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= = = Biographies and studies = = = |
In 1960 , Ronald William Clark published a biography titled Sir Mortimer Wheeler . FitzRoy Somerset , 4th Baron Raglan reviewed the volume for the journal Man , describing " this very readable little book " as being " adulatory " in tone , " but hardly more so than its subject deserves . " In 1982 , the archaeologist Jacquetta Hawkes published a second biography , Mortimer Wheeler : Adventurer in Archaeology . Hawkes admitted she had developed " a very great liking " for Wheeler , having first met him when she was an archaeology student at the University of Cambridge . She believed that he had " a daemonic energy " , with his accomplishments in India being " almost superhuman " . Ultimately , she thought of him as being " an epic hero in an anti @-@ heroic age " in which growing social egalitarianism had stifled and condemned aspects of his greatness . |
In the 2000 film Hey Ram , the lead character , Saket Ram ( played by Kamal Haasan ) and his friend , Amjad Khan ( played by Shah Rukh Khan ) are shown as employees of Wheeler , who was portrayed by Lewis K. Elbinger , before the 1947 Hindu @-@ Muslim riots . In a 2003 volume of the South Asian Studies journal , Sudeshna Gusha published a research article examining Wheeler 's use of photography in his excavations and publications in the Indian subcontinent . In 2011 , the academic journal Public Archaeology published a research paper by Moshenska and Schadla @-@ Hall that analysed Wheeler 's role in presenting archaeology to the British public . Two years later , the Papers from the Institute of Archaeology issued a short comic strip by Moshenska and Alex Salamunovich depicting Wheeler 's activities in studying the archaeology of Libya during World War II . |
= Species of Allosaurus = |
There have been a number of potential species assigned to the carnosaurian dinosaur genus Allosaurus since its description in 1877 by Othniel Charles Marsh , but only a handful are still regarded as valid . Allosaurus was originally described from material from the Upper Jurassic Morrison Formation of the western United States of America ; the type species A. fragilis became one of the best @-@ known species of dinosaur . |
The genus Allosaurus was part of the Marsh / Cope " Bone Wars " of the late 19th century , and its taxonomy became increasingly confused due to the competition , with several genera and species named by Cope and Marsh now regarded as synonyms of Allosaurus or A. fragilis . Since the description of Allosaurus , scientists have proposed additional species from such far @-@ flung locales as Portugal , Siberia , and Tanzania . |
= = Query about type specimen = = |
The issue of synonyms is complicated by the type specimen of Allosaurus fragillis ( catalogue number YPM 1930 ) being extremely fragmentary , consisting of a few incomplete vertebrae , limb bone fragments , rib fragments , and a tooth . Because of this , several scientists have noted that the type specimen , and thus the genus Allosaurus itself or at least the species A. fragillis , is technically a nomen dubium ( " dubious name " , based on a specimen too incomplete to compare to other specimens or to classify ) . In an attempt to fix this situation , Gregory S. Paul and Kenneth Carpenter ( 2010 ) submitted a petition to the ICZN to have the name A. fragillis officially transferred to the more complete specimen USNM4734 ( as a neotype ) . This request is currently pending review . |
= = Potentially valid species = = |
It is unclear how many species of Allosaurus there were . Eight species have been considered potentially valid since 1988 ( A. amplexus , A. atrox , A. europaeus , the type species A. fragilis , the as @-@ yet not formally described " A. jimmadseni " , A. lucasi , A. maximus , and A. tendagurensis ) , although only about half are usually considered valid at any given time . There are also at least ten dubious or undescribed species that have been assigned to Allosaurus over the years , along with the species belonging to genera now sunk into Allosaurus . In the most recent review of basal tetanuran theropods , only A. fragilis ( including A. amplexus and A. atrox ) , " A. jimmadseni " ( as an unnamed species ) , and A. tendagurensis were accepted as potentially valid species , with A. europaeus not yet proposed and A. maximus assigned to Saurophaganax . |
