Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Murakawa, Y
Right arrow Articles by Kanamaru, R
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Murakawa, Y
Right arrow Articles by Kanamaru, R
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Japanese Journal of Clinical Oncology Pages 631-637

Astrocytoma and B-cell Lymphoma Development in a Man with a p53 Germline Mutation
Introduction
Case Report
   Magnetic Resonance Imaging (MRI) of the Brain
   Histopathological Finding of the Brain Tumor
   Abdominal CT, Positron Emission tomography (PET) and Gallium Scintigraphy (Ga-scinti)
   Characterization of the Ascites
   Characterization of the Peritoneal Tumor
   Examination of p53
   Autopsy Findings
Discussion
References
Astrocytoma and B-cell Lymphoma Development in a Man with a p53 Germline Mutation

Astrocytoma and B-cell Lymphoma Development in a Man with a p53 Germline Mutation

Yasuko Murakawa1, Akiko Yokoyama1, Shunsuke Kato1, Takashi Yoshioka1, Ryo Ichinohasama3, Toshihiro Kumabe2, Takashi Yoshimoto2, Chikashi Ishioka1 and Ryunosuke Kanamaru1

1Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 2Department of Neurosurgery, Tohoku University School of Medicine and 3Department of Oral Pathology, Tohoku University School of Dentistry, Sendai, Miyagi, Japan

We report a case with a germline mutation of the p53 gene develpoing both a non-Hodgkin's lymphoma and an astrocytoma. The astrocytoma could be cured by two operations and combined chemotherapy but 33 months after the onset of the disease, he suffered from a diffuse, large cell centroblastic malignant lymphoma of B-cell lineage. In spite of clear rearranged fragments observed with IgH and c-MYC gene probes, we could not diagnose a Burkitt's lymphoma morphologically. The malignant lymphoma was chemoresistant and the patient died of multi-organ failure. He was confirmed to have a germline mutation of the p53 gene by analysis of c-DNA from peripheral lymphocytes and loss of heterozygosity (LOH) of p53 was evident in the lymphoma. The results were suggestive of the Li-Fraumeni syndrome (LFS), a rare autosomal dominantly inherited syndrome with a germline mutation of p53 gene and diverse malignancies, but this could not be confirmed in the present case. Alternatively, a de novo mutation could have been involved.

Key words: germline mutation of p53 gene - non-Hodgkin's lymphoma - astrocytoma - Li-Fraumeni syndrome

INTRODUCTION

It is well known that the p53 is a tumor suppressor gene, often inactivated by deletion or point mutation in many types of solid tumors and blood malignancies (1-8). A strong correlation has been reported between p53 mutations and loss of chemosensitivity (9-11). A germline mutation of the p53 gene has been reported in a cancer-prone family, described as the Li-Fraumeni syndrome (LFS) (12-16). Here, we report a case of a male patient with a p53 gene germline mutation developing both an astrocytoma and a non-Hodgkin's lymphoma.

CASE REPORT

The patient was a 30-year-old Japanese male. He was operated on for a brain tumor in September 1993, this being histologically diagnosed as an anaplastic astrocytoma. Subsequently, he received anticancer chemotherapy (interferon-[beta], nimustine), but recurrence was found in February 1994 and a second operation was performed. Chemotherapy with cisplatin and etoposide was then continued with no recurrence of the brain tumor.

Thirty-three months after the onset of astrocytoma, he complained of epigastric discomfort and abdominal fullness in March 1996. He was diagnosed as suffering from a diffuse, large cell centroblastic variant (WHO) malignant lymphoma of B-cell lineage from examination of biopsy material from the peritoneal tumor.

After the diagnosis, he received chemotherapy. At first, a VEPA regimen (adriamycin, cyclophosphamide, vincristine, prednisolone) was tried but tumor regression was transient and therefore irinotecan and a CNOP regimen (cyclophosphamide, mitoxantrone, vincristine, prednisolone) were applied. However, these therapies were not effective and finally he died of multi-organ failure (Fig. 1).


Figure 1. Clinical course: ADR, adriamycin; VCR, vincristine; CPM, cyclophosphamide; PSL, prednisolone; CPT-11, irinotecan; MIT, mitoxantrone; Ara-C, cytosine arabinoside.

Magnetic Resonance Imaging (MRI) of the Brain

MRI revealed a cystic brain tumor (6 cm in diameter) in the left temporal lobe with a mural nodule that was strongly enhanced by gadolinium (Fig. 2). After the second operation, no recurrence of the brain tumor was detected (Fig. 2).


