous cell carcinoma subtype (P = 0.058) were observed. At univariate analysis, high Ki67 proved to be the only marker associated with disease-free survival (P = 0.047). After adjusting for stage, none of the examined immunocytochemical markers emerged as an independent factor for disease-free and overall survival; only pathological stage was identified as an independent prognostic factor for disease-free survival (P = 0.0001) and overall survival (P = 0.0001). In the group of 76 patients classified as TNM stage I, high Ki67 was the only marker associated with recurrence of disease (P = 0.05). Conclusions Our data do not support a relevant prognostic role of immunocytochemical markers in NSCLC, even if the Ki67 index might have particular relevance to identify patients with more aggressive tumors who are at high risk for disease relapse.