A. fragilis is the type species and was named by Marsh in 1877 . It is known from the remains of at least sixty individuals , all found in the Kimmeridgian – Tithonian Upper Jurassic @-@ age Morrison Formation of the United States , spread across the states of Colorado , Montana , New Mexico , Oklahoma , South Dakota , Utah , and Wyoming . Details of the humerus ( upper arm ) of A. fragilis have been used as diagnostic among Morrison theropods , but the discovery of " A. jimmadseni " indicates that this will no longer be the case at the species level . |
A. amplexus was named by Gregory S. Paul for giant Morrison allosaur remains , and included in his conception Saurophagus maximus ( later Saurophaganax ) . A. amplexus was originally coined by Cope in 1878 as the type species of his new genus Epanterias , and is based on what is now AMNH 5767 , parts of three vertebrae , a coracoid , and a metatarsal . Following Paul 's work , this species has been accepted as a synonym of A. fragilis . |
Allosaurus material from Portugal was first reported in 1999 on the basis of MHNUL / AND.001 , a partial skeleton including a quadrate , vertebrae , ribs , gastralia , chevrons , part of the hips , and hindlimbs . This specimen was assigned to A. fragilis , but the subsequent discovery of a partial skull and neck ( ML 415 ) near Lourinhã , in the Kimmeridgian @-@ age Porto Novo Member of the Lourinhã Formation , spurred the naming of the new species A. europaeus . It differs from other species of Allosaurus in cranial details . However , more material may show it to be A. fragilis , as originally described . |
Daniel Chure 's work on Morrison allosaurid remains has been responsible , directly or indirectly , for " A. jimmadseni " and A. maximus . " A. jimmadseni " is the proposed name for a new species of Morrison allosaur , based on a nearly complete skeleton and skull . A. sp . 2 , as it is also known , differs from A. fragilis in several anatomical details including a jugal or cheekbone with a straight lower margin , and is also found only in the Salt Wash Member of the Morrison Formation , with A. fragilis only present in the higher Brushy Basin Member . A. maximus was coined by David K. Smith for Chure 's Saurophaganax maximus , a taxon created by Chure in 1995 for giant allosaurid remains from the Morrison of Oklahoma . These remains had been known as Saurophagus , but that name was already in use , leading Chure to propose a substitute . Smith , in his 1998 analysis of variation , concluded that S. maximus was not different enough from Allosaurus to be a separate genus , but did warrant its own species , A. maximus . This reassignment was rejected in the most recent review of basal tetanurans . |
= = Biological variation , A. atrox , and A. fragilis = = |
The perception that there were two common Allosaurus species in the Morrison Formation was popularized in Gregory S. Paul 's 1988 book Predatory Dinosaurs of the World . Paul proposed that A. fragilis had tall pointed horns and a slender build compared to a postulated second species A. atrox , and was not a different gender due to rarity . Allosaurus atrox was originally named by Marsh in 1878 as the type species of its own genus , Creosaurus , and is based on YPM 1890 , an assortment of bones including a couple of pieces of the skull , portions of nine tail vertebrae , two hip vertebrae , an illium , and ankle and foot bones . Although the idea of two common Morrison allosaur species has had support in semi @-@ technical and popular works , it has generally been rejected in the technical literature . |
David K. Smith , examining Allosaurus fossils by quarry , found that the Cleveland Lloyd Dinosaur Quarry ( Utah ) specimens are generally smaller than those from Como Bluff ( Wyoming ) or Brigham Young University 's Dry Mesa Quarry ( Colorado ) , but the shapes of the bones themselves did not vary between the sites . A later study by Smith incorporating Garden Park ( Colorado ) and Dinosaur National Monument ( Utah ) specimens found no justification for multiple species based on skeletal variation ; skull variation was most common and was gradational , suggesting individual variation was responsible . Further work on size @-@ related variation again found no consistent differences , although the Dry Mesa material tended to clump together on the basis of the astragalus , an ankle bone . Kenneth Carpenter , using skull elements from the Cleveland Lloyd site , found wide variation between individuals , calling into question previous species @-@ level distinctions based such features as the shape of the horns , and the proposed differentiation of " A. jimmadseni " based on the shape of the jugal . |
= = Invalid and synonymous species = = |
