Wikipedia - Waldenström's Macroglobulinemia (CHECKED)

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6/3/15, Waldenstrm's macroglobulinemia - Wikipedia, the free encyclopedia

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Waldenstrm's macroglobulinemia

Classification and external resources

Specialty Hematology and oncology

ICD-10 C88.0

(http://apps.who.int/classifications/icd10/browse/2015/en#/C88

ICD-9 273.3 (http://www.icd9data.com/getICD9Code.ashx?icd9=273

ICD-O M9761/3 (http://www.progenetix.net/progenetix/I97613/)

OMIM 153600 (http://omim.org/entry/153600)

DiseasesDB 14030 (http://www.diseasesdatabase.com/ddb14030.htm)

MedlinePlus 000588

(http://www.nlm.nih.gov/medlineplus/ency/article/000588.htm

eMedicine med/2395(http://www.emedicine.com/med/topic2395.htm)

MeSH D008258 (https://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?

field=uid&term=D008258)

Waldenstrm's macroglobulinemiaFrom Wikipedia, the free encyclopedia

Waldenstrm's macroglobulinemia

WM, also known as

ymphoplasmacytic lymphoma) is

cancer affecting Bcells, a type ofwhite blood cell. The main attributing

antibodyis immunoglobulin M

IgM). WM is an "indolent

ymphoma," (i.e., one that tends to

grow and spread slowly). It is a type

of lymphoproliferative disease, which

shares clinical characteristics with the

ndolent non-Hodgkin lymphomas.[1]

The disease, named after the Swedishoncologist Jan G. Waldenstrm, was

first identified in 1944. As with other

ymphomas, the disease is

characterized by an uncontrolled

ncrease of B-cells, i.e., white blood

cells formed in the bone marrow and

ymph nodes. The proliferation of B-cells interferes with the production of red blood cells,resulting in anem

A unique characteristic of the disease is that the B-cells produce excess amounts of immunoglobulin protein

IgM), thickening the blood, and requiring additional treatment. WM is a rare disease,with only about 1,500

cases per year in the U.S. While thedisease isincurable, it is treatable. Because of its indolent nature, manypatients are able to lead active lives, and, when treatment is required, may experience years of symptom-free

remission.[2]

Contents

1 History and classification2 Signs and symptoms3 Causes

3.1 Genetics4 Pathophysiology5 Diagnosis6 Prognosis7 Treatment

7.1 Watchful waiting7.2 First-line7.3 Salvage therapy7.4 Drug pipeline
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7.5 Patient stratification8 Epidemiology9 Research10 See also11 References12 External links

History and classification

WM was first described by Jan G. Waldenstrm (19061996) in 1944 in two patients with bleeding from the

nose and mouth, anemia, decreased levels of fibrinogen in the blood (hypofibrinogenemia), swollen lymph

nodes, neoplastic plasma cells in bone marrow, and increased viscosity of the blood due to increased levels o

class of heavy proteins called macroglobulins.[3]

For a time, WM was considered to be related to multiple myeloma due to the presence of monoclonal

gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new

World Health Organization (WHO) classification, however, places WM under the category of

ymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas.[4

recent years, there have been significant advances in the understanding and treatment of WM.[5]

Signs and symptoms

Signs and symptoms of WM include weakness, fatigue, weight loss and chronic oozing of blood from the no

and gums.[6]Peripheral neuropathy can occur in 10% of patients. Lymphadenopathy, enlargement of the sple

and/or liver are present in 3040% of cases.[7]

Other possible signs and symptoms include blurring or loss ofvision, headache, and (rarely) stroke or coma.

Causes

Waldenstrm's macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally

differentiated B lymphocytes. The most common causes are a somatic mutation in MYD88 (90% of patients)

and a somatic mutation in CXCR4 (27% of patients).[8]There has been an association demonstrated with the

ocus 6p21.3 on chromosome 6.[9]There is a 2- to 3-fold risk increase of developing WM in people with a

personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with

iver inflammation, human immunodeficiency virus, and rickettsiosis.[10]

There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting

Waldenstrm's.[11]There is also evidence to suggest that environmental factors including exposure to farmin

pesticides, wood dust, and organic solvents may influence the development of Waldenstrm's.[12]

Genetics
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Although believed to be a sporadic disease, studies have shown increased susceptibility within families,

ndicating a genetic component.[13][14]A mutation in gene MYD88 has been found to occur frequently in

patients.[15]WM cells show only minimal changes in cytogenetic and gene expression studies. Their miRNA

signature however differs from their normal counterpart. It is therefore believed that epigenetic modification

play a crucial role in the disease.[16]

Comparative genomic hybridization identified the following chromosomal abnormalities: deletions of 6q23 a

13q14, and gains of 3q13-q28, 6p and 18q.[17]FGFR3 is overexpressed.[18]The following signalling pathwa

have been implicated:

CD154/CD40[19]

Akt[20]

ubiquitination, p53 activation, cytochrome c release[21]

NF-!B[22][23]

WNT/beta-catenin[24]

mTOR[25]

ERK[22]

MAPK[26]

Bcl-2[27]

The protein Src tyrosine kinase is overexpressed in Waldenstrm macroglobulinemia cells compared with

control B cells.[28]Inhibition of Src arrests the cell cycle at phase G1and has little effect on the survival of W

or normal cells.

