| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Short Communications |
From the Departments of Pathology,
Surgery,*
and Biostatistics,
Memorial Sloan-Kettering Cancer Center, New York, New York
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The significance of IHC data derived from tissue microarrays—comprised of small core biopsies of cancer specimens—relative to full section IHC has not been clearly determined. Based on the small size of tissue cores (0.6 mm) taken from paraffin-embedded tumor specimens heterogeneous expression patterns of investigated proteins could lead to significant differences in results between the two techniques. The number of tissue cores per tumor specimen required on an array to reduce the error rate attributable to tissue heterogeneity and to maintain efficient processing of tissues remains to be determined. It seems reasonable that this error rate may be reduced by using multiple tissue cores per specimen, a hypothesis that we tested in this study.
Cut-off values established for full section IHC may not be useful for assessment based only on a 0.6-mm tissue sample; eg, Ki-67 nuclear staining in >20% of tumor nuclei of full sections is frequently considered to be a high proliferative index.2 Most standard IHC stains result in readings that distinguish between positive (+) and negative (-) categories, whereas others have a higher degree of complexity requiring the distinction between three different categories; eg, pRB: high (++), intermediate (+), and negative (-). The effect of staining complexity on tissue array-derived data may also lead to different concordance rates relative to full tissue sections.
In an effort to validate the tissue array technique, we conducted a study that defined the concordance of single, duplicate, and triplicate 0.6-mm core biopsies on tissue arrays in comparison to full section analysis. We arrayed a cohort of 59 human fibroblastic tumors known to have heterogeneous expression of investigated proteins and analyzed abnormalities in expression of Ki-67, p53, and pRB by IHC. Readings of full sections were compared with readings of three independent core biopsies per specimen sampled on one tissue microarray. The impact of data discrepancies between the two methods with regard to patient outcome was also evaluated.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The cohort analyzed consisted of 59 patients with fibroblastic neoplasms that included desmoid tumors (n = 24), low-grade (n = 21) and high-grade fibrosarcomas (n = 14) treated and followed at Memorial Sloan-Kettering Cancer Center between August 1982 and January 1999. Median age of the cohort was 40 years (range, 10 to 86 years). Median follow-up for the entire group was 36 months. Twenty-seven patients from all three groups developed local recurrence, whereas 10 fibrosarcoma patients developed metastasis. At last follow-up 41 patients had no evidence of disease, eight were alive with disease, nine died of disease, and one died of other causes. Recurrence-free and overall survival were defined as time from primary tumor resection to first recurrence (either local or distant) or death from disease, respectively. Median recurrence-free survival was 18 months and median overall survival was 35 months.
Tissues, Array Construction, and IHC
Normal and tumor tissues were embedded in paraffin and five-µm sections stained with hematoxylin and eosin were obtained to identify viable, morphologically representative areas of the specimen from which core biopsies were taken. This was done with a precision instrument (Beecher Instruments, Silver Spring, MD) as previously described.1 From each specimen triplicate tissue cores with a diameter of 0.6 mm were punched and arrayed on a recipient paraffin block. Five-µm sections of these tissue array blocks were cut and placed on charged polylysine-coated slides. These sections were used for immunohistochemical analysis.7 Tissues and cell lines known to express the antigens under study were used as positive controls. Arrayed normal tissues served as baseline controls. All normal tissue samples showed physiological expression patterns of the analyzed markers.
Sections from paraffin-embedded tissue were deparaffinized, treated with 1% H2O2 in phosphate-buffered saline, and submitted to antigen retrieval by microwave oven treatment for 15 minutes in 0.01 mmol/L citrate buffer at pH 6.0. This procedure was performed for all antibodies under study. For MIB-1 antibody, an additional step of incubation in preheated 0.05% Trypsin, 0.05% CaCl2 in Tris-HCl (pH 7.6) for 5 minutes at 37°C before microwave treatment was performed. Slides were subsequently incubated in 10% normal horse serum for 30 minutes followed by appropriately diluted primary antibody incubation overnight at 4°C. Mouse anti-human monoclonal antibodies to p53 (1:500, Ab-2, clone 1801; Calbiochem, Cambridge, MA), pRB (1.28 µg/ml; clone 3c8; QED Bioscience, San Diego, CA), and Ki-67 (1:50, Mib-1; Immunotech, Marseille, France) were used. The anti-p53 antibody detects wild-type and mutated p53, whereas the anti-pRB antibody detects normal and hyperphosphorylated pRB products (manuscript in preparation).8 The antibody for Ki-67 recognizes epitopes from human recombinant peptides of the Ki-67 protein. Samples were then incubated with biotinylated anti-mouse immunoglobulins at 1:500 dilution (Vector Laboratories, Inc., Burlingame, CA) at room temperature for 30 minutes followed by avidin-biotin peroxidase complexes (1:25, Vector Laboratories, Inc.) for 30 minutes. Diaminobenzidine was used as the chromogen and hematoxylin as the nuclear counterstain.