A number of species assigned to Allosaurus are no longer recognized as valid , for one reason or another . Species " A. agilis " , seen in Zittel , 1887 , and Osborn , 1912 , is a typographical error for A. fragilis . Marsh 's A. ferox ( 1896 ; not to be confused with his 1884 Labrosaurus ferox , also part of Allosaurus taxonomy ) was coined for a partial skull in a footnote , and has been recognized as a specimen of A fragilis . A. lucaris , another Marsh name , was given to a partial skeleton in 1878 . He later decided it warranted its own genus , Labrosaurus , but this has not been accepted , and A. lucaris is also regarded as another specimen of A. fragilis . Allosaurus lucaris , is known mostly from vertebrae , sharing characters with Allosaurus . Paul and Carpenter stated that the type specimen of this species , YPM 1931 , was from a younger age than Allosaurus , and might represent a different genus . However , they found that the specimen was undiagnostic , and thus A. lucaris was a nomen dubium . " A. whitei " , an informally described species coined by Pickering in 1996 , is a recasting of the A. atrox versus A. fragilis debate using a better specimen to represent the A. atrox form , and has not been recognized . |
Several species coined in genera other than Allosaurus are also now thought to be synonymous with A. fragilis . Labrosaurus ferox was named in 1884 by Marsh for an oddly formed partial lower jaw , with a prominent gap in the tooth row at the tip of the jaw , and a rear section greatly expanded and turned down . Later researchers suggested that the bone was pathologic , showing an injury to the living animal , and that part of the unusual form of the rear of the bone was due to plaster reconstruction . It is recognized as most likely a specimen of A. fragilis . Allosaurus valens is a typo for Antrodemus valens accidentally used by Friedrich von Huene in 1932 ; Antrodemus valens itself may also pertain to Allosaurus fragilis , as Gilmore suggested in 1920 . Apatodon mirus , based on a scrap of vertebra Marsh first thought to be a mammalian jaw , may or may not be the same as Allosaurus . |
= = Misassigned species = = |
Several species initially classified within or referred to Allosaurus do not belong within the genus . A. medius was named by Marsh in 1888 for " various specimens " from the Early Cretaceous of Maryland , although most of the remains were removed by Richard Swann Lull to the new ornithopod species Dryosaurus grandis , except for a tooth . Gilmore considered the tooth nondiagnostic but transferred it to a new species , Dryptosaurus medius . The referral was not accepted in the most recent review , and Allosaurus medius was simply listed as a dubious species of theropod . Allosaurus sibiricus was described in 1914 by A. N. Riabinin on the basis of a bone , later identified as a partial fourth metatarsal , from the Early Cretaceous of Buryatia , Russia . It was transferred to Chilantaisaurus in 1990 . |
Allosaurus meriani was described in 1870 by Greppin as a species of Megalosaurus , based on a tooth from the Late Jurassic of Switzerland . It has occasionally been referred to Allosaurus , but recent reviews have listed it as dubious theropod species Megalosaurus meriani , or included it in Ceratosaurus sp . Allosaurus stechowi was described in 1920 by Janensch as Labrosaurus stechowi for isolated Ceratosaurus @-@ like teeth from the Tendaguru beds of Tanzania . With the synonymization of Labrosaurus and Allosaurus , Donald F. Glut listed it as a species of Allosaurus , but it is now either assigned to Ceratosaurus sp. or considered a dubious ceratosaurian . |
There are also several species left over from the synonymizations of Creosaurus and Labrosaurus with Allosaurus . Creosaurus potens was named by Lull in 1911 for a vertebra from the Early Cretaceous of Maryland . It is now regarded as a dubious theropod . Labrosaurus fragilis is a typographical error by Marsh ( 1896 ) for Labrosaurus ferox . L. sulcatus , named by Marsh in 1896 for a Morrison theropod tooth , which like L. stechowi is now regarded as either Ceratosaurus sp. or a dubious ceratosaurian . |
A. tendagurensis was named in 1925 by Werner Janensch for a partial shin ( HM 67 ) found in the Kimmeridgian @-@ age rocks of Tendaguru , in Mtwara , Tanzania . This species has not had strong support in recent years , with opinions on its identity ranging from a tentatively valid species of Allosaurus , to a basal tetanuran . The most recent analysis has placed it in Carcharodontosauridae . Although obscure , it was a large theropod , possibly around 10 meters long ( 33 ft ) and 2 @.@ 5 metric tons ( 2 @.@ 8 short tons ) in weight . |
= = Specimens misassigned to Allosaurus though not described as new species = = |