MicroRNAs involved in Waldenstrm's:[29][30]

increased expression of miRNAs-363*,[31]-206,[32]-494,[33]-155,[34]-184,[35]-5423p.[36]

decreased expression of miRNA-9*.[37]

MicroRNA-155 regulates the proliferation and growth of WM cells in vitro and in vivo, by inhibiting

MAPK/ERK, PI3/AKT, and NF-!B pathways.

n WM-cells, histone deacetylases and histone-modifying genes are de-regulated.[38]

Bone marrow tumour cells express the following antigen targets CD20 (98.3%), CD22 (88.3%), CD40 (83.3

CD52 (77.4%), IgM (83.3%), MUC1 core protein (57.8%), and 1D10 (50%).[39]

Pathophysiology

Symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma are due to the effects of t

gM paraprotein, which may cause autoimmune phenomenon or cryoglobulinemia. Other symptoms of WM

due to the hyperviscosity syndrome, which is present in 6-20% of patients.[40][41][42][43]This is attributed to
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gM monoclonal protein increasing the viscosity of the blood by forming aggregates to each other, binding

water through their carbohydrate component and by their interaction with blood cells.[44]

Diagnosis

A diagnosis of Waldenstrm's macroglobulinemia depends on a significant monoclonal IgM spike evident in

blood tests and malignant cells consistent with the disease in bone marrow biopsy samples.[45]

Blood tests shhe level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of W

A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sam

s extracted through a needle and examined under a microscope. A pathologist identifies the particular

ymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or insid

he lymphocytes.[46]

Additional tests such as computed tomography (CT or CAT) scan may be used to evaluate the chest, abdome

and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish

between WM and multiple myeloma.[46]Anemia is typically found in 80% of patients with WM. A low whit

blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific

ype of white blood cell) may also be found in some individuals with WM.[45]

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate

ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric ac

evel may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high

blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicatin

he extent of Waldenstrm macroglobulinemiarelated tissue involvement. Rheumatoid factor, cryoglobulins

direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2-microglobulin and C-reactive

protein test results are not specific for Waldenstrm macroglobulinemia. Beta-2-microglobulin is elevated in

proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial

hromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies ar

optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish

spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenstrm

macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of

mmunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein.

High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and

characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenstr

macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results fromcharacterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually

he kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3%

of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimy

associated glycoprotein serology.
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Criteria for diagnosis of Waldenstrom macroglobulinemia 1. IgM monoclonal gammopathy that excludes

chronic lymphocytic leukemia and Mantle cell lymphoma 2. Evidence of anemia, constitutional symptoms,

hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an

underlying lymphoproliferative disorder.[47]

Prognosis

Current medical treatments result in survival of some longer than 10 years; in part this is because better

diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published

reports of median survival of approximately 5 years from time of diagnosis.[1]Currently, median survival is

years.[48]In rare instances, WM progresses to multiple myeloma.[49]

The International Prognostic Scoring System for Waldenstrms Macroglobulinemia (IPSSWM) is a predicti

model to characterise long-term outcome.[50][51]According to the model, factors predicting survival (n.b. the

study quoted conversely refers to them as "5 adverse covariates") are:

Age >65 yearsHemoglobin "11.5 g/dL

Platelet count "100#109/LB2-microglobulin >3 mg/LSerum monoclonal protein concentration >70 g/L

The risk categories are:

Low: "1 adverse variable except ageIntermediate: 2 adverse characteristics or age >65 yearsHigh: >2 adverse characteristics

Five-year survival rates for these categories are 87%, 68% and 36%, respectively.[52]

The IPSSWM has been shown to be reliable.[53]It is also applicable to patients on a Rituximab-based treatm

regimen.[52]An additional predictive factor is elevated serum lactate dehydrogenase (LDH).[54]

Treatment

There is no single accepted treatment for WM.[55]There is marked variation in clinical outcome due to gaps knowledge of the disease's molecular basis. Objective response rates are high (>80%) but complete response

rates are low (015%).[5]Recently Yang et al. showed that the MYD88 L265P mutation induced activation o

