Clonal Heterogeneity of Small-Cell Anaplastic Carcinoma of the Lung Demonstrated by Flow-Cytometric
Clonal Heterogeneity of Small-Cell Anaplastic Carcinoma of the Lung Demonstrated by Flow-Cytometric DNA Analysis1
Lars L. Vindeløv2, Heine H. Hansen, Ib J. Christensen, Mogens Spang-Thomsen, Fred R. Hirsch, Mogens Hansen and Nis I. Nissen Refer to : http://cancerres.aacrjournals.org/cgi/content/abstract/40/11/4295 The Finsen Institute [L. L. V., H. H. H., I. J. C., F. R. H., M. H., N. I. N.] and the University Institute of Pathological Anatomy [M. S.], Copenhagen, Denmark Flow-cytometric DNA analysis yields information on ploidy and proliferative characteristics of a cell population. The analysis was implemented on small-cell anaplastic carcinoma of the lung using a rapid detergent technique for the preparation of fine-needle aspirates for DNA determination and a newly developed procedure for storing aspirates at -80°. Thirty-eight different metastases in 30 consecutive patients with small-cell anaplastic carcinoma of the lung were examined with a total of 273 fine-needle aspirations. The results on ploidy are reported in this paper. The degree of contamination of the aspirates with normal cells was determined by differential counts. The ratio of the peak channel numbers for the G1 phase of the tumor cells to that of the diploid standard (DNA index) was calculated and used for ploidy identification. Twenty-nine patients were evaluable with respect to DNA index determination. The coefficient of variation of the DNA index determinations was estimated as 0.039. In 23 (79%) patients, only one cell line could be detected. Evidence of the presence of 2 tumor cell clones with different ploidy was obtained in the remaining 6 (21%) patients. Of the 35 malignant clones thus demonstrated, 26 (74%) were significantly different from diploid (p 0.01). Four (11%) were hypodiploid, 3 (9%) were hypotriploid, and 19 (54%) were hypo- or near-tetraploid. Clonal heterogeneity in the tumors of 21% of the patients is a conservative estimate. Assessment of the detection limit set by the methodology used and the restricted number of samples studied in each patient indicate that the true occurrence of clonal heterogeneity in small-cell carcinoma of the lung may be much higher.
1 Supported by grants from the Lundbeck Foundation, The Danish Medical Research Council, The Danish Hospital Foundation for Medical Research, Region of Copenhagen, and The Danish Cancer Society.
2 To whom requests for reprints should be addressed, at the Department of Internal Medicine, The Finsen Institute, 49, Strandboulevarden, DK-2100 Copenhagen, Denmark.
Ann Arbor - A University of Michigan Comprehensive Cancer Center doctor is part of a team that was awarded the Michigan Cancer Consortium's highest honor. The Lung Cancer Early Detection Workgroup, which Gregory Kalemkerian, M.D., co-chaired, received the MCC Spirit of Collaboration Award.
Kalemkerian's group produced a position statement for Michigan health care providers in the public and private sectors about lung cancer detection, an issue that has created significant controversy in the field today. The statement recommends that health care providers not use a certain type of screening technique, called the low-dose spiral CT scan, for screening patients who show no symptoms of lung cancer. Current studies have not clearly demonstrated the potential benefits of this procedure. Instead, the group encourages the individual evaluation of patients according to their risk until research shows that spiral CT scans save lives.
"Our statement will help physicians address their patients' concerns regarding an area of medicine where the available information is inconclusive and controversial," says Kalemkerian, director of the Multidisciplinary Lung Cancer Clinic at the U-M Comprehensive Cancer Center.
The MCC is a statewide organization that coordinates the efforts of various researchers, doctors and health care providers to produce position statements aimed at reducing the rates of particular types of cancer in the state.
Since 2001, the Spirit of Collaboration Award has been given to MCC member organizations that have produced superior and collaborative work to push forth significant cancer control policies and activities in the state of Michigan. The award was presented during the organization's annual meeting in Lansing on Oct. 31.
"This award has special meaning to me. It took a lot of work to get a group of people with very divergent interests to agree on a statement that is practical and useful to health care providers and their patients," Kalemkerian says.
Abstract Background: Platinum-based chemotherapy has been shown to beeffective in improving survival and quality of life in advancednon-small-cell lung cancer (NSCLC) patients. The objective of this studywas to identify patients more likely to benefit from chemotherapy inorder to avoid the indiscriminate treatment of all patients.
Patients and methods: A multivariate analysis of survivalwas performed using the database of the European randomized phase IIItrial that compared vinorelbine (navelbine®) (NVB),vinorelbinecisplatin (NVB-P) and vindesinecisplatin(VDS-P) in 612 patients with inoperable NSCLC (stage III or IV).Interactions between treatment and the prognostic factors singled out bythe Cox procedure were specifically tested.