Figure 2. Magnetic resonance imaging (MRI) findings. (a) At the time of diagnosis. The brain tumor is apparent as a cystic mass (6 cm in diameter) in the left temporal lobe with a mural nodule that is strongly enhanced by gadolinium. (b) After two operations and chemotherapy. There is no apparent brain tumor.

Histopathological Finding of the Brain Tumor

In the specimens obtained at the first resection, the tumor was richly supplied by blood vessels and composed of thickly clustered cells and spindle-shaped cells (Fig. 3). These tumor cells showed nuclear atypism and high mitotic activity and were immunoreactive for glial fibrillary acidic protein (GFAP). Thus the tumor was diagnosed as an anaplastic astrocytoma. In the tissue removed at the second operation, cellular pleomorphism with multinucleated giant cells containing hyperchromatic irregular-shaped nuclei was prominent (Fig. 3). Nuclear atypism might have been caused by the previous radiation therapy.


Figure 3. Histopathology of the brain tumor. (a) First operation. The tumor is composed of thickly clustered cells around these vessels and spindle cells. (Hematoxylin-eosin stain, ×200.) (b) Second operation. Cellular pleomorphism with multinucleated giant cells containing hyperchromatic irregular-shaped nuclei and vascular proliferation are more prominent. (Hematoxylin-eosin stain, ×200.)

Abdominal CT, Positron Emission tomography (PET) and Gallium Scintigraphy (Ga-scinti)

Abdominal CT showed massive ascites and giant mass of convoluted mesenterium (Fig. 4). PET showed uptake of fluorodeoxyglucose in the tumor (Fig. 4) and Ga-scinti showed a hot lesion broadly disseminated in the abdomen (Fig. 4).


Figure 4. (a) Abdominal CT in March 1996, showing a mass in convoluted mesenterium. (b) Positron emission tomography (PET) findings at about the same time, demonstrating uptake of fluorodeoxyglucose. (c) Gallium scintigraphy. A hot lesion is broadly disseminated in the abdomen.

Characterization of the Ascites

In samples of ascites, lymphoblast-like large cells were apparent (Fig. 5) and by flow cytometry these showed CD10+ and CD19+ and a lymphoid malignancy was strongly suggested (Fig. 5). The lymphoma cells showed various chromosomal abnormalities. Of 20 cells, three had 43, 12 had 44, two had 45 and only two had the normal chromosome count. Common abnormalities were -4, add(7) (q22), add(14) (q32), -15, add(17) (p11) and add(18) (q23) (Fig. 6).


Figure 5. (a) Cytospin specimen of ascites lymphoblast-like large cells are present alongside small reactive lymphocytes. (May-Giemsa staining, ×1000.) (b) Flow cytometry. Scattergrams show the tumor cells to be large with surface markers, CD10+ and CD19+. The relatively small cells are CD3+ T lymphocytes that are reactive lymphocytes.


Figure 6. Results of chromosome analysis of lymphoma cells (ascites). 44, XY, add(1) (q32), -4, add(7) (q22), dup(8) (q13q22), add(11) (q23), add(14) (q32), -15, add(17) (p11), add(18) (q23) are prevalent (12/20 cells).

Characterization of the Peritoneal Tumor

To obtain a definite diagnosis, a biopsy was taken of the peritoneal tumor. The tumor cells were round-shaped, ranging from 12 to 15 µm in diameter and had polymorphic nuclei with a few distinct nucleoli and relatively abundant cytoplasm. Cytoplasmic droplets were rarely seen on Giemsa staining (Fig. 7). Electron microscopic examination clearly defined these as lipid (Fig. 7). The tumor cells showed CD10+, CD19+, CD20+, CD22+, CD38+, CD45+, IgG+ and IgL[kappa]+ by both flow cytometry and immunohistochemistry of frozen sections. Rearranged bands were detected by Southern blot analysis with probes for the IgH and kappa light chain genes as well as the c-MYC gene. Other probes used showed germline configurations. In spite of the CD10 positivity and clear rearranged fragments with c-MYC probe, we could not diagnose this patient as having a `Burkitt's lymphoma' because of the atypical proliferation pattern and cellular morphology. He was diagnosed as suffering from a diffuse, large cell centroblastic variant (WHO) malignant lymphoma of B-cell lineage.


