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Biomedical subjects

J L Mulshine

Publications and source records attributed to J L Mulshine.

At least 55 records · Page 3Linked to original sources
PubMed1996

Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl-10-deazaaminopterin (10-EDAM) against human lung cancer cell lines.

10-ethyl-10-deazaaminopterin (10-EDAM) is a rationally designed derivative of the antifolate, methotrexate (MTX). In a number of tumor models these design features have resulted in an improved spectrum of antiproliferative activity as compared with the parent compound. Using an MTT growth assay, we compared in vitro antiproliferative activity of 10-EDAM with MTX in eight lung cancer cell lines. Growth was inhibited in all lines tested by clinically achievable concentrations of 10-EDAM (0.1-1,000 nM). 10-EDAM was more cytotoxic than MTX at the same concentrations in all eight lung cancer cell lines. In an effort to enhance the antiproliferative effect, we evaluated the addition of dipyridamole (DPM), an inhibitor of nucleoside transport, to 10-EDAM (0.1-10 microns). DPM decreased the concentration of 10-EDAM required to cause 50% growth inhibition (IC50) in all eight cell lines tested. This suppression was statistically significant by 2-sided sign test (P = .0078). By contrast, the IC50 of MTX was decreased in only two of the eight cell lines when DPM was added (0.1-10 microM). In defined thymidine depleted media, cell kill by the combination of 10-EDAM and DPM was no greater than 10-EDAM alone, consistent with the possibility that DPM exerts some of its effect by inhibition of extrinsic nucleoside salvage. In consideration of the published activity of 10-EDAM in lung cancer and the modest clinical toxicity of DPM based biochemical modulation, we conclude the current in vitro data provide justification for clinical evaluation of this combination in patients with lung cancer.

Aminopterin↗
PubMed1996

Correlation of in vitro drug sensitivity testing results with response to chemotherapy and survival: comparison of non-small cell lung cancer and small cell lung cancer.

Clinical protocols for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) were devised to prospectively select individualized chemotherapy based on in vitro drug sensitivity testing (DST) of cell lines derived from the patient's SCLC tumor cell lines or the patient's fresh NSCLC tumor. DST data derived from SCLC tumor cell lines were available for 33/115 (29%) patients. The DST-selected chemotherapy regimen was administered to 21 (18%) patients, or 64% of patients with DST. In SCLC< the DST-selected chemotherapy was administered either during weeks 13-24 following 12 weeks of etoposide/cisplatin, or at relapse after complete response to etoposide/cisplatin. Several parameters of in vitro drug sensitivity were significantly associated (two-sided P < 0.05) with clinical response to primary therapy and also with response to the DST-selected chemotherapy regimen, but were not associated with survival (P = 0.24). Five patients treated with their DST-selected chemotherapy attained a complete or partial response, compared to 5 of 68 who received an empiric regimen (P = 0.057). A total of 36/165 (22%) NSCLC patients had DST successfully completed. These results directed management for 21/96 (22%) patients who eventually received chemotherapy, or 58% of patients with DST. Response to chemotherapy for the patients treated prospectively with their DST-selected chemotherapy regimen (2/21; 9%) was not significantly different than the response rate for patients treated empirically with etoposide/cisplatin (10/69; 14%) in the absence of in vitro results to direct chemotherapy (P = 0.73). There was no difference in survival by treatment group for the NSCLC patients. The correlation between in vitro and clinical response was not significant for any individual drug or for all drugs considered together, illustrating the poor predictive value of in vitro testing with currently available chemotherapy in NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Monoclonal antibody alpha IR-3 inhibits non-small cell lung cancer growth in vitro and in vivo.

The ability of monoclonal antibody (mAb) alpha IR-3 to interact with non-small cell lung cancer (NSCLC) cells was investigated. MAb alpha IR-3 inhibited specific binding of 125I-IGF-I and 125I-alpha IR-3 to a panel of 8 NSCLC cell lines with high affinity (IC50 = 200 and 50 ng/ml, respectively). 125I-alpha IR-3 bound with high affinity (Kd = 40 ng/ml) to a single class of sites (Bmax = 8,000/cell) using NCI-H838 cells. 125I-alpha IR-3 was internalized when exposed to NCI-H838 or H1299 cells at 37 degrees C but not 4 degrees C. alpha IR-3 immunoprecipitated major 90 and 130 kD proteins. IGF-I stimulated and alpha IR-3 inhibited the clonal growth of NCI-H1299 cells. alpha IR-3 slowed the growth of NCI-H157 and H838 xenografts in nude mice. In a biodistribution study 125I-alpha IR-3 was preferentially localized to the tumor as opposed to other organs. These data suggest that IGF-I may be a regulatory agent in NSCLC.