Bruton's tyrosine kinase, the target of the drug ibrutinib. Among previously treated patients ibrutinib induced

responses in 91% of patients, and at 2 years 69% of patients had no progression of disease and 95% were aliv

Treon et al, New England Journal of Medicine 2015). Based on this study, the FDA approved ibrutinib for u

n WM in 2015.[56]
http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-56http://en.wikipedia.org/wiki/Ibrutinibhttp://en.wikipedia.org/wiki/Ibrutinibhttp://en.wikipedia.org/wiki/Bruton%27s_tyrosine_kinasehttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-cite_pmid.7C_20040909-5http://en.wikipedia.org/wiki/Response_ratehttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-55http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-54http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-PMID_18641029-52http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-53http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-PMID_18641029-52http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-51http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-50http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Johansson-49http://en.wikipedia.org/wiki/Multiple_myelomahttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-48http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Cheson-1http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-47http://en.wikipedia.org/wiki/Hepatosplenomegalyhttp://en.wikipedia.org/wiki/Lymphadenopathyhttp://en.wikipedia.org/wiki/Mantle_cell_lymphomahttp://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia


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There are different treatment flowcharts: Treon[57]and mSMART.[58]

WM patients are at higher risk of developing second cancers than the general population, however it is not y

clear whether treatments are contributory.[59]

Watchful waiting

n the absence of symptoms, many clinicians will recommend simply monitoring the patient.[60]Waldenstrm

himself stated "let well do" referring to watch and wait for patients who can simply be monitored without

reatment. But on occasion the disease can be fatal, as it was to the French president Georges Pompidou, who

died in office in 1974. The Shah of Iran also suffered from Waldenstrom's Macroglobulinemia which resulted

his ill fated trip to the US for therapy in 1979, leading to the takeover of the US Embassy in Tehran.[61]

First-line

Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.[62]

n 2002, a panel at the International Workshop on Waldenstrm Macroglobulinemia agreed on criteria for the

nitiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as

recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy

spleen enlargement, and anemia due to bone marrow infiltration. Complications such as hyperviscosity

syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, kidney failure, or

symptomatic cryoglobulinemia were also suggested as indications for therapy.[63]

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic dr

such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide.[64]Corticosteroids, such as

prednisone, may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrom

by removing the paraprotein from the blood, although it does not address the underlying disease.[65]

Recently, autologous bone marrow transplantation has been added to the available treatment

options.[66][67][68][69]

Salvage therapy

When primary or secondary resistance invariably develops, salvage therapy is considered. Allogeneic stem c

ransplantation can induce durable remissions for heavily pre-treated patients.[70]

Drug pipeline

As of October 2010, there have been a total of 44 clinical trials on Waldenstrom's macroglobulinemia, exclud

ransplantion treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with

relapsed or refractory Waldenstrom's.[71]A database of clinical trials investigating Waldenstrm's

macroglobulinemia is maintained by the National Institutes of Health in the US.[72]
http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-72http://en.wikipedia.org/wiki/National_Institutes_of_Healthhttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-71http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-70http://en.wikipedia.org/wiki/Allogeneic_stem_cell_transplantationhttp://en.wikipedia.org/wiki/Salvage_therapyhttp://en.wikipedia.org/wiki/Drug_resistancehttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Tournilhac-69http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Anagnostopoulos-68http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Martino-67http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Yang-66http://en.wikipedia.org/wiki/Bone_marrow_transplantationhttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Gertz-65http://en.wikipedia.org/wiki/Plasmapheresishttp://en.wikipedia.org/wiki/Prednisonehttp://en.wikipedia.org/wiki/Corticosteroidhttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-64http://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Vincristinehttp://en.wikipedia.org/wiki/Cyclophosphamidehttp://en.wikipedia.org/wiki/Chlorambucilhttp://en.wikipedia.org/wiki/Rituximabhttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-Kyel2003-63http://en.wikipedia.org/wiki/Cryoglobulinemiahttp://en.wikipedia.org/wiki/Kidney_failurehttp://en.wikipedia.org/wiki/Amyloidosishttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Splenomegalyhttp://en.wikipedia.org/wiki/Lymphadenopathyhttp://en.wikipedia.org/wiki/Weight_losshttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Fatigue_(medical)http://en.wikipedia.org/wiki/Night_sweatshttp://en.wikipedia.org/wiki/Feverhttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-62http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-61http://en.wikipedia.org/wiki/Georges_Pompidouhttp://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-60http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-59http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-58http://en.wikipedia.org/wiki/Waldenstr%C3%B6m's_macroglobulinemia#cite_note-57


