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IMMUNOBIOLOGY
From the Institute of Pathology, University of
Wuerzburg; Department of Neurology, Universities of Wuerzburg, Mainz,
and Regensburg; Department of Thoracic and Cardiac Surgery,
Universities of Wuerzburg and Muenster, Germany; and Department of
Microbiology and Immunology, University of Melbourne, Australia.
Myasthenia gravis (MG) is the leading paraneoplastic manifestation
of thymomas and is probably related to the capacity of thymomas to
mature and export potentially autoreactive T cells. Why some thymomas
are MG associated (MG+) and others are not (MG Myasthenia gravis (MG) is an autoimmune disease
mediated by anti-acetylcholine receptor autoantibodies that cause
muscle weakness by impairing neuromuscular transmission.1
Of note, autoantibody production in MG is a CD4+
T-cell-dependent process.2-5
The frequent but incomplete association of thymomas (ie, thymic
epithelial tumors) with paraneoplastic MG and the generally unpredictable clinical course of MG after thymectomy are issues with
relevance for basic immunobiology and for patient
management.2 The current World Health Organization (WHO)
classification of thymomas6 recognizes 5 thymoma subtypes
that can be associated with MG: type A (or medullary), type AB (or
mixed), type B1 (or organoid), type B2 (or cortical), and type B3 (or
well-differentiated thymic carcinoma). Among these, AB, B2, and B3
thymomas are by far the most frequent subtypes and at the same time
show the highest association with MG.6,7
In recent years, it has been recognized that MG-associated thymomas
share critical features, namely (1) intratumorous enrichment for
acetylcholine receptor reactive T cells,4 (2)
intratumorous thymopoiesis with the generation of mature and
potentially autoreactive T cells from immature
precursors,5,6,8 and (3) export of mature T cells to the
peripheral compartment of the immune system.9,10 The
importance of export of potentially autoreactive T cells from thymomas
for MG development has also been supported by the observation that a
minority of initially MG( However, when the histologic thymoma subtype is taken into
account, no systematic difference between MG(+) and MG( To address these questions, we first analyzed the intratumorous
generation of the mature naive CD45RA+ thymocyte
subsets13 in thymomas with and without associated MG, and
we next analyzed the circulating naive (CD45RA+) T-cell
subsets by flow cytometry. Determination of the naive T-cell phenotype
is difficult and has led to the use of complex techniques, such as
polychromatic flow cytometry18 or molecular biologic
analysis of TRECS.16 From these studies, however, it is
also known that the contamination of the naive T-cell pool with memory
cells is relatively small.16,18,19 Moreover, analysis of
naive T cells by measurement of TRECS may also be confounded by
mechanisms such as peripheral homeostatic proliferation.19 Thus, the assessment of thymic output by measurement of CD45RA can
still be regarded as an orientating, pragmatic method for use in
routine procedures.
Our results clearly indicate that the presence of paraneoplastic MG is
highly correlated with the efficiency of thymomas to produce and export
mature naive CD4+ T cells. The identification of this
T-cell subset in thymomas may help to identify patients who are MG( Patients
The diagnosis of MG was based on clinical features, decrement testing
on 3 Hz serial stimulation, and detection of anti-AChR antibodies as
described previously.13 All MG(+) patients were autoantibody positive. Among the MG( Tumors and cell preparation