Kurzanov and colleagues in 2003 designated six teeth from Siberia as Allosaurus sp . ( meaning the authors found the specimens to be most like those of Allosaurus , but did not or could not assign a species ) . Also , reports of Allosaurus in Shanxi , China go back to at least 1982 . |
An astragalus ( ankle bone ) thought to belong to a species of Allosaurus was found at Cape Paterson , Victoria in Early Cretaceous beds in southeastern Australia . It was thought to provide evidence that Australia was a refugium for animals that had gone extinct elsewhere . This identification was challenged by Samuel Welles , who thought it more resembled that of an ornithomimid , but the original authors defended their identification . With fifteen years of new specimens and research to look at , Daniel Chure reexamined the bone and found that it was not Allosaurus , but could represent an allosauroid . Similarly , Yoichi Azuma and Phil Currie , in their description of Fukuiraptor , noted that the bone closely resembled that of their new genus . This specimen is sometimes referred to as " Allosaurus robustus " , an informal museum name . It may have belonged to something similar to , or the same as , Australovenator , or it may represent an abelisaur . A speculative " polar " or " dwarf allosaur " was used for the " Spirits of the Ice Forest " episode of Walking with Dinosaurs . |
= Astraeus hygrometricus = |
Astraeus hygrometricus , commonly known as the hygroscopic earthstar , the barometer earthstar , or the false earthstar , is a species of fungus in the Diplocystaceae family . Young specimens resemble a puffball when young and unopened . In maturity , the mushroom displays the characteristic earthstar shape that is a result of the outer layer of fruit body tissue splitting open in a star @-@ like manner . The false earthstar is an ectomycorrhizal species that grows in association with various trees , especially in sandy soils . A. hygrometricus has a cosmopolitan distribution , and is common in temperate and tropical regions . Its common names refer to the fact that it is hygroscopic ( water @-@ absorbing ) , and can open up its rays to expose the spore sac in response to increased humidity , and close them up again in drier conditions . The rays have an irregularly cracked surface , while the spore case is pale brown and smooth with an irregular slit or tear at the top . The gleba is white initially , but turns brown and powdery when the spores mature . The spores are reddish @-@ brown , roughly spherical with minute warts , measuring 7 @.@ 5 – 11 micrometers in diameter . |
Most rails are secretive wetland birds that have made little cultural impression , but as a formerly common farmland bird with a loud nocturnal call that sometimes led to disturbed sleep for rural dwellers , the corn crake has acquired a variety of folk names and some commemoration in literature . |
= = = Names = = = |
The favoured name for this species among naturalists has changed over the years , with " landrail " and variants of " corncrake " being preferred at various times . " Crake gallinule " also had a period of popularity between 1768 and 1813 . The originally Older Scots " cornecrake " was popularised by Thomas Bewick , who used this term in his 1797 A History of British Birds . Other Scots names include " corn scrack " and " quailzie " ; the latter term , like " king of the quail " , " grass quail " , the French " roi de caille " , and the German " Wachtelkönig " refer to the association with the small gamebird . Another name , " daker " , has been variously interpreted as onomatopoeic , or derived from the Old Norse ager @-@ hoene , meaning " cock of the field " ; variants include " drake " , " drake Hen " and " gorse drake " . |
= = = In literature = = = |
Corn crakes are the subject of three stanzas of the seventeenth century poet Andrew Marvell 's " Upon Appleton House " , written in 1651 about the North Yorkshire country estate of Thomas Fairfax . The narrator depicts the scene of a mower cutting the grass , before his " whistling Sithe " unknowingly " carves the Rail " . The farmhand draws out the scythe " all bloody from its breast " and " does the stroke detest " . It continues with a stanza that demonstrates the problematic nature of the corn crake 's nesting habits : |
John Clare , the nineteenth @-@ century English poet based in Northamptonshire , wrote " The Landrail " , a semi @-@ comic piece which is primarily about the difficulty of seeing corn crakes – as opposed to hearing them . In the fourth verse he exclaims : " Tis like a fancy everywhere / A sort of living doubt " . Clare wrote about corn crakes in his prose works too , and his writings help to clarify the distribution of this rail when it was far more widespread than now . |