Animals↗
PubMed1996

Transferrin dependence of Ga (NO3)3 inhibition of growth in human-derived small cell lung cancer cells.

The effect of a combination of anti-transferrin receptor (TFR) antibody, 42/6, and Ga(NO3)3 on cell growth was examined in small cell lung cancer (SCLC) cell lines: classic, NCI-H209, NCI-H345, NCI-H510; and variant, NCI-H82 and NCI-N417. The role of TFR and transferrin (TF) in Ga(NO3)3 cellular uptake was also tested. Exogenous TF did not enhance the cytotoxicity of Ga. At > 3 micrograms/mL, Ga(NO3)3 inhibited growth in all cell lines in TF-supplemented or deficient media. At < 3 micrograms/mL, Ga stimulated growth for all cells but this effect was eliminated by TF or 42/6. Classic SCLC lines required 3-4-fold less exogenous gallium than variant lines to reduce cell number by 50%. The mean Ga uptake (ng/10(6) cells) in H345 and H209 cell lines was 4-5-fold compared to H82 and N417 uptake (P < 0.001). 42/6 reduced exogenous TF-stimulated growth. Antibody plus Ga(NO3)3 caused a slight further cell number decline in all cell lines in TF-supplemented or deficient media. These results suggest that the addition of 42/6 antibody treatment would not increase the effectiveness of Ga(NO3)3 in patients. Both exogenous and endogenous TF and TFR play an important role in Ga uptake in these cells.

Antibodies, Monoclonal↗
PubMed1996

Expression of early lung cancer detection marker p31 in neoplastic and non-neoplastic respiratory epithelium.

In an immunocytochemical study of sputum, two antibodies, including a mouse monoclonal antibody (703D4) to a 31 kDa protein (p31) antigen, have been previously shown to detect lung cancer earlier than routine cytomorphology or chest X-ray. To understand the basis of p31 expression, the distribution of this antigen in the respiratory epithelium of individuals known to have lung cancer was mapped. These individuals are likely to demonstrate extensive changes throughout the epithelium due to field cancerization. p31 immunoreactivity was examined in primary tumors and surrounding non-neoplastic lungs containing both histologically normal and abnormal areas obtained from 28 Stage I non-small cell lung cancer (NSCLC) patients. Distribution and intensity of p31 expression was scored in three lung compartments (bronchi, bronchioli, alveoli). While p31 was present in histologically unremarkable bronchial and bronchiolar epithelium, no expression was detected in bronchi or bronchioli containing histologic abnormalities. Furthermore, in the peripheral lung p31 staining was frequently observed in alveolar type II cells and was most commonly detected in reactive, hyperplastic type II cells. When p31 immunoreactivity was correlated with clinicopathological features, a statistically significant increase in p31 expression was found both in bronchioli and alveoli of older individuals a well as in bronchioli of patients with most extensive smoking exposure. We conclude that p31 expression occurs in both non-neoplastic and neoplastic epithelium of the human respiratory tract. The increased expression of p31 in the peripheral lung may be potentially informative as to what critical cell populations are involved in the development of invasive cancers. Moreover, this study provides a model approach for analysis of the nature of early epithelial changes leading to the development of lung cancer.

Antibodies, Monoclonal↗
PubMed1996

Peptide amidating activity in human bronchoalveolar lavage fluid.