Immunoreactivities were classified as a continuum data (undetectable levels or 0% to homogeneous staining or 100%) for all three markers. Slides were reviewed by three investigators (CCC, AH, MU) and results were scored by estimating the percentage of tumor cells showing characteristic staining. The cut-off values used in this study have been shown to be highly sensitive2-4 and were defined as follows: 1) high proliferative Ki-67 index if >20% tumor nuclei stained, 2) p53 nuclear overexpression if >10% tumor nuclei stained. For pRB no cut-off value was defined. Tumors were then grouped into two categories defined as follows: normal expression (neoplasms below defined cut-off value of immunoreactivity in tumor cells) and abnormal expression (neoplasms above defined cut-off values of immunoreactivity in tumor cells).
Validation of Tissue Arrays
Full sections from tumor blocks and sections from the tissue array containing three representative core biopsies per tumor block were read in a blinded manner and later compared to one another. Single readings from each core were obtained and evaluated as three separate experiments. Also, cumulative values were established summarizing the results from two and three core readings. All possible combinations of cores taken from one specimen were evaluated. Concordance criteria between full sections and cumulative values of tissue cores were as follows: if three cores per specimen were available for reading either three or two cores matching the full section were sufficient to define the case as a match; if only two cores were available for reading both had to match the full section to define the case as a match.
Two different analyses were performed. First, we simulated the
construction of three tissue arrays containing either one, two, or
three cores per specimen by assembling one tissue array with three
physically separated cores per specimen. We then compared the accuracy
of each of these arrays to the full tissue section. For single core
analysis we excluded cases in which cores were lost during sectioning
and staining. For two and three core analyses the following case
exclusions were made: cases in which there were two cores available and
two different IHC readings were obtained, cases in which only one core
was available and cases in which all cores were lost. These were
described but not included in the analysis. All three scenarios were
evaluated for numbers of cases lost from the analysis because of tissue
loss or inconclusive data, and for concordance (percent matches of
evaluated cases). Average values were obtained from three single cores
in the one-core analysis and from the three possible combinations of
two cores per specimen in the two-core analysis. For the triplicate
core analysis all three cores were used to obtain a single value. This
analysis demonstrated the importance of triplicate cores to keep
numbers of lost cases as low and concordance rates as high as possible.
Second, based on the first analysis, the specific details of a
triplicate core tissue array were evaluated (summarized in Table 1
).
|
The association between full section analysis and tissue microarrays was studied using kappa statistics.9 Kappa values >0.7 were considered to express a strong association between the two methods. Survival analysis was performed by the method of Kaplan-Meier10 and statistical significance (P < 0.05) of outcome comparisons were evaluated using the log-rank test.11
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IHC readings from single cores were compared to cumulative values
from two and three cores simulating the situation of tissue arrays
constructed with only one core, two cores, or three cores per tumor
specimen. These were then compared to the full tissue section. Examples
are shown in Figure 1
. Numbers of cases
lost from the analysis were either because of tissue loss or
inconclusive data coming from two available cores with different
readings. The rates of lost cases for the single core array were 10,
18, and 25% for Ki-67, p53, and pRB, respectively. These rates were
17, 30, and 37% with two evaluated cores. The rates for two-core
analysis include cases in which both cores were lost as well as cases
in which only one core was lost because the remaining core was
insufficient to reflect the information for both. The combination of
data taken from two experiments had an additive effect on the number of
excluded cases in that analysis. For three-core analysis these rates
were at 10, 17, and 20%, respectively. The reduced rate of lost cases
was because of the availability of the third core allowing a majority
decision in problematic cases (2 > 1). Disagreements between
duplicate cores from one specimen were more common for two-core
analysis (Ki-67, 13%; pRB, 8%) than for cases from the three-core
analysis, in which one of the three was lost (2% each for Ki-67 and
pRB). This may be attributable to statistical variation. No such
disagreement was seen for p53 because there was only one mismatch case
in that analysis. Nonconcordance (percent mismatches of evaluated
cases) was the lowest for three cores (Ki-67, 3.7%; pRB, 6.4%)
versus two cores (4.4%, 6.5%) and one core alone (9.4%,
11.4%). For p53 these rates were uniformly 2% because of only one
nonconcordant case. Taken together, this demonstrates the importance of
triplicate cores to keep numbers of lost cases as low and concordance
rates as high as possible. Based on this analysis the specific details
of a triplicate core tissue array were evaluated.