The Finnish poet Eino Leino also wrote about the bird in his poem " Nocturne " . |
The proverbial use of the corn crake 's call to describe someone with a grating or unmelodious voice is illustrated in the quotation " thanks to a wee woman with a voice like a corncrake who believed she was an apprentice angel " . This usage dates from at least the first half of the nineteenth century , and continues through to the present . |
= Acute myeloid leukemia = |
Acute myeloid leukemia ( AML ) , also known as acute myelogenous leukemia or acute nonlymphocytic leukemia ( ANLL ) , is a cancer of the myeloid line of blood cells , characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells . AML is the most common acute leukemia affecting adults , and its incidence increases with age . Although AML is a relatively rare disease , accounting for roughly 1 @.@ 2 % of cancer deaths in the United States , its incidence is expected to increase as the population ages . |
The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells , which causes a drop in red blood cells , platelets , and normal white blood cells . These symptoms include fatigue , shortness of breath , easy bruising and bleeding , and increased risk of infection . Several risk factors and chromosomal abnormalities have been identified , but the specific cause is not clear . As an acute leukemia , AML progresses rapidly and is typically fatal within weeks or months if left untreated . |
AML has several subtypes ; treatment and prognosis vary among subtypes . AML is cured in 35 – 40 % of people less than 60 years old and 5 – 15 % more than 60 years old . Older people who are not able to withstand intensive chemotherapy have an average survival of 5 – 10 months . |
AML is treated initially with chemotherapy aimed at inducing a remission ; people may go on to receive additional chemotherapy or a hematopoietic stem cell transplant . Recent research into the genetics of AML has resulted in the availability of tests that can predict which drug or drugs may work best for a particular person , as well as how long that person is likely to survive . The treatment and prognosis of AML differ from those of chronic myelogenous leukemia ( CML ) in part because the cellular differentiation is not the same ; AML involves higher percentages of dedifferentiated and undifferentiated cells , including more blasts ( myeloblasts , monoblasts , and megakaryoblasts ) . |
= = Signs and symptoms = = |
Most signs and symptoms of AML are caused by the replacement of normal blood cells with leukemic cells . A lack of normal white blood cell production makes people more susceptible to infections ; while the leukemic cells themselves are derived from white blood cell precursors , they have no infection @-@ fighting capacity . A drop in red blood cell count ( anemia ) can cause fatigue , paleness , and shortness of breath . A lack of platelets can lead to easy bruising or bleeding with minor trauma . |
The early signs of AML are often vague and nonspecific , and may be similar to those of influenza or other common illnesses . Some generalized symptoms include fever , fatigue , weight loss or loss of appetite , shortness of breath , anemia , easy bruising or bleeding , petechiae ( flat , pin @-@ head sized spots under the skin caused by bleeding ) , bone and joint pain , and persistent or frequent infections . |
Enlargement of the spleen may occur in AML , but it is typically mild and asymptomatic . Lymph node swelling is rare in AML , in contrast to acute lymphoblastic leukemia . The skin is involved about 10 % of the time in the form of leukemia cutis . Rarely , Sweet 's syndrome , a paraneoplastic inflammation of the skin , can occur with AML . |
Some people with AML may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue . Rarely , the first sign of leukemia may be the development of a solid leukemic mass or tumor outside of the bone marrow , called a chloroma . Occasionally , a person may show no symptoms , and the leukemia may be discovered incidentally during a routine blood test . |
= = Risk factors = = |
A number of risk factors for developing AML have been identified , including : other blood disorders , chemical exposures , ionizing radiation , and genetics . |
= = = Preleukemia = = = |
" Preleukemic " blood disorders , such as myelodysplastic syndrome ( MDS ) or myeloproliferative disease ( MPS ) , can evolve into AML ; the exact risk depends on the type of MDS / MPS . |
= = = Chemical exposure = = = |