Nomenclature of naive thymocyte subsets and T-cell subsets In the thymus, T cells expressing either CD4 or CD8 together with CD3, CD69, and CD45 RA were designated as mature naive CD4 or CD8 T cells, respectively. In the peripheral blood, the term naive CD4 or CD8 T cells refers to T cells expressing CD4 or CD8 together with CD3 and CD45RA, but not CD69, which is lost on emigration from the thymus.20Flow cytometry and cell separation procedures Sampling and data analyses of thymocytes and PBMCs were performed on a FACScan flow cytometer with Lysis II software (Becton Dickinson, Heidelberg, Germany) as described.13 The CD3+ T-cell subset was gated for all analyses.Cells (2 × 105) were stained for 3-color FACS analysis with a panel of surface antigen-directed monoclonal antibodies, as described previously.13 The panel of antibodies included anti-CD3 (phycoerythrin [PE]-labeled), anti-CD4 (fluorescein isothiocyanate [FITC]-labeled), and anti-CD8 (PE-labeled) (DAKO, Hamburg, Germany); anti-CD69 (either FITC- or PE-labeled) (Becton Dickinson); anti-CD45RO and anti-CD45RA (either FITC- or PE-labeled) (Dianova, Hamburg, Germany); and anti-CD3 (Tricolor-labeled) and the isotype control IgG2a (FITC-labeled) (Medac, Hamburg, Germany). Other isotype controls and anti-CD3 (FITC-labeled) were purchased from Sigma (Deisenhofen, Germany). To further characterize a phenotypically unusual
CD4+CD8 Confocal laser scanning microscopy Immunofluorescence double staining of formalin-fixed, paraffin-embedded tissues was performed in 4 patients with combination of CD45RA and CD4 or CD8. Four-micrometer sections were dewaxed overnight in xylene. Indirect immunohistochemical staining was performed in the following order at room temperature: (1) blocking with 5% donkey serum (Dianova) for 20 minutes; (2) primary monoclonal antibody against CD4 (1:5) or CD8 (DAKO) (1:10 for 1 hour); (3) biotinylated goat anti-mouse IgG (Biogenex supersensitive; 1 hour); (4) Cy3-conjugated streptavidin (Jackson ImmunoResearch, West Grove, PA; 1 hour); (5) anti-CD45RA, directly conjugated with FITC (DAKO, 1 hour); (6) rabbit anti-FITC antibody (Molecular Probes, Eugene, OR; 1 hour); and (7) Cy2-conjugated donkey anti-rabbit antibody (Dianova; 1 hour). The latter 2 steps were necessary to reach adequate signal strength. For each fluorochrome labeling, negative and positive control sections were included. Confocal fluorescence images were obtained using a Leica TCS SP2 (Leica Microsystems, Heidelberg, Germany) system. Images were taken using a ×40 1.25 NA objective. Color photomicrographs were taken from the single fluorescences and from electronic overlays.Statistical analyses All statistical analyses were performed using 2
analysis and Mann-Whitney U test (P < .05,
unless otherwise indicated) provided by the SPSS software (version
2000; SPSS, Chicago, IL). The  coefficient was used to determine
correlations between different parameters (low, 0.01-0.40; moderate,
0.41-0.70; high, 0.71-1.00). In all column graphs shown, the
statistical mean ± SEM are depicted.
MG(  ) thymomas (data not shown). In MG(+) thymomas, the percentage of
mature naive CD8+ T cells was statistically significantly
(P = .01) increased compared with nonneoplastic thymus
controls, whereas the percentage of total
CD3+CD45RA+ cells and of mature naive
CD4+ T cells was not significantly altered, resulting in a
highly decreased CD4:CD8 ratio. In MG() thymomas, by stark contrast, the percentage of CD45RA+ thymocytes among the
CD3+ subpopulation was highly significantly reduced
compared with MG(+) thymomas (49.2% ± 23.1 vs 20.1 ± 15.2;
P = .003) and thymus controls (P = .03).
Further analysis of the naive CD4+ and CD8+
subsets revealed that the percentage of the CD4+ subset was
highly significantly reduced in all MG() thymomas analyzed compared
with MG(+) thymomas and thymus controls (4.3 ± 2.0 in MG()
thymomas vs 24.4 ± 18.9 in MG(+) thymomas; P < .0001;
Table 2; Figure
1). Thus, on 2
analysis, the presence of MG was significantly linked to high levels of
mature naive CD4+ T cells (P < .01). However,
our finding of 9.8% naive CD4+ T cells in the thymoma of
the MG() patient 17, compared with the virtually identical
percentages in MG(+) patients 1 and 2 (10.1% and 10.0%,
respectively), show that a minor overlap between the 2 groups exists.
This overlap extended to the CD8+ subset because several
patients (eg, patients 9, 10, 12, 17) had marked reduction of mature
naive CD8+ cells among MG(+) and MG() thymomas. In
addition, this latter finding suggests for the first time that
maturation not only of the CD4+ but also of the
CD8+ lineage might be affected in a subset of thymomas
(Table 2; Figure 2).