|
Ki-67 Proliferative Index
Fifty-three of 59 cases (90%) on the tissue array were assessable
because six cases were excluded because of tissue loss or inconclusive
readings between two cores. High Ki-67 proliferative index was found in
18 of these 53 cases (34%) but was not detected in 35 cases (66%)
using standard full-section IHC. In comparison, high proliferative
index was read slightly less frequently from the tissue array from
which 16 cases (30%) were considered to show overexpression (>20%
nuclear staining) whereas 37 (70%) were read as normal. Overall, the
nonconcordance between full sections and tissue array was 4% (two
cases). In 10% of cases the concordance was because of two cores
displaying the same pattern as the full section and one core showing a
different pattern. These data demonstrate reliable readings from a
triplicate core array in 96% of the assessable cases (Table 1)
. The
two methods showed a strong statistical association (kappa value,
0.874).
p53 Nuclear Overexpression
p53 protein half-life is short and expression levels are low in
normal cells and therefore IHC cannot detect these normal p53 levels.
In cancer cells, most p53 mutations lead to products that are not
ubiquitinated, accumulate in the nuclei, and can be demonstrated by
IHC. Because of tissue loss or inconclusive readings between two cores,
49 of 59 cases (83%) were assessable. Five cases (10%) showed nuclear
staining >10% of tumor nuclei, whereas 44 cases (90%) were negative
on full section analysis. In comparison, four cases (8%) were read as
positive and 45 cases as negative (92%) on the array. Overall, the
nonconcordance was 2% (one case) for a concordance of 98% among the
assessable cases (Table 1)
. A strong statistical association between
full sections and array for p53 IHC was also demonstrated (kappa value,
0.878).
pRB Expression Patterns
Genetic alterations of RB are either deletions or point mutations. Patterns of expression of pRB have been classified as wild type when low nuclear staining is observed (+), and abnormal when undetectable (because of genetic deletion/mutation) (-) or when producing high nuclear staining (mainly because of nonactive, hyperphosphorylated proteins) (++). All three phenotypes of RB were observed in this study and were evaluated as three categories for the array validation. Because of tissue loss or inconclusive readings between two cores, 47 of 59 cases (80%) were assessable. Twenty-two cases (47%) were read as abnormal and 25 (53%) as normal based on full section and tissue array analysis. These numbers include four mismatches (nonconcordance 9%), two occurring in the abnormal and two in the normal category, and therefore leading to equal counts in both categories. A strong statistical association between both methods was also seen for this stain (kappa value, 0.853). For clinicopathological correlation of data three category readings were grouped in two functional categories: normal (wild type) and abnormal (deleted/mutated or hyperphosphorylated) (see below).
Clinicopathological Correlations
To identify differences in clinicopathological correlations between the data generated with the two methods we independently analyzed both data sets with regard to their predictive value for patient outcome. The comparison of molecular data to patient outcome displayed a significant association between recurrence-free and overall survival and overexpression of Ki-67 if full sections were used (P = 0.03, P = 0.03). These associations remained significant if the tissue array-derived data were used (P = 0.01, P = 0.01).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We used well characterized antibodies against Ki-67 and p53 that
require a distinction between two categories (+ or -) and a pRB
antibody that requires a distinction between three categories
(manuscript in preparation)8
(Figure 1)
. Thus, we
investigated the potential adverse impact that staining complexity
might have on the accuracy of IHC data generated from tissue arrays. In
addition, these markers were chosen because of their relevance in human
cancer development and our extensive previous
experience.5,7,16
IHC was done on a group of 59
fibroblastic tumors known to show heterogeneous expression patterns for
Ki-67, p53, and pRB.2,3,15,17
Processing of tissue
sections from both tumor blocks and arrays was based on previously
established protocols as they can have significant influence on the
results (see Materials and Methods).