Monitoring respiratory epithelial biology may reveal individuals with incipient lung cancer. The expression of neuroendocrine (NE) markers in pulmonary epithelium is thought to be central to lung development, repair of injury and may contribute to carcinogenesis. In this study, we evaluate several candidate NE markers to determine the feasibility of prospective analysis of clinical specimens. The potential NE markers include the enzyme L-DOPA decarboxylase (DDC), the neuropeptide gastrin releasing peptide (GRP), and peptidyl-glycine alpha-amidating monooxygenase (PAM), the bifunctional enzyme responsible for the final bioactivation step of many neuropeptides. A comparison of PAM activity and DDC levels in 30 lung cancer cell lines indicated that peptide amidating activity may be an indicator of NE status. Bronchoalveolar lavage (BAL) fluid from subjects at risk of developing second primary lung cancer and from volunteers was obtained. The activity of the first PAM enzyme, peptidylglycine alpha-hydroxylating monooxygenase (PHM), ranged from not detectable to 507 pmol/h/mg protein in 57 specimens. The second PAM enzyme, peptidylamidoglycolate lyase (PAL), ranged from not detectable to 414 pmol/h/mg protein in 56 specimens. Using cluster analysis by the average linkage method, a group of enzyme values with PHM greater than 230 pmol/h/mg protein was determined. Long-term follow-up of these patients for new second primary lung cancers may help to determine the potential predictive value of PAM detected in the BAL fluid.

Biomarkers, Tumor↗
PubMed1996

Biochemical characterization of mouse liver IBE1-amide immunoreactivity: limitations of antibody-based approaches for verification of peptide expression.

A high titer, specific antiserum, raised against a synthetic analogue of a unique peptide region within the human IGF-IB prohormone, detected specific immunoreactivity in extracts of mouse, chicken, sheep, and human liver. Specificity was confirmed by the ablation of immunoreactivity in the presence of excess synthetic immunogen. Here we report the isolation and characterization of one of the immunoreactive species from an extract of mouse liver: amino acid sequencing revealed that the purified product was 78% identical to the NH2-terminus of the alpha-subunit of mouse hemoglobin. Immunoblot analysis of a commercial preparation of mouse hemoglobin confirmed that the antiserum recognized hemoglobin. Addition of excess synthetic peptide to the antiserum eliminated the immunobinding to hemoglobin. The apparent "specificity" of even affinity-purified antiserum for hemoglobin provides a cautionary note for the interpretation of studies concluding antigen expression based solely on the presence of positive immunoreactivity.

Amino Acid Sequence↗
PubMed1996

Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine.

PURPOSE: A phase II trial in patients with limited-stage small-cell lung cancer treated with induction etoposide/cisplatin plus twice-daily chest radiotherapy was conducted in an attempt to increase response rates and prolong survival. PATIENTS AND METHODS: Fifty-four previously untreated patients with limited-stage small-cell cancer were treated with etoposide/cisplatin and concurrent radiotherapy at 1.5 Gy twice daily for 3 weeks to a total dose of 45 Gy. Patients then received three more cycles of etoposide/cisplatin followed by four cycles of vincristine, doxorubicin, and cyclophosphamide or an individualized chemotherapy regimen. RESULTS: Nine patients are alive and free of cancer a median of 4 years (range, 2 to 7) from the start of treatment. Thirty-eight have had progression of their cancer at a median of 1.2 years (range, 0.5 to 5.4) and all have died of small-cell cancer. Thirteen of these 38 patients' (34%) only site of initial relapse was in the CNS and all died of CNS metastases. Five patients died during therapy or from its complications and two patients died of causes other than relapsed small-cell lung cancer and toxicity. The median survival time is 21.3 months, with an actual survival rate of 83% at 1 year, and actuarial survival rates of 43% at 2 years and 19% at 5 years. CONCLUSION: This combined modality regimen for patients with limited-stage small-cell lung cancer results in a 2-year survival rate of 43%, but the principal cause of death in these patients is still relapse of the original cancer. Isolated CNS metastases caused more than 30% of the cancer deaths.

Adult↗
PubMed1995

Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines.