Some MG( ) thymomas (2 WHO type AB and 1 type B2) but none
of the MG(+) thymomas contained a peculiar population of CD3high thymocytes that were CD4+ and
CD8 . This population has hitherto not been described in
the human thymus and was also absent from all nonneoplastic thymuses
studied (Figure 3). The cells were small
by forward and side scatter (not shown). To further characterize this
population, we removed CD8+ thymocytes from thymoma-derived
thymocyte suspensions of the 3 patients through anti-CD8 cell depletion
columns and then stained for a marker of interest in addition to CD3
and CD4. The CD3high T cells were negative for CD69 (Figure
3), nonactivated, and negative (CD25) for all other
surface molecules tested, in particular CD1a, and for CD45RA and CD45RO
(not shown).
CD45RA+CD4+ T cells are reduced in the blood of thymoma patients without MG Having shown that MG status was significantly associated with distinct abnormalities of intratumorous thymopoiesis (Figures 1 and 2), we next asked whether the observed differences in thymopoiesis might be mirrored by respective abnormalities in the peripheral blood. To this end, we compared the percentages of CD4+ and CD8+ T cells among the naive CD45RA+ subset in the blood of thymoma patients and of MG(+) patients with nonneoplastic thymuses to age- and sex-matched blood controls (Table 3; Figure 4). This strategy has been shown to be a valid method to indirectly assess T-cell export from the thymus and presumably from thymomas.9,21 Compared with blood controls, MG(+) and MG() thymoma patients showed a statistically
significant increase of the naive CD8+ subset
(P = .009 and P = .002, respectively) and a
decreased CD4-CD8 ratio (P = .01 and
P = .006, respectively). Both alterations were slightly
more prominent in MG() than in MG(+) patients. By contrast, the
percentage of naive CD4+ T cells was significantly reduced
only in MG() (P = .02), but not in MG(+), patients
(P = .34) (Figure 4). Together, these data clearly
indicate that virtually all thymomas contribute to the naive peripheral
T-cell pool by export of mature naive T cells. This conclusion was
further supported by a moderate positive correlation between
percentages of naive CD4+ T cells in the thymoma and the
peripheral blood of MG(+) patients (r = 0.59). However,
presence of MG appears to be critically associated only with the export
of mature naive CD4+, but not CD8+, T cells
from the thymoma into the peripheral compartment.
The percentage of CD45RA+ T cells was not increased in the peripheral blood of patients with TFH compared with healthy age- and sex-matched control persons (P = .17), and there were no statistically significant alterations with respect to the percentage of naive CD4+ and CD8+ T cells (P = .74 and P = .06, respectively). However, there was a trend toward a reduction of peripheral naive CD8+ T cells in patients with TFH (Figure 4), and the percentages of intrathymic and peripheral naive CD8+ T cells showed a moderate statistical correlation (r = 0.43). Clinical course after thymectomy The clinical course after thymectomy was followed for up to 66 months in all 22 thymoma patients. In patients with MG at the time of surgery, thymectomy in combination with immunosuppression generally resulted in amelioration of myasthenic symptoms (9 of 9 patients), but complete cure without the requirement for medication was not achieved in any patient (follow-up 5-60 months). None of the patients without MG at the time of thymectomy acquired postsurgery MG (follow-up 1 to 70 months), though this is a well-known but rare complication in primarily MG() thymomas22-25 and though one MG() patient (patient
17) had high anti-AChR antibody titers.