Our first analysis comparing one, two, and three cores per specimen demonstrated a higher number of lost cases and lower concordance with the full section reading for one or two cores per case in comparison to three cores. Tissue loss is a significant factor for tissue array-based analysis with previously reported rates of tissue damage ranging from 15 to 33%.6,12,13 Our data show that the presence of a third core reduces the risk of losing the case because of tissue damage. Nonconcordance was the lowest for three cores identified as 4, 2, and 9% for Ki-67, p53, and pRB, respectively. This again shows the importance of the third core because three cores allow a majority decision (2 > 1) if one core differs from the other two. Taken together, three cores provide a relatively high concordance compared to only one core and reduce the problems of higher case loss that is seen with two cores. Thus, three cores per specimen increase both the accuracy and the strength of array-based data.
Theoretically, accuracy levels would probably rise with the use of more than three cores per specimen. However, from a practical point of view it is desirable to identify the minimal number of cores necessary to obtain highly accurate results from tissue arrays and allow the most economic processing of the tissues without the need to array a larger number of cores per tumor specimen. The high accuracy achieved with triplicate cores for stains that require two-category distinction suggests that this may be a useful setup for routine application of tissue microarrays.
Based on this information we further evaluated the three-core tissue
array. The reduction of assessable cases because of tissue loss during
cutting and transfer of array sections and vigorous staining procedures
or because of inconclusive data derived from two cores with different
readings was 10, 17, and 20% for Ki-67, p53, and pRB, respectively.
Other groups reported similar or higher rates of tissue
loss.6,12-14
Cases were excluded if all three cores were
lost and if only one core or two cores with discrepant readings
remained. This was done to eliminate cases that were inconclusive or
nonassessable and thus simulate the situation of a tissue array without
the control of a full section (Table 1)
.
The concordance between full tissue sections and triplicate core arrays
for Ki-67, p53, and pRB was 96, 98, and 91%, respectively. These
results include 10% of evaluated cases for Ki-67 and pRB for which
concordance was based on the dominant result of two tissue cores
matching the full section and one core not matching the full section
(Table 1)
. This demonstrates the relevance of the third core for
difficult cases. Despite the use of triplicate cores the nonconcordance
for pRB was still 9%. This can be explained by the complexity of the
staining pattern obtained for pRB requiring a three-category
distinction. Statistically it is less likely to obtain identical
readings for this three-category distinction than for the standard
two-category distinctions used for Ki-67 and p53. This is clearly
reflected by the low nonconcordance of 4 and 2% for these stains. The
nonconcordance of 9% for pRB suggests that tissue array analysis of
pRB or other three-category markers may not be technically feasible or
readily applicable for clinicopathological analyses.
The few nonconcordant readings that we found, changed abnormal readings into normal readings and therefore lead to less frequent detection of abnormal expression patterns. Full tissue section analysis resulted in 10, 34, and 47% of cases in detection of abnormal expression of p53, Ki-67, and pRB, respectively. Corresponding rates of expression on the triplicate core tissue array were 8, 30, and 47%, respectively. These concordances suggest that triplicate cores on tissue arrays accurately reflect IHC results from full section analysis. This is supported by strong statistical associations between the two methods with kappa values of >0.853.
In this context, it must be emphasized that the selection of areas on hematoxylin and eosin-stained full sections from tissue blocks based on tumor morphology are crucial for the assembly of a tissue array. This requires meticulous attention of the investigator before the array is constructed and data are evaluated. Thus, it is ensured that the resulting arrays potentially provide relevant information about tumor-specific immunophenotypes.
To identify potential changes in outcome correlations caused by differences between the two techniques we compared survival data with the two data sets obtained by full tissue sections and tissue arrays and analyzed for local recurrence-free survival and overall survival. As suggested by the strong association between the two methods no differences were detected in correlation on the basis of patient outcome. This suggests that tissue arrays will allow reliable clinicopathological analysis of tumor specimens. This observation is based on a relatively small cohort of patients (n = 59) that permits limited conclusions about the applicability of tissue microarrays for clinicopathological studies. However, the strong association between the two methods and the fact that even full section analysis often represents only a small portion of the whole tumor specimen but still allows identification of clinicopathologically relevant immunophenotypes is promising. Therefore, we believe that tissue microarray-derived data will be useful for clinicopathological studies.