Results: Theperformance status (PS) was the only significant interaction among theselected prognostic factors and treatment. Subgroup analysis showed thatthe advantage obtained with NVB-P predominantly concerned PS 01patients, whose median survival lasted 43 weeks (95% confidenceinterval (95% CI): 3950 weeks) with a one-year survivalrate of 38% (95% CI: 31%46%)versus36 weeks (95% CI: 3040 weeks) and34% (95% CI: 27%42%) for NVB alone,and 33 weeks (95% CI: 3039 weeks) and 29%(95% CI: 22%36%) for VDS-P. In sharpcontrast, survival in PS 2 patients was similar (median 18 weeks)(NVB-P 95% CI: 1134 weeks; NVB 95% CI: 1135weeks; VDS-P 95% CI: 1432 weeks) whatever thetreatment.
Conclusion: PS 2 patients with advancedNSCLC might not benefit from cisplatin combination therapy.
chemotherapy - multivariate analysis - non-small-cell lung cancer - performance status - prognostic factor
(1) Sarah Cannon Minnie Pearl Cancer Center, Nashville, TN, USA
Abstract The newer or 'third generation' chemotherapeutic agents (paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, topotecan) have all recently been shown to have substantial Many of these agents are now being incorporated into the therapy for patients with advanced disease. Paclitaxel was the first 'third generation' drug to be studied. The use of paclitaxel and carboplatin has proven to be a well tolerated and quite active regimen with one-year survival in patients with stage IV disease of about 40% and two-year survival of about 20%. These survival rates are at least twice as good as previous platinum-based regimens. We have simplified the administration of paclitaxel by using a one-hour infusion and many other investigators and clinicians have followed suit. The results are equivalent to a three-hour infusion schedule. Given the degree of activity in patients with stage IV disease, it is imperative to begin neoadjuvant and adjuvant trials with the newer drugs and drug combinations. We and others have started a neoadjuvant strategy which has proven to be feasible and most patients tolerate surgery well. While the results are quite preliminary, we have seen some complete pathologic responses (about 20%) and are encouraged by these early data. In addition, we have routinely used adjuvant paclitaxel and carboplatin in patients with stage IBIIIA disease who have been previously resected. Radiotherapy and a weekly schedule of paclitaxel and carboplatin have been incorporated for patients with stages IIIIIB (selected IIIB patients). Randomized comparisons are certainly needed in the neoadjuvant and adjuvant arena and the other 'third generation' drugs need to be quickly evaluated. We have chosen to add a third agent to paclitaxel and carboplatin. The evaluation of several triple combinations including the addition of gemcitabine, vinorelbine and topotecan, respectively to the paclitaxelcarboplatin combination has been completed. Preliminary results from these trials will be briefly summarized and plans for additional studies of the newer agents will also be discussed. Studies to learn the appropriate combinations, doses and schedules of the newer drugs in concert with radiotherapy and/or resection are also urgently needed. Since the newer 'third generation' drugs appear to genuinely improve the survival of patients with stage IV disease, it is likely that incorporation of these more active agents into therapy for lower stages of disease will make an even greater impact on overall survival for patients with this common neoplasm. non-small-cell lung cancer - paclitaxel This revised version was published online in June 2006 with corrections to the Cover Date.
Vitamin D and Surgery Season Associated With Improved Survival in Early Lung Cancer
Vitamin D has anti-proliferative and anti-invasive properties in vitro and in animal studies and may induce apoptosis of cancer cells. In humans, dietary vitamin D intake, regional ultraviolet light B levels, and sunlight exposure all contribute to vitamin D levels. Wei Zhou, M.D., Ph.D., of Harvard School of Public Health, and colleagues examined the association of surgery season, as a marker for sunlight exposure, and vitamin D intake with recurrence-free and overall survival in 456 patients with early-stage non-small cell lung cancer. Patients undergoing surgery in the summer had a higher recurrence-free survival rate than patients undergoing surgery in the winter (Hazard Ratio (HR): 0.75). No association between vitamin D intake and survival was found. However, analysis of the joint effects of vitamin D and surgery season showed that patients with the highest vitamin D intake who had surgery in the summer had a 5-year recurrence-free survival rate of 56 percent, compared to 23 percent for patients with low intake who had surgery in the winter. These findings should be confirmed in a prospective study to assess the serum vitamin D levels at time of surgery, say the researchers; if confirmed, dietary vitamin D supplementation may be advisable for early-stage lung cancer patients, particularly during the winter and in groups that tend to be deficient in vitamin D. This research was supported in part by an EGRP grant to David Christiani, M.D., M.P.H., M.S., of the same institution. Zhou W, Suk R, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Giovannucci E, Christiani DC. Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev 2005 Oct;14(10):2303-9.