Exposure to anticancer chemotherapy , in particular alkylating agents , can increase the risk of subsequently developing AML . The risk is highest about three to five years after chemotherapy . Other chemotherapy agents , specifically epipodophyllotoxins and anthracyclines , have also been associated with treatment @-@ related leukemias , which are often associated with specific chromosomal abnormalities in the leukemic cells . |
Occupational chemical exposure to benzene and other aromatic organic solvents is controversial as a cause of AML . Benzene and many of its derivatives are known to be carcinogenic in vitro . While some studies have suggested a link between occupational exposure to benzene and increased risk of AML , others have suggested the attributable risk , if any , is slight . |
= = = Radiation = = = |
High amounts of ionizing radiation exposure can increase the risk of AML . Survivors of the atomic bombings of Hiroshima and Nagasaki had an increased rate of AML , as did radiologists exposed to high levels of X @-@ rays prior to the adoption of modern radiation safety practices . People treated with ionizing radiation after treatment for prostate cancer , non @-@ Hodgkin lymphoma , lung cancer and breast cancer have the highest chance of acquiring AML , but this increased risk returns to the background risk observed in the general population after 12 years . |
= = = Genetics = = = |
A hereditary risk for AML appears to exist . Multiple cases of AML developing in a family at a rate higher than predicted by chance alone have been reported . Several congenital conditions may increase the risk of leukemia ; the most common is probably Down syndrome , which is associated with a 10- to 18 @-@ fold increase in the risk of AML . |
= = Diagnosis = = |
The first clue to a diagnosis of AML is typically an abnormal result on a complete blood count . While an excess of abnormal white blood cells ( leukocytosis ) is a common finding , and leukemic blasts are sometimes seen , AML can also present with isolated decreases in platelets , red blood cells , or even with a low white blood cell count ( leukopenia ) . While a presumptive diagnosis of AML can be made by examination of the peripheral blood smear when there are circulating leukemic blasts , a definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy . |
Marrow or blood is examined under light microscopy , as well as flow cytometry , to diagnose the presence of leukemia , to differentiate AML from other types of leukemia ( e.g. acute lymphoblastic leukemia - ALL ) , and to classify the subtype of disease . A sample of marrow or blood is typically also tested for chromosomal abnormalities by routine cytogenetics or fluorescent in situ hybridization . Genetic studies may also be performed to look for specific mutations in genes such as FLT3 , nucleophosmin , and KIT , which may influence the outcome of the disease . |
Cytochemical stains on blood and bone marrow smears are helpful in the distinction of AML from ALL , and in subclassification of AML . The combination of a myeloperoxidase or Sudan black stain and a nonspecific esterase stain will provide the desired information in most cases . The myeloperoxidase or Sudan black reactions are most useful in establishing the identity of AML and distinguishing it from ALL . The nonspecific esterase stain is used to identify a monocytic component in AMLs and to distinguish a poorly differentiated monoblastic leukemia from ALL . |
The diagnosis and classification of AML can be challenging , and should be performed by a qualified hematopathologist or hematologist . In straightforward cases , the presence of certain morphologic features ( such as Auer rods ) or specific flow cytometry results can distinguish AML from other leukemias ; however , in the absence of such features , diagnosis may be more difficult . |
The two most commonly used classification schemata for AML are the older French @-@ American @-@ British ( FAB ) system and the newer World Health Organization ( WHO ) system . According to the widely used WHO criteria , the diagnosis of AML is established by demonstrating involvement of more than 20 % of the blood and / or bone marrow by leukemic myeloblasts , except in the three best prognosis forms of AML with recurrent genetic abnormalities ( t ( 8 ; 21 ) , inv ( 16 ) , and t ( 15 ; 17 ) ) in which the presence of the genetic abnormality is diagnostic irrespective of blast percent . The French – American – British ( FAB ) classification is a bit more stringent , requiring a blast percentage of at least 30 % in bone marrow ( BM ) or peripheral blood ( PB ) for the diagnosis of AML . AML must be carefully differentiated from " preleukemic " conditions such as myelodysplastic or myeloproliferative syndromes , which are treated differently . |