In summary, our data demonstrate a high reliability of tissue array-based IHC using standard cut-off values established for full section analysis. The use of three tissue cores is preferable to one or two cores and IHC stains with two-category distinction should be preferred over more complex stains where possible. Such triplicate core biopsies of 0.6-mm diameter taken per specimen provide a reliable system for large-scale analysis of cancer tissues on tissue microarrays without compromising the efficiency of the array technology and may be useful tools for clinicopathological analysis.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported by National Institutes of Health grant P01-CA47179 and the Gorin Fund.
Accepted for publication January 9, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  C. Karlsson, L. Bodin, K. Piehl-Aulin, and M. G. Karlsson Tissue Microarray Validation: A Methodologic Study with Special Reference to Lung Cancer Cancer Epidemiol. Biomarkers Prev., July 1, 2009; 18(7): 2014 - 2021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Buhmeida, R. Bendardaf, M. Hilska, J. Laine, Y. Collan, M. Laato, K. Syrjanen, and S. Pyrhonen PLA2 (group IIA phospholipase A2) as a prognostic determinant in stage II colorectal carcinoma Ann. Onc., July 1, 2009; 20(7): 1230 - 1235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Gravdal, O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen Proliferation of Immature Tumor Vessels Is a Novel Marker of Clinical Progression in Prostate Cancer Cancer Res., June 1, 2009; 69(11): 4708 - 4715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. SCHMIDT, S. BIESTERFELD, A. KUMMEL, A. FALDUM, M. SEBASTIAN, C. TAUBE, R. BUHL, and R. WIEWRODT Tissue Microarrays are Reliable Tools for the Clinicopathological Characterization of Lung Cancer Tissue Anticancer Res, January 1, 2009; 29(1): 201 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Mulligan, D. Pinnaduwage, S. B. Bull, F. P. O'Malley, and I. L. Andrulis Prognostic Effect of Basal-Like Breast Cancers Is Time Dependent: Evidence from Tissue Microarray Studies on a Lymph Node-Negative Cohort Clin. Cancer Res., July 1, 2008; 14(13): 4168 - 4174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. Sarkaria, M. F. Zakowski, D. Pham, M. Hezel, M. I. Ebright, S. Chuai, E. S. Venkatraman, M. G. Kris, V. W. Rusch, and B. Singh Epidermal Growth Factor Receptor Signaling in Adenocarcinomas With Bronchioloalveolar Components Ann. Thorac. Surg., January 1, 2008; 85(1): 216 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gravdal, O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer Clin. Cancer Res., December 1, 2007; 13(23): 7003 - 7011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Keller, B. C. Keller, P. Grest, C. T. Borger, and F. Guscetti Validation of tissue microarrays for immunohistochemical analyses of canine lymphomas J Vet Diagn Invest, November 1, 2007; 19(6): 652 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Cohen, B. Maly, I. Simon, A. Meirovitz, E. Pikarsky, E. Zcharia, T. Peretz, I. Vlodavsky, and M. Elkin Tamoxifen Induces Heparanase Expression in Estrogen Receptor Positive Breast Cancer Clin. Cancer Res., July 15, 2007; 13(14): 4069 - 4077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rolland, S. Deen, I. Scott, L. Durrant, and I. Spendlove Human Leukocyte Antigen Class I Antigen Expression Is an Independent Prognostic Factor in Ovarian Cancer Clin. Cancer Res., June 15, 2007; 13(12): 3591 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Burum-Auensen, P. M. De Angelis, A. R. Schjolberg, K. L. Kravik, M. Aure, and O. P. F. Clausen Subcellular Localization of the Spindle Proteins Aurora A, Mad2, and BUBR1 Assessed by Immunohistochemistry J. Histochem. Cytochem., May 1, 2007; 55(5): 477 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fons, S. M Hasibuan, J. van der Velden, and F. J W ten Kate Validation of tissue microarray technology in endometrioid cancer of the endometrium J. Clin. Pathol., May 1, 2007; 60(5): 500 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Lam, A. J. Pantuck, A. S. Belldegrun, and