Figure 7. (a) Histopathology of the peritoneal tumor. Light microscopic features of the biopsied material. The lymphoma cells are proliferating diffusely and are [sim]12-15 µm in diameter. Polymorphic nuclei have two or three distinct nucleoli. (Hematoxylin-eosin stain, ×1000.) (b) Electron microscopic appearance of lymphoma cells. Note the lipid droplets in their cytoplasm (×4800).

Examination of p53

We first analysed p53 cDNA from the patient's lymphocytes using a yeast-based functional assay (FASAY) which has been used to detect heterozygous p53 mutations (17). As shown in Fig. 8, only 60% of transformants showed a His+ phenotype (control lymphocytes: 96%), indicating the presence of a heterozygous mutation of the p53 gene. Sequence analysis demonstrated a functionally inactivating heterozygous missense mutation, C242Y (Fig. 8) in the lymphocytes. To confirm inactivation of both alleles of p53 in the tumor, polymerase chain reaction-restriction length polymorphism analysis (PCR-RFLP) was performed using a set of primers (see caption to Fig. 8) which generated a 105 bp fragment containing a novel PstI site at codons 242 and 243. As shown in Fig. 6, the PCR product from the patient's lymphocytes was partially digested by PstI, generating both a digested fragment (82 bp) and an undigested fragment (105 bp) because of the heterozygous mutation at codon 242 (lane 2). The PCR product derived from his lymphoma tissue retained the mutant p53 allele. Whereas that from his mother's lymphocytes was completely digested by PstI, indicating the lack of any germline p53 mutation (lane 1). We also examined 17 autopsy specimens including cerebrum, cerebellum, spinal cord, skin, tongue, esophagus, stomach, small intestine, lung, heart, liver, kidney, adrenal gland, bone marrow, aorta, muscle and adipose tissue by PCR-RFLP analysis and confirmed the heterozygous p53 mutation in all cases (data not shown).


Figure 8. (a) Functional analysis of separated alleles in yeast (FASAY). PCR-amplified p53 cDNA was introduced and expressed in a His 3- yeast strain and the resulting transformations were tested for the ability to trans-activate the HIS3 gene by the expressed p53. WT, no p53 mutation; WT/mt, heterozygous p53 mutation. (b) Sequencing analysis of p53 cDNA. G to A change at nucleotide 725, resulting in a cysteine to tyrosine substitution at codon 242, is evident as showing in the left lane. Other four lanes derived from normal controls. (c) PCR-RFLP analysis around codon 242. Genomic DNA was amplified by PCR using a set of primers, 5-GGCCTCATCTTGGGCCTGTG-3 and 5-CTCCGGTTCATGCCGCCCCTG-3 with a mismatch base (underlined) to generate a novel PstI site at codon 242-243. The products were digested by PstI and separated in a 2% agarose gel. Lane 1, lymphocytes from patient's mother; lane 2, lymphocytes from the patient; lane 3, lymphoma tissue; lane 4, lymphocytes from a healthy donor (control). 105 bp, undigested fragment; 82 bp, digested fragment.

Autopsy Findings

There was thickening and fibrous adhesion of the whole peritoneum, 2-8 cm in thickness, involving the entire intestines, liver and urinary bladder. Swelling of the mesentrial and parapancreatic lymph nodes was observed up to 1 cm in diameter. No recurrence of the astrocytoma in the left temporal lobe of the cerebrum was apparent.

DISCUSSION

In the present case, the patient suffered from astrocytoma and malignant lymphoma at a young age and he had a germline mutation of p53 gene and LOH of p53 was shown in the lymphoma tissue. This finding suggests a strong link between a germline mutation of the p53 gene and the astrocytoma and non-Hodgkin's lymphoma development.

Germline mutations of the p53 gene have been reported in cancer-prone families. The Li-Fraumeni syndrome (LFS) is a rare autosomal dominantly inherited syndrome with the following familial characteristics: a proband with either acute lymphocytic leukemia, sarcoma, breast cancer, brain tumor and/or adrenocortical carcinoma before the age of 45; a first-degree relative with a cancer in this group; and a first- or second-degree relative with sarcoma at any age or any cancer before age 45. The affected individuals have a germline mutation of p53 (12-16). The prevalence of a germline p53 mutation is approximately 0.01% in the general population, but is 5-10% among young patients with multiple cancers. For example, in one study examining 59 children and young adults who would not otherwise be considered as having LFS, but who had developed two malignancies, the overall frequency of germline p53 mutations was [sim]7% (18,19).