BACKGROUND: The CDKN2 gene encodes the human cyclin-dependent kinase 4 inhibitor. This inhibitor protein is believed to be a tumor suppressor that plays an essential role in cell cycle regulation. One half of all cancer cell lines and one fourth of lung cancer cell lines examined to date contain homozygous deletions (i.e., both alleles lost) of CDKN2. However, the relative frequency of homozygous CDKN2 deletions in non-small-cell lung cancers (NSCLC) and in small-cell lung cancers (SCLC) has not been determined. Inactivation or loss of another tumor suppressor encoded by the retinoblastoma gene (the Rb protein) is more common in SCLC than in NSCLC. PURPOSE: We measured the frequency of homozygous CDKN2 deletions in 77 NSCLC and in 93 SCLC tumor cell lines. In addition, possible associations were explored between CDKN2 gene loss, the presence or absence of Rb protein, and the clinical status of lung cancer patients. METHODS: DNA was isolated from each tumor cell line and from the primary tumor and normal tissue of one NSCLC patient. Sequences corresponding to exons 1 and 2 of the CDKN2 gene were amplified by use of the polymerase chain reaction, and the resulting amplification products were analyzed by agarose gel electrophoresis and DNA blotting. Genomic DNA blotting was also used to evaluate CDKN2 gene deletions. The frequency of homozygous CDKN2 loss and the presence or absence of functional Rb protein (reported previously) in the cell lines were compared. RESULTS: Homozygous deletion of CDKN2 was detected in 18 (23%) of 77 cell lines established from patients with NSCLC, compared with one (1%) of 93 cell lines established from patients with SCLC (P < .001). No CDKN2 gene loss was observed in the normal tissue of an NSCLC patient whose tumor cell line showed homozygous deletion of the gene; however, the primary tumor from this patient had evidence of CDKN2 loss. Homozygous CDKN2 deletion was detected in 13 (28%) of 46 tumor cell lines from patients with stage III or stage IV NSCLC, compared with zero of 10 tumor cell lines from patients with stage I or stage II NSCLC. Coincident loss of CDKN2 genes and functional Rb protein was rarely observed (in two of 135 cell lines). CONCLUSION: The frequency of homozygous CDKN2 gene deletion in NSCLC cell lines is greater than that observed for any other known, or candidate, tumor suppressor gene. IMPLICATION: Further study of the role of CDKN2 gene alteration in the pathogenesis of NSCLC is needed.

Base Sequence↗
PubMed1995

Fostering chemopreventive agent development: how to proceed?

Improved molecular-based detection of early epithelial cancer creates an opportunity for selective pharmacologic agents to arrest the development of emerging cancers. Developing a successful prevention approach to cancer control could eventually lead to a significant decline in cancer mortality rates; progress depends on the amount of resources committed to this area. Most major prevention trials are federally supported due to their size, duration, and cost. Much of the initial developmental cost for advanced cancer treatment agents was supported by the pharmaceutical industry. Developing a cancer treatment agent is perceived as more clearly defined and achievable than for prevention agents. Preliminary discussions with representatives of the pharmaceutical and biotech industry have identified a number of barriers to chemoprevention product development. Researchers agree that a number of promising agents are being passed over for expeditious development due to the uncertainty associated with chemoprevention drug development. The major factors affecting this circumstance are considered, including cost of clinical trials, absence of a positive model, and inability to project liability exposure. Similar problems were encountered in the area of childhood vaccine development. Insights from that process may have applicability to prevention drug development. Resolving these problems now can have a significant effect on the rate of progress in this promising new approach to cancer control.

Anticarcinogenic Agents↗
PubMed1995

Molecular markers in early cancer detection. New screening tools.

Better early detection strategies for lung cancer are clearly needed. About 20 years ago, cytomorphologic criteria were developed for use in staging bronchial epithelium carcinoma. Yet, when sputum cytology was added to chest radiograph in the largest early-screening-of-lung-cancer study carried out to date, the three-arm trial sponsored by the National Cancer Institute, no major outcome benefit was shown. Sputum samples of participants in one of these trials, the Johns Hopkins Lung Project, have been archived. Currently, sputum immunostaining using two monoclonal antibodies directed at a difucosylated Lewis X epitope and a 31-kilodalton protein show correlation between positive staining of these samples and eventual development of lung cancer in the sampled population. Strategies to neutralize the stimulation of growth factors like gastrin-releasing peptide, which are seen in small-cell disease, are also being explored. Development of an epithelial-directed diagnostic test is the most important goal in obtaining early detection tools for lung cancer. Several new tests await prospective trials to evaluate their utility. In developing an early detection test for lung cancer, due to the chronic nature of the risk and the vast at-risk population, cost and patient compliance are two major concerns.