R. A. Figlin Protein Expression Profiles in Renal Cell Carcinoma: Staging, Prognosis, and Patient Selection for Clinical Trials Clin. Cancer Res., January 15, 2007; 13(2): 703s - 708s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zimpfer, S. Schonberg, A. Lugli, C. Agostinelli, S. A Pileri, P. Went, and S. Dirnhofer Construction and validation of a bone marrow tissue microarray J. Clin. Pathol., January 1, 2007; 60(1): 57 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Su, M. J. Shrubsole, R. M. Ness, Q. Cai, N. Kataoka, K. Washington, and W. Zheng Immunohistochemical Expressions of Ki-67, Cyclin D1, {beta}-Catenin, Cyclooxygenase-2, and Epidermal Growth Factor Receptor in Human Colorectal Adenoma: A Validation Study of Tissue Microarrays. Cancer Epidemiol. Biomarkers Prev., September 1, 2006; 15(9): 1719 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Wang, T.-T. Wu, E. Resetkova, H. Wang, A. M. Correa, W. L. Hofstetter, S. G. Swisher, J. A. Ajani, A. Rashid, S. R. Hamilton, et al. Expression of Annexin A1 in Esophageal and Esophagogastric Junction Adenocarcinomas: Association with Poor Outcome Clin. Cancer Res., August 1, 2006; 12(15): 4598 - 4604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. M. Bachmann, O. J. Halvorsen, K. Collett, I. M. Stefansson, O. Straume, S. A. Haukaas, H. B. Salvesen, A. P. Otte, and L. A. Akslen EZH2 Expression Is Associated With High Proliferation Rate and Aggressive Tumor Subgroups in Cutaneous Melanoma and Cancers of the Endometrium, Prostate, and Breast J. Clin. Oncol., January 10, 2006; 24(2): 268 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Bachmann, O. Straume, H. E. Puntervoll, M. B. Kalvenes, and L. A. Akslen Importance of P-Cadherin, {beta}-Catenin, and Wnt5a/Frizzled for Progression of Melanocytic Tumors and Prognosis in Cutaneous Melanoma Clin. Cancer Res., December 15, 2005; 11(24): 8606 - 8614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Anttonen, L. Unkila-Kallio, A. Leminen, R. Butzow, and M. Heikinheimo High GATA-4 Expression Associates with Aggressive Behavior, whereas Low Anti-Mullerian Hormone Expression Associates with Growth Potential of Ovarian Granulosa Cell Tumors J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6529 - 6535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. L. Ince, A. M. Jubb, S. N. Holden, E. B. Holmgren, P. Tobin, M. Sridhar, H. I. Hurwitz, F. Kabbinavar, W. F. Novotny, K. J. Hillan, et al. Association of k-ras, b-raf, and p53 Status With the Treatment Effect of Bevacizumab J Natl Cancer Inst, July 6, 2005; 97(13): 981 - 989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Belbin, B. Singh, R. V. Smith, N. D. Socci, V. B. Wreesmann, M. Sanchez-Carbayo, J. Masterson, S. Patel, C. Cordon-Cardo, M. B. Prystowsky, et al. Molecular Profiling of Tumor Progression in Head and Neck Cancer Arch Otolaryngol Head Neck Surg, January 1, 2005; 131(1): 10 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Sarkaria, D. Pham, R. A. Ghossein, S. G. Talbot, M. Hezel, M. E. Dudas, M. I. Ebright, S. Chuai, N. Memoli, E. S. Venkatraman, et al. SCCRO Expression Correlates With Invasive Progression in Bronchioloalveolar Carcinoma Ann. Thorac. Surg., November 1, 2004; 78(5): 1734 - 1741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Kay, A O'Grady, J M Morgan, S Wozniak, and B Jasani Use of tissue microarray for interlaboratory validation of HER2 immunocytochemical and FISH testing J. Clin. Pathol., November 1, 2004; 57(11): 1140 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Suo, K. U. Daehli, C. Fr. Lindboe, E. Borgen, A. Bassarova, and J. M. Nesland Real-Time PCR Quantification of c-erbB-2 Gene is an Alternative for Fish in the Clinical Management of Breast Carcinoma Patients International Journal of Surgical Pathology, October 1, 2004; 12(4): 311 - 318. [Abstract] [PDF]
|
|
|
|
|
|
F. R. Hirsch, M. Varella-Garcia, P. A. Bunn Jr, M. V. Di Maria, R. Veve, R. M. Bremnes, A. E. Baron, C. Zeng, and W. A. Franklin In Reply: J. Clin. Oncol., September 1, 2004; 22(17): 3646 - 3648. [Full Text]
|
|
|
|