Detection of intratumorous CD45RA+CD4+ thymocytes in a thymoma patient with postsurgery MG Among the thymoma patients studied here by flow cytometry, none acquired MG after thymoma resection (postsurgery MG [ps-MG]). In addition, among MG() thymomas, only one patient (patient 17) maintained production of mature naive CD4+ thymocytes. The
latter finding is surprising because the occurrence of ps-MG has been
taken as circumstantial evidence that thymomas might start to generate
and export mature autoreactive T cells long before MG
develops.5,7 To address this question, we checked our
files for thymoma patients with ps-MG (2 in 532 patients). Paraffin-embedded tissue was available in one of them, but frozen material was not available in either. We applied
double-immunofluorescence laser scanning microscopy to analyze this
material and 3 exemplary thymomas from the FACS series (patient 4, MG(+) thymoma with a high percentage of CD4+ and
CD8+ mature naive thymocytes; patient 18, MG() thymoma
with a high percentage of mature naive CD8+ cells, but
strong reduction of naive CD4+ cells; patient 10, MG()
thymoma with virtual absence of both naive T-cell subsets; Table 2).
Moreover, 3 nonneoplastic thymuses were stained as controls. Results of
the immunofluorescence investigations (Figure
5) were highly concordant with the FACS
data and showed abundant numbers of mature naive CD4+
thymocytes inside nonneoplastic thymuses and MG(+) thymomas and a
significantly reduced percentage of naive CD4+ thymocytes
in MG() thymomas. In the patient with ps-MG, naive CD4+
thymocytes were as frequent as in the patient with MG(+) thymoma. These
preliminary findings suggest that the presence of mature naive
CD4+ T cells in MG() thymomas is rare but might be
predictive of the risk for ps-MG. Of note, immunofluorescence
microscopy findings in a given section were remarkably homogeneous
throughout at least 20 microscopic fields studied per patient,
indicating that thymopoietic incompetence during the very late stage of
thymopoiesis, as indicated by FACS (Table 2), was an evenly distributed
malfunction in a given tumor. We did not detect "hot spots" along
with either well-preserved or highly reduced terminal thymopoiesis.
This observation suggests that incompetence for terminal thymopoiesis
in MG() thymomas is probably related to an early genetic event in the
clonal neoplastic thymic epithelial cells of thymomas.
In this article, we demonstrate for the first time a significant
qualitative difference in intratumorous thymocyte maturation between
MG(+) and MG( Although the exact mechanisms for the defective T-cell maturation in
MG( The observed reduction of intratumorous mature naive CD4+ T
cells in MG( In the second part of the investigation, we asked whether the observed
differences in thymopoiesis between MG(+) and MG( With respect to the clinical history of MG after thymoma surgery,
follow-up of the MG(+) patients included in this study showed the
typical course with slow, moderate amelioration but not with complete
resolution of the myasthenic symptoms over years. By contrast, none of
the MG( In summary, our findings provide new conceptual insight into the
pathogenesis of paraneoplastic MG. A maintained but nontolerogenic intra-tumorous T-cell maturation appears to be a prerequisite for MG
development, whereas more profound disturbances with the abrogation of
intra-tumorous thymopoiesis interfere with autoimmunization. In
particular, our findings highlight the pivotal role of thymoma-derived CD4+ T cells in the pathogenesis of paraneoplastic MG. A
comparison of MG(+) and MG(
We thank Andrea Homburger, Sonja Rotzoll, Elke Oswald, Sabine Roth, and Erwin Schmidt for expert technical assistance.
Submitted October 16, 2001; accepted February 20, 2002.
Supported by DFG grant FOR 303/2 (P.S., A.M.), BMBF 2000 grant IZKF 01 KS 903/C5 (V.H.), the National Health and Medical Research Council of Australia, and the Ian Potter Foundation (S.R.L.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Philipp Ströbel, Institute of Pathology, University of Wuerzburg, Josef-Schneider-Strasse 2, 97080 Wuerzburg, Germany; e-mail: path036{at}mail.uni-wuerzburg.de.
1.
Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD.
Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value.
Neurology.
1998;51:933-939 2. Hohlfeld R, Toyka KV, Heininger K, Grosse-Wilde H, Kalies I. Autoimmune human T lymphocytes specific for acetylcholine receptor. Nature. 1984;310:244-246[CrossRef][Medline] [Order article via Infotrieve]. 3. Kaul R, Shenoy M, Goluszko E, Christadoss P. Major histocompatibility complex class II gene disruption prevents experimental autoimmune myasthenia gravis. J Immunol. 1994;152:3152-3157[Abstract].
4.