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Patient stratification

Patients with polymorphic variants (alleles) FCGR3A-48 and -158 were associated with improved categorica

responses to Rituximab-based treatments.[73]

Epidemiology

Of all cancers involving the lymphocytes, 1% of cases are WM.[74]

WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually.[1]The median ag

of onset of WM is between 60 and 65 years, with some cases occurring in late teens.[1][7]

Research

One recent investigation showed that a population of cells, lacking both B-cell and plasma cell markers, has

characteristics of cancer-initiating cells in Waldenstrom macroglobulinemia.[75]

See also

Waldenstrm hyperglobulinemic purpuraList of hematologic conditions

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FCGR3A in Waldenstrom macroglobulinaemia".British Journal of Haematology154(2): 223228. doi:10.1111/j.13

2141.2011.08726.x (https://dx.doi.org/10.1111%2Fj.1365-2141.2011.08726.x). PMID 21564078


74. Turgeon, Mary Louise (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams &

Wilkins. p. 283. ISBN 0-7817-5007-5. "Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book

Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)"

75. Wada N (Jan 2014). "Characterization of subpopulation lacking both B-cell and plasma cell markers in Waldenstrommacroglobulinemia cell line" (http://www.nature.com/labinvest/journal/v94/n1/full/labinvest2013129a.html).Lab Inv

94(1): 7988. doi:10.1038/labinvest.2013.129 (https://dx.doi.org/10.1038%2Flabinvest.2013.129). PMID 24189269


External links

The Bing Center for Waldenstrm's Research (http://www.wmprogram.com/)The International Workshops on Waldenstrm's Macroglobulinemia (http://www.wmworkshop.org/)The International Patient-Physician Summits on Waldenstrm's Macroglobulinemia(http://www.wmsummit.org/)The Waldenstrm's Macroglobulinemia Clinical Trials Group (http://www.wmctg.org/)The International Waldenstrm's Macroglobulinemia Foundation site (http://www.iwmf.com/)American Cancer Society Detailed Guide: Waldenstrm's Macroglobulinemia(http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=76)Lymphoma Association Specialist UK charity providing free information and support to patients, thefamilies, friends and carers (http://www.lymphomas.org.uk)WMUK- Charitable Point of Contact and Support for Waldenstrm's Macroglobulinemia in the UK(http://www.wmuk.org.uk/)
http://www.wmuk.org.uk/http://www.lymphomas.org.uk/http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=76http://www.iwmf.com/http://www.wmctg.org/http://www.wmsummit.org/http://www.wmworkshop.org/http://www.wmprogram.com/http://www.ncbi.nlm.nih.gov/pubmed/24189269http://en.wikipedia.org/wiki/PubMed_Identifierhttp://dx.doi.org/10.1038%2Flabinvest.2013.129http://en.wikipedia.org/wiki/Digital_object_identifierhttp://www.nature.com/labinvest/journal/v94/n1/full/labinvest2013129a.htmlhttp://en.wikipedia.org/wiki/Special:BookSources/0-7817-5007-5http://en.wikipedia.org/wiki/International_Standard_Book_Numberhttp://www.ncbi.nlm.nih.gov/pubmed/21564078http://en.wikipedia.org/wiki/PubMed_Identifierhttp://dx.doi.org/10.1111%2Fj.1365-2141.2011.08726.xhttp://en.wikipedia.org/wiki/Digital_object_identifierhttp://clinicaltrials.gov/ct2/results?term=Waldenstromhttp://dx.doi.org/10.3109%2F10428194.2010.499977http://en.wikipedia.org/wiki/Digital_object_identifierhttp://www.ncbi.nlm.nih.gov/pubmed/20956626http://en.wikipedia.org/wiki/PubMed_Identifierhttp://dx.doi.org/10.1200%2FJCO.2009.27.3607http://en.wikipedia.org/wiki/Digital_object_identifierhttp://www.ncbi.nlm.nih.gov/pubmed/12720155http://en.wikipedia.org/wiki/PubMed_Identifierhttp://dx.doi.org/10.1053%2Fsonc.2003.50048http://en.wikipedia.org/wiki/Digital_object_identifierhttp://www.ncbi.nlm.nih.gov/pubmed/11438816http://en.wikipedia.org/wiki/PubMed_Identifierhttp://dx.doi.org/10.1038%2Fsj.bmt.1703041http://en.wikipedia.org/wiki/Digital_object_identifierhttp://www.ncbi.nlm.nih.gov/pubmed/10218857http://en.wikipedia.org/wiki/PubMed_Identifierhttp://dx.doi.org/10.1038%2Fsj.bmt.1701633http://en.wikipedia.org/wiki/Digital_object_identifier


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