Antibodies, Monoclonal↗
PubMed1995

Analysis of small cell lung cancer cell growth inhibition by 13-cis-retinoic acid: importance of bioavailability.

13-cis-Retinoic acid can mediate differentiation of transformed cells and slow the proliferation of malignant cells, suggesting its use as a potential intervention tool. Specific cDNA probes for retinoic acid receptors demonstrated the expression of mRNAs for the different retinoic acid receptor isoforms in small cell lung cancer cell lines. Addition of 13-cis-retinoic acid to small cell lung cancer cells cultured using serum-free, hormonally defined medium resulted in a 5-8-fold increase in the level of the retinoic acid receptor-beta mRNAs; in medium containing serum, the increase in expression of the retinoic acid receptor-beta mRNAs was less pronounced, usually no more than 2-fold. Using an in vitro proliferation assay, addition of 13-cis-retinoic acid resulted in a significant dose-dependent, growth-inhibitory effect on the small cell lung cancer cell lines tested using serum-free conditions. These inhibitory effects decreased when cells were cultured in medium containing serum or serum components. Molecular size exclusion chromatography and native gel electrophoresis showed that the causative serum component eluted and migrated with serum albumin. Preincubating serum with triglycerides restored the inhibitory effects of 13-cis-retinoic acid demonstrated in serum-free systems. These data suggest that 13-cis-retinoic acid preferentially binds to serum albumin, restricting its inhibitory effects on epithelial cell receptors. Blocking retinoic acid-albumin interactions with a fatty acid source may improve the bioavailability of 13-cis-retinoic acid and significantly enhance the inhibitory effect in vivo.

Blotting, Northern↗
PubMed1994

Relationship of p53 overexpression and up-regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer.

p53 is known to play a central role in the control of cell proliferation and carcinogenesis. In non-small cell lung cancer, however, the clinicopathological studies of p53 have yielded conflicting results. In the current study, we examined 123 non-small cell lung cancers with detailed clinical information, 71 primary and 52 metastatic tumors, using formalin-fixed and paraffin-embedded surgical specimens to show the clinicopathological correlation of the immunohistochemical (DO-7) overexpression of p53. Nuclear specific p53 overexpression appeared in 48 (39%; any number of tumor cells positive) of 123 tumors (35% of primary and 44% of metastatic tumors). The distribution and intensity of staining were variable. Ninety-eight % of all tumors also expressed nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA; PC 10) to a varying degree. In a univariate analysis, both p53 (> 10% of tumor cells positive; n = 11) and PCNA (> 50% of tumor cells positive; n = 32) were associated with shorter survival in the curative intent group (stages I, II, and IIIA) of 63 patients. In a multivariate analysis including all clinicopathological variables, the overexpression of p53 (but not PCNA) was found to be an independent prognostic factor (P2 = 0.0011) in the curative intent group. No correlation was detected between the immunoreactivities and patient characteristics, such as age, gender, or smoking. Double immunohistochemistry of both p53 and PCNA revealed a distinct pattern, whereas its clinicopathological correlation remained elusive. We conclude that p53 overexpression in non-small cell lung cancer (but not PCNA) is independently associated with a shortened survival and may be of prognostic significance in selected patients with earlier stage cancer.

Adolescent↗
PubMed1994

Integrated clinical and basic studies related to circumventing non-small cell lung cancer drug resistance.

Consideration of a range of clinical and basic studies conducted at the National Cancer Institute which explore the nature of the tumor biology of lung identify the limitations of using chemotherapy for the treatment of advanced lung cancer. No single mechanistic explanation for lung cancer's chemoresistance is apparent, although considerable information about the biology of lung cancer and some of its clinical consequences have been elucidated. In contrast to previous works from our group, this presentation will focus principally on studies of the nature of drug resistance with non-small cell cancer. An alternative combined modality strategy for lung cancer control is to focus on epithelial progression of lung cancer using local modalities while it is still confined to the bronchial epithelium. Particular high risk populations may be appropriate to determine if local tools such as photodynamic laser therapy can be effective in this application. To deal with the underlying biochemical perturbations resulting from critical exposure of the bronchial epithelium to carcinogens, rational biochemical intervention with 13 cis retinoic acid are being evaluated in several clinical trials. An evolution towards more effective lung cancer control may involve the combined modalities of laser ablation of accessible dysplastic epithelium and chronic administration of intervention agents, such as retinoids, to neutralize cancer promotion dynamics in the more remote areas of the lung epithelium.