Zhang GX, Xiao BG, Bakhiet M, et al.
Both CD4+ and CD8+ T cells are essential to induce experimental autoimmune myasthenia gravis.
J Exp Med.
1996;184:349-356 5. Vincent A, Willcox N. The role of T-cells in the initiation of autoantibody responses in thymoma patients. Pathol Res Pract. 1999;195:535-540[Medline] [Order article via Infotrieve]. 6. Rosai J. Histological typing of tumours of the thymus. 2nd ed. Berlin: Springer-Verlag; 1999:1-65. 7. Muller-Hermelink HK, Marx A. Thymoma. Curr Opin Oncol. 2000;12:426-433[CrossRef][Medline] [Order article via Infotrieve].
8.
Drachman DB.
Myasthenia gravis.
N Engl J Med.
1994;330:1797-1810
9.
Hoffacker V, Schultz A, Tiesinga JJ, et al.
Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease.
Blood.
2000;96:3872-3879 10. Buckley C, Douek D, Newsom-Davis J, Vincent A, Willcox N. Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol. 2001;50:64-72[CrossRef][Medline] [Order article via Infotrieve]. 11. Sommer N, Willcox N, Harcourt GC, Newsom-Davis J. Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor-reactive T cells. Ann Neurol. 1990;28:312-319[CrossRef][Medline] [Order article via Infotrieve].
12.
Takeuchi Y, Fujii Y, Okumura M, Inada K, Nakahara K, Matsuda H.
Accumulation of immature CD3 13. Nenninger R, Schultz A, Hoffacker V, et al. Abnormal thymocyte development and generation of autoreactive T cells in mixed and cortical thymomas. Lab Invest. 1998;78:743-753[Medline] [Order article via Infotrieve]. 14. Strobel P, Helmreich M, Kalbacher H, MullerHermelink HK, Marx A. Evidence for distinct mechanisms in the shaping of the CD4 T-cell repertoire in histologically different myasthenia gravis-associated thymomas. Dev Immunol. 2001;8:279-290[Medline] [Order article via Infotrieve]. 15. Okumura M, Miyoshi S, Fujii Y, et al. Clinical and functional significance of WHO classification on human thymic epithelial neoplasms: a study of 146 consecutive tumors. Am J Surg Pathol. 2001;25:103-110[Medline] [Order article via Infotrieve]. 16. Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396:690-695[CrossRef][Medline] [Order article via Infotrieve]. 17. Marelli-Berg FM, Weetman A, Frasca L, et al. Antigen presentation by epithelial cells induces anergic immunoregulatory CD45RO+ T cells and deletion of CD45RA+ T cells. J Immunol. 1997;159:5853-5861[Abstract]. 18. De Rosa SC, Herzenberg LA, Roederer M. 11-Color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity. Nat Med. 2001;7:245-248[CrossRef][Medline] [Order article via Infotrieve]. 19. Hazenberg M-D, Otto S-A, Cohen Stuart J-W, et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med. 2000;6:1036-1042[CrossRef][Medline] [Order article via Infotrieve]. 20. Vanhecke D, Leclercq G, Plum J, Vandekerckhove B. Characterization of distinct stages during the differentiation of human CD69+CD3+ thymocytes and identification of thymic emigrants. J Immunol. 1995;155:1862-1872[Abstract].
21.
Heitger A, Neu N, Kern H, et al.
Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation.
Blood.
1997;90:850-857 22. Namba T, Brunner NG, Grob D. Myasthenia gravis in patients with thymoma, with particular reference to onset after thymectomy. Medicine (Baltimore). 1978;57:411-433[Medline] [Order article via Infotrieve]. 23. Neau JP, Robert R, Pourrat O, Patte F, Gil R, Lefevre JP. Myasthenia appearing after the ablation of a thymoma: two cases. Presse Med. 1988;17:391-392[Medline] [Order article via Infotrieve].
24.
Onoda K, Namikawa S, Takao M, et al.
Fulminant myasthenia gravis manifested after removal of anterior mediastinal tumor.
Ann Thorac Surg.