In this case, his mother suffered from breast cancer at 36 years of age but her germline p53 was wild type. The p53 status of the father was unknown but he was free of neoplasia. As far as we could determine, there was no other family history of malignancies except for the mother's brother (rectal cancer). We could not diagnose him as LFS. If he had not died at a young age, he might have been shown to be a LFS proband.

It is well known that the p53 is a tumor suppressor gene often inactivated in many types of solid tumors and blood malignancies (1-8). Several studies have shown that p53 can mediate apoptotic cell death and that it is required for efficient activation of apoptosis following irradiation or chemotherapy (9-11). There is a clear link between p53 gene mutation and aggressive tumor behavior and a poor prognosis, in some cases associated with activation of the MDR1 (multidrug resistance) gene (20). With regard to hematological malignancies, a strong correlation has been found between p53 mutations and chemosensitivity in AML, MDS and CLL (21). It has recently been reported that non-Hodgkin's lymphomas with a p53 abnormality are more likely to be drug resistant but that does not correlate with any other particular clinical characteristic (22). A similar situation appears to be the case for some types of B-cell lymphomas (23,24).

Regarding brain tumors, p53 gene mutations have been examined in astrocytomas, glioblastomas and some other tumors (25-28). In anaplastic astrocytomas and glioblastomas, almost 30-40% were found to be positive (26,28). In our survey of p53 germline mutations in brain tumors, we found a case of a yolk sac carcinoma that demonstrated an additional mutation, known to lead to functional alteration of p53 protein (29).

It has been reported that the presence of both p53 inactivation and c-MYC oncogene activation may be important in the pathogenesis of Burkitt's lymphoma (30), along with t(8:14) invoiving translocation of the IgH gene at 14q32 and the c-MYC gene at 8q24. Actually, p53 alterations in Burkitt's lymphoma are present in about 40% of cases. In the present study, chromosome analysis of ascites revealed various abnormalities, but no t(8:14). While rearranged bands were obtained by Southern blot analysis with probes for the IgH and c-MYC genes, a diagnosis of `Burkitt's lymphoma' was impossible on morphological grounds.

In this case, CA-125 was very high (1279.5 U/ml; normal <35.0 U/ml) and on chemotherapy it rapidly decreased. While this is typical of mediastinal B-cell lymphomas with sclerosis, no intratumoral CA-125 could be demonstrated by immunohistochemical staining, so aspecific secretion by extratumor tissues was concluded (31).

The present case of a p53 germline mutaion in an individual developing both an astrocytoma and a non-Hodgkin's lymphoma appears not to represent LFS but rather a de novo change in the gene.

References

1. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 1989;244:217-21. MEDLINE Abstract

2. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989;342:705-8. MEDLINE Abstract

3. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991;253:49-53. MEDLINE Abstract

4. Thor AD, Moore DH II, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 1992;84:845-55. MEDLINE Abstract

5. Vogelstei B, Kinzler KW. p53 function and dysfunction. Cell 1992;70:523-6.

6. Horio Y, Takahashi T, Kuroishi T, Hibi K, Suyama M, Niimi T, et al. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 1993;53:1-4. MEDLINE Abstract

7. Sarkis AS, Dalbagni G, CordonCardo C, Zhang ZF, Sheinfeld J, Fair WR, et al. Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 1993;85:53-9. MEDLINE Abstract

8. Imamura J, Miyoshi I, Koeffler P. p53 in hematologic malignancies. Blood 1994;84:2412-21. MEDLINE Abstract

9. Lowe SW, Schimitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993;362:847-9. MEDLINE Abstract

10. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993;74:957-67. MEDLINE Abstract

11. Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994;78:539-42. MEDLINE Abstract

12. Frederick PL, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, et al. A cancer family syndrome in twenty-four kindred. Cancer Res 1988;48:5358-62.

13. Frederick PL. Cancer family. Human models of susceptibility to neoplasia. The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 1988;48:5381-6.

14. Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 1990;250:1233-8. MEDLINE Abstract

15. Srivastava S, Zou Z, Pirollo K, Blattner W, Chang EH. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990;348:747-9. MEDLINE Abstract

16. Metzger AK, Sheffield VC, Duyk G, Daneshvar L, Edwards MS, Cogen PH. Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma. Proc Natl Acad Sci USA 1991;88:7825-9. MEDLINE Abstract

17. Ishioka C, Frebourg T, Yan YX, Vidal M, Friend SH, Schmidt S, et al. Screening patients for heterozygous p53 mutations using functional assay in yeast. Nature Genet 1993;5:124-9. MEDLINE Abstract

18. Li FP, Correa P, Fraumeni JF. Testing for germline p53 mutations in cancer families. Cancer Epidemiol Biomarkers Prev 1991;1:91-4.

19. Toguchida J, Yamaguch T, Herrera G, Beauchamp R, Yandell DW. A survey of germ-line and somatic p53 gene mutations in patients with bone and soft tissue sarcomas. Am J Hum Genet 1991;49(S):458.

20. Chin KV, Ueda K, Pastan I, Gottesman MM. Modulation of activity of the promoter of the human MDR1 gene by ras and p53. Science 1992;255:459-62. MEDLINE Abstract

21. Wattle E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Derivite I, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 1994;84:3148-57.

22. Wilson WH, Feldstein JT, Fest T, Harris C, Steinberg SM, Jaffe E, et al. Relationship of p53, bcl-2 and tumor proliferation to clinical drug resistance in non-Hodgkin's lymphomas. Blood 1997;89:601-9. MEDLINE Abstract

23. Ichikawa A, Hotta T, Takagi N, Tsushita K, Kinoshita T, Nagai H, et al. Mutations of p53 gene and their relation to disease progression in B-cell lymphoma. Blood 1992;79:2701-2. MEDLINE Abstract

24. Ichikawa A, Kinoshita T, Watanabe T, Kato H, Nagai H, Tsushita K, et al. Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. N Engl J Med 1997;337:529-34. MEDLINE Abstract

25. Mashiyama S, Murakami Y, Yoshimoto T, Sekiya T. Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase cahin reaction. Oncogene 1991;6:1313-8. MEDLINE Abstract

26. Fults D, Brockmeyer D, Tullous MW, Pedone CA, Cawthon RM. p53 mutation and loss of heterozygosity on chromosomes 17 and 10 during human astrocytoma progression. Cancer Res 1992;52:674-9. MEDLINE Abstract

27. Frankel RH, Bayona W, Koslow M, Newcomb EW. p53 mutations in human malignant gliomas: comparison of loss of heterozygosity with mutation frequency. Cancer Res 1992;52:1427-33. MEDLINE Abstract

28. Deimling A, Eibl RH, Ohgaki H, Louis DN, Ammon K, Petersen I, et al. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Res 1992;52:2987-90.

29. Feng X, Zhang S, Ichikawa T, Koga H, Washiyama K, Motoyama T, et al. Intracranial germ cell tumors: detection of p53 gene mutations by single-strand conformation polymorphism analysis. Jpn J Cancer Res 1995;86:555-61. MEDLINE Abstract

30. Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW, et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1991;88:5413-7. MEDLINE Abstract

31. Ravoet C, Dargent LL, Moine, FL, Feremans W. CA-125 in primary mediastinal B-cell lymphoma with sclerosis. J Clin Oncol 1995;13:530. MEDLINE Abstract

Received January 22, 1998; accepted July 3, 1998
For reprints and all correspondence: Yasuko Murakawa, Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1, Seiryomachi, Aobaku, Sendai, Japan 980
Abbreviations: LOH, loss of heterozygosity; LFS, Li-Fraumeni syndrome; MRI, magnetic resonance imaging; GFAP, glial fibrillary acidic protein; PET, positron emission tomography; Ga-scinti, gallium scintigraphy; FASAY, functional analysis of separated alleles in yeast; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism analysis; MDR1 gene, multidrug resistance gene; ADR, adriamycin; VCR, vincristine; CPM, cyclophosphamide; PSL, predonisolone, CPT-1, irinotecan; MIT, mitoxantrone; Ara-C, cytosine arabinoside

This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 16 Oct 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Jpn J Clin OncolHome page
K. Kimura, K. Shinmura, T. Hasegawa, Y. Beppu, R. Yokoyama, and J. Yokota
Germline p53 Mutation in a Patient with Multiple Primary Cancers
Jpn. J. Clin. Oncol., July 1, 2001; 31(7): 349 - 351.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Murakawa, Y
Right arrow Articles by Kanamaru, R
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Murakawa, Y
Right arrow Articles by Kanamaru, R
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?