|
|
A M Jubb, T Q Pham, A M Hanby, G D Frantz, F V Peale, T D Wu, H W Koeppen, and K J Hillan Expression of vascular endothelial growth factor, hypoxia inducible factor 1{alpha}, and carbonic anhydrase IX in human tumours J. Clin. Pathol., May 1, 2004; 57(5): 504 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Stefansson, H. B. Salvesen, and L. A. Akslen Prognostic Impact of Alterations in P-Cadherin Expression and Related Cell Adhesion Markers in Endometrial Cancer J. Clin. Oncol., April 1, 2004; 22(7): 1242 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Gurrieri, P. Capodieci, R. Bernardi, P. P. Scaglioni, K. Nafa, L. J. Rush, D. A. Verbel, C. Cordon-Cardo, and P. P. Pandolfi Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins J Natl Cancer Inst, February 18, 2004; 96(4): 269 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Diaz, X. Zhou, K. Welch, A. Sahin, and M. Z. Gilcrease Chromogenic In Situ Hybridization for {alpha}6{beta}4 Integrin in Breast Cancer: Correlation with Protein Expression J. Mol. Diagn., February 1, 2004; 6(1): 10 - 15. [Abstract] [Full Text]
|
|
|
|
|
|
R. Simon, S. Panussis, R. Maurer, H. Spichtin, K. Glatz, C. Tapia, M. Mirlacher, A. Rufle, J. Torhorst, and G. Sauter KIT (CD117)-Positive Breast Cancers Are Infrequent and Lack KIT Gene Mutations Clin. Cancer Res., January 1, 2004; 10(1): 178 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Puig, P. Capodieci, M. Drobnjak, D. Verbel, C. Prives, C. Cordon-Cardo, and C. J. Di Como p73 Expression in Human Normal and Tumor Tissues: Loss of p73{alpha} Expression Is Associated with Tumor Progression in Bladder Cancer Clin. Cancer Res., November 15, 2003; 9(15): 5642 - 5651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. S. Choi, Y. M. Shim, S.-H. Kim, D. S. Son, H.-S. Lee, G. Y. Kim, J. Han, and J. Kim Prognostic significance of E-cadherin and {beta}-catenin in resected stage I non-small cell lung cancer Eur. J. Cardiothorac. Surg., September 1, 2003; 24(3): 441 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sanchez-Carbayo, N. D. Socci, J. J. Lozano, W. Li, E. Charytonowicz, T. J. Belbin, M. B. Prystowsky, A. R. Ortiz, G. Childs, and C. Cordon-Cardo Gene Discovery in Bladder Cancer Progression using cDNA Microarrays Am. J. Pathol., August 1, 2003; 163(2): 505 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Gibson, J. H. Gill, P. A. Khan, J. M. Seargent, S. W. Martin, P. A. Batman, J. Griffith, C. Bradley, J. A. Double, M. C. Bibby, et al. Cytochrome P450 1B1 (CYP1B1) Is Overexpressed in Human Colon Adenocarcinomas Relative to Normal Colon: Implications for Drug Development Mol. Cancer Ther., June 1, 2003; 2(6): 527 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. L. Wapnir, M. van de Rijn, K. Nowels, P. S. Amenta, K. Walton, K. Montgomery, R. S. Greco, O. Dohan, and N. Carrasco Immunohistochemical Profile of the Sodium/Iodide Symporter in Thyroid, Breast, and Other Carcinomas Using High Density Tissue Microarrays and Conventional Sections J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1880 - 1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hendriks, P. Franken, J. W. Dierssen, W. de Leeuw, J. Wijnen, E. Dreef, C. Tops, M. Breuning, A. Brocker-Vriends, H. Vasen, et al. Conventional and Tissue Microarray Immunohistochemical Expression Analysis of Mismatch Repair in Hereditary Colorectal Tumors Am. J. Pathol., February 1, 2003; 162(2): 469 - 477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sanchez-Carbayo, P. Capodieci, and C. Cordon-Cardo Tumor Suppressor Role of KiSS-1 in Bladder Cancer: Loss of KiSS-1 Expression Is Associated with Bladder Cancer Progression and Clinical Outcome Am. J. Pathol., February 1, 2003; 162(2): 609 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sanchez-Carbayo Use of High-Throughput DNA Microarrays to Identify Biomarkers for Bladder Cancer Clin. Chem., January 1, 2003; 49(1): 23 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sanchez-Carbayo, N. D. Socci, E. Charytonowicz, M. Lu, M. Prystowsky, G. Childs, and C. Cordon-Cardo Molecular Profiling of Bladder Cancer Using cDNA Microarrays: Defining Histogenesis and Biological Phenotypes Cancer Res., December 1, 2002; 62(23): 6973 - 6980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hoos, A. Nissan, A. Stojadinovic, J. Shia, C. V. Hedvat, D. H. Y. Leung, P. B. Paty, D. Klimstra, C. Cordon-Cardo, and W. D. Wong Tissue Microarray Molecular Profiling of Early, Node-negative Adenocarcinoma of the Rectum: A Comprehensive Analysis Clin. Cancer Res., December 1, 2002; 8(12): 3841 - 3849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Urist, C. J. Di Como, M.