1996;62:1534-1536 25. Mineo TC, Biancari F, D'Andrea V. Late onset of myasthenia gravis after total resection of thymoma: report of two cases. J Cardiovasc Surg. 1996;37:531-533[Medline] [Order article via Infotrieve].
26.
Merkenschlager M, Fisher AG.
CD45 isoform switching precedes the activation-driven death of human thymocytes by apoptosis.
Int Immunol.
1991;3:1-7 27. Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature. 1994;372:100-103[CrossRef][Medline] [Order article via Infotrieve]. 28. Muller-Hermelink HK, Wilisch A, Schultz A, Marx A. Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma. Arch Histol Cytol. 1997;60:9-28[Medline] [Order article via Infotrieve].
29.
MacDonald HR, Radtke F, Wilson A.
T cell fate specification and 30. Hogquist KA. Signal strength in thymic selection and lineage commitment. Curr Opin Immunol. 2001;13:225-231[CrossRef][Medline] [Order article via Infotrieve]. 31. Berg LJ, Kang J. Molecular determinants of TCR expression and selection. Curr Opin Immunol. 2001;13:232-241[CrossRef][Medline] [Order article via Infotrieve]. 32. Rosai J. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1976:1-30. 33. Shimosato Y, Mukai K. Tumors of the mediastinum Rosai J, Sobin LH, editors. Atlas of Tumor Pathology. 3rd edition. Washington, DC: Armed Forces Institute of Pathology; 1997:93-115. 34. Muller-Hermelink HK, Marx A. Pathological aspects of malignant and benign thymic disorders. Ann Med. 1999;31(suppl 2):5-14[Medline] [Order article via Infotrieve].
35.
Melms A, Malcherek G, Gern U, et al.
Thymectomy and azathioprine have no effect on the phenotype of CD4 T lymphocyte subsets in myasthenia gravis.
J Neurol Neurosurg Psychiatry.
1993;56:46-51
36.
Berzins SP, Boyd RL, Miller JF.
The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool.
J Exp Med.
1998;187:1839-1848
37.
Berzins SP, Godfrey DI, Miller JF, Boyd RL.
A central role for thymic emigrants in peripheral T cell homeostasis.
Proc Natl Acad Sci U S A.
1999;96:9787-9791
© 2002 by The American Society of Hematology.
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  C. Schoch, S. Schnittger, M. Klaus, W. Kern, W. Hiddemann, and T. Haferlach AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases Blood, October 1, 2003; 102(7): 2395 - 2402. [Abstract] [Full Text] [PDF]
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 S. Hue, R. C. Monteiro, S. Berrih-Aknin, and S. Caillat-Zucman Potential Role of NKG2D/MHC Class I-Related Chain A Interaction in Intrathymic Maturation of Single-Positive CD8 T Cells J. Immunol., August 15, 2003; 171(4): 1909 - 1917. [Abstract] [Full Text] [PDF]
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 M. Inoue, P. Starostik, A. Zettl, P. Strobel, S. Schwarz, F. Scaravilli, K. Henry, N. Willcox, H.-K. Muller-Hermelink, and A. Marx Correlating Genetic Aberrations with World Health Organization-defined Histology and Stage across the Spectrum of Thymomas Cancer Res., July 1, 2003; 63(13): 3708 - 3715. [Abstract] [Full Text] [PDF]
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A. M. Masci, G. Palmieri, L. Vitiello, L. Montella, F. Perna, P. Orlandi, G. Abbate, S. Zappacosta, R. De Palma, and L. Racioppi Clonal expansion of CD8+ BV8 T lymphocytes in bone marrow characterizes thymoma-associated B lymphopenia Blood, April 15, 2003; 101(8): 3106 - 3108. [Abstract] [Full Text] [PDF]
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 C. Schoch, A. Kohlmann, S. Schnittger, B. Brors, M. Dugas, S. Mergenthaler, W. Kern, W. Hiddemann, R. Eils, and T. Haferlach Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles PNAS, July 23, 2002; 99(15): 10008 - 10013. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
WHO type A (medullary) and type C thymomas (thymic carcinomas)
/
lineage commitment.
Curr Opin Immunol.
2001;13:219-224