Antineoplastic Agents↗
PubMed1994

Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer.

PURPOSE: We performed a prospective randomized clinical trial to determine whether higher doses of etoposide and cisplatin (EP) yield more complete responses or longer survival in small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Ninety patients with previously untreated extensive-stage SCLC fulfilled criteria for randomization to standard-dose versus high-dose EP. Another 25 patients at risk of excessive toxicity from high-dose treatment were given standard-dose therapy. During cycles 1 and 2 of EP, patients on standard-dose treatment received intravenous etoposide 80 mg/m2 on days 1 to 3 and cisplatin 80 mg/m2 on day 1 every 3 weeks; high-dose treatment consisted of etoposide 80 mg/m2 on days 1 to 5 and cisplatin 27 mg/m2 on days 1 to 5 every 3 weeks. All patients received standard-dose EP in cycles 3 and 4. In cycles 5 through 8, completely responding patients continued standard-dose EP; all other patients received either cyclophosphamide, doxorubicin, and vincristine, or (if possible) a combination drug program based on in vitro drug sensitivity testing of tumor-cell lines established from individual patients. RESULTS: Despite 68% higher doses and a 46% higher dose-rate intensity actually given to patients randomized to receive high-dose relative to those randomized to receive standard-dose EP, complete response rates (23% v 22%; P = .99) and median survival durations (10.7 and 11.4 months, respectively; P = .68) were virtually identical. Complete responses occurred in 4% of patients and the median survival duration was 5.8 months in nonrandomized patients. Leukopenia (P < .0001), thrombocytopenia (P < .0001), febrile neutropenia (P = .01), and weight loss (P = .02) were significantly more common in patients randomized to receive high-dose compared with standard-dose EP. CONCLUSION: No therapeutic benefits resulted from increasing planned doses by 67% for the first two cycles of EP in patients with extensive-stage SCLC. Higher doses were associated with substantially worse toxicities.

Adult↗
PubMed1994

The early detection of second primary lung cancers by sputum immunostaining. LCEWDG Investigators. Lung Cancer Early Detection Group.

STUDY OBJECTIVE: To determine whether monoclonal antibody (Mab) detection of tumor-associated antigen expressed on sputum epithelial cells precedes clinical presentation of second primary lung cancer. DESIGN SETTING/PARTICIPANTS: Eleven oncology centers collaborate in the accrual of 1,000 patients with stage I non-small cell lung cancer (NSCLC) who had undergone resection. The Mabs examined in this study (624H12, 703D4) detect two promising oncofetal/differentiation markers (ie, a difucosylated Lewis X and a 31-Kd glycoprotein antigen). INTERVENTIONS: Induced sputum specimens are evaluated for quality, then are Papanicolaou and immunostained by independent central laboratories at enrollment and annually thereafter. The predictive value of Mab markers is compared with routine morphologic study for detection of second primary lung cancer during an anticipated 3 years of accrual and 1 year of follow-up. MEASUREMENTS AND RESULTS: Five hundred eighty of an anticipated 1,000 patients have been accrued on schedule. Patients are primarily white (88.6%), former smokers (75.9%), men (55.6%), with a median age of 66.7, and joined the study at an average of 3.7 years following resection of a stage 1 NSCLC (34.4% squamous, 43.6% adenocarcinoma). Central laboratories found less dysplasia and more unsatisfactory specimens (27.3%) than do the accrual institution laboratories. Immunostaining identifies more suspicious cells than does morphologic study. However, only two second primary lung cancers (eight total deaths) have occurred to date. CONCLUSIONS: Halfway through the accrual, we describe the study design and preliminary observations. This study illustrates rational selection of carcinogenesis markers by linkage of marker expression on preneoplastic specimens with subsequent expression on tumor tissue.

Aged↗