-L. Lu, E. Charytonowicz, D. Verbel, C. P. Crum, T. A. Ince, F. D. McKeon, and C. Cordon-Cardo Loss of p63 Expression Is Associated with Tumor Progression in Bladder Cancer Am. J. Pathol., October 1, 2002; 161(4): 1199 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ginestier, E. Charafe-Jauffret, F. Bertucci, F. Eisinger, J. Geneix, D. Bechlian, N. Conte, J. Adelaide, Y. Toiron, C. Nguyen, et al. Distinct and Complementary Information Provided by Use of Tissue and DNA Microarrays in the Study of Breast Tumor Markers Am. J. Pathol., October 1, 2002; 161(4): 1223 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P.H. Pritzker Cancer Biomarkers: Easier Said Than Done Clin. Chem., August 1, 2002; 48(8): 1147 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Bremnes, R. Veve, E. Gabrielson, F. R. Hirsch, A. Baron, L. Bemis, R. M. Gemmill, H. A. Drabkin, and W. A. Franklin High-Throughput Tissue Microarray Analysis Used to Evaluate Biology and Prognostic Significance of the E-Cadherin Pathway in Non-Small-Cell Lung Cancer J. Clin. Oncol., May 15, 2002; 20(10): 2417 - 2428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Gancberg, A Di Leo, G Rouas, T Jarvinen, A Verhest, J Isola, M J Piccart, and D Larsimont Reliability of the tissue microarray based FISH for evaluation of the HER-2 oncogene in breast carcinoma J. Clin. Pathol., April 1, 2002; 55(4): 315 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Straume and L. A. Akslen Importance of Vascular Phenotype by Basic Fibroblast Growth Factor, and Influence of the Angiogenic Factors Basic Fibroblast Growth Factor/Fibroblast Growth Factor Receptor-1 and Ephrin-A1/EphA2 on Melanoma Progression Am. J. Pathol., March 1, 2002; 160(3): 1009 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Stojadinovic, R. A. Ghossein, A. Hoos, A. Nissan, D. Marshall, M. Dudas, C. Cordon-Cardo, D. P. Jaques, and M. F. Brennan Adrenocortical Carcinoma: Clinical, Morphologic, and Molecular Characterization J. Clin. Oncol., February 15, 2002; 20(4): 941 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Di Como, M. J. Urist, I. Babayan, M. Drobnjak, C. V. Hedvat, J. Teruya-Feldstein, K. Pohar, A. Hoos, and C. Cordon-Cardo p63 Expression Profiles in Human Normal and Tumor Tissues Clin. Cancer Res., February 1, 2002; 8(2): 494 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hoos, A. Stojadinovic, B. Singh, M. E. Dudas, D. H. Y. Leung, A. R. Shaha, J. P. Shah, M. F. Brennan, C. Cordon-Cardo, and R. Ghossein Clinical Significance of Molecular Expression Profiles of Hurthle Cell Tumors of the Thyroid Gland Analyzed via Tissue Microarrays Am. J. Pathol., January 1, 2002; 160(1): 175 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Chung, E. Provost, E. P. Kielhorn, L. A. Charette, B. L. Smith, and D. L. Rimm Tissue Microarray Analysis of {beta}-Catenin in Colorectal Cancer Shows Nuclear Phospho-{beta}-catenin Is Associated with a Better Prognosis Clin. Cancer Res., December 1, 2001; 7(12): 4013 - 4020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Polsky, B. C. Bastian, C. Hazan, K. Melzer, J. Pack, A. Houghton, K. Busam, C. Cordon-Cardo, and I. Osman HDM2 Protein Overexpression, but not Gene Amplification, is Related to Tumorigenesis of Cutaneous Melanoma Cancer Res., October 1, 2001; 61(20): 7642 - 7646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Srinivas, S. Srivastava, S. Hanash, and G. L. Wright Jr Proteomics in Early Detection of Cancer Clin. Chem., October 1, 2001; 47(10): 1901 - 1911. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