Because acute promyelocytic leukemia ( APL ) has the highest curability and requires a unique form of treatment , it is important to quickly establish or exclude the diagnosis of this subtype of leukemia . Fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose , as it readily identifies the chromosomal translocation [ t ( 15 ; 17 ) ( q22 ; q12 ) ; ] that characterizes APL . There is also a need to molecularly detect the presence of PML / RARA fusion protein , which is an oncogenic product of that translocation . |
= = = World Health Organization = = = |
The WHO 2008 classification of acute myeloid leukemia attempts to be more clinically useful and to produce more meaningful prognostic information than the FAB criteria . Each of the WHO categories contains numerous descriptive subcategories of interest to the hematopathologist and oncologist ; however , most of the clinically significant information in the WHO schema is communicated via categorization into one of the subtypes listed below . |
The WHO subtypes of AML are : |
Acute leukemias of ambiguous lineage ( also known as mixed phenotype or biphenotypic acute leukemia ) occur when the leukemic cells can not be classified as either myeloid or lymphoid cells , or where both types of cells are present . |
= = = French @-@ American @-@ British = = = |
The French @-@ American @-@ British ( FAB ) classification system divides AML into eight subtypes , M0 through to M7 , based on the type of cell from which the leukemia developed and its degree of maturity . This is done by examining the appearance of the malignant cells with light microscopy and / or by using cytogenetics to characterize any underlying chromosomal abnormalities . The subtypes have varying prognoses and responses to therapy . Although the WHO classification ( see above ) may be more useful , the FAB system is still widely used . |
Eight FAB subtypes were proposed in 1976 . |
The morphologic subtypes of AML also include rare types not included in the FAB system , such as acute basophilic leukemia , which was proposed as a ninth subtype , M8 , in 1999 . |
= = Pathophysiology = = |
The malignant cell in AML is the myeloblast . In normal hematopoiesis , the myeloblast is an immature precursor of myeloid white blood cells ; a normal myeloblast will gradually mature into a mature white blood cell . In AML , though , a single myeloblast accumulates genetic changes which " freeze " the cell in its immature state and prevent differentiation . Such a mutation alone does not cause leukemia ; however , when such a " differentiation arrest " is combined with other mutations which disrupt genes controlling proliferation , the result is the uncontrolled growth of an immature clone of cells , leading to the clinical entity of AML . |
Much of the diversity and heterogeneity of AML stems is because leukemic transformation can occur at a number of different steps along the differentiation pathway . Modern classification schemes for AML recognize the characteristics and behavior of the leukemic cell ( and the leukemia ) may depend on the stage at which differentiation was halted . |
Specific cytogenetic abnormalities can be found in many people with AML ; the types of chromosomal abnormalities often have prognostic significance . The chromosomal translocations encode abnormal fusion proteins , usually transcription factors whose altered properties may cause the " differentiation arrest " . For example , in acute promyelocytic leukemia , the t ( 15 ; 17 ) translocation produces a PML @-@ RARα fusion protein which binds to the retinoic acid receptor element in the promoters of several myeloid @-@ specific genes and inhibits myeloid differentiation . |
The clinical signs and symptoms of AML result from the growth of leukemic clone cells , which tends to displace or interfere with the development of normal blood cells in the bone marrow . This leads to neutropenia , anemia , and thrombocytopenia . The symptoms of AML are , in turn , often due to the low numbers of these normal blood elements . In rare cases , people with AML can develop a chloroma , or solid tumor of leukemic cells outside the bone marrow , which can cause various symptoms depending on its location . |
An important pathophysiological mechanism of leukemogenesis in AML is the epigenetic induction of dedifferentiation by genetic mutations that alter the function of epigenetic enzymes , such as the DNA demethylase TET2 and the metabolic enzymes IDH1 and IDH2 , which lead to the generation of a novel oncometabolite , D @-@ 2 @-@ hydroxyglutarate , which inhibits the activity of epigenetic enzymes such as TET2 . The hypothesis is that such epigenetic mutations lead to the silencing of tumor suppressor genes and / or the activation of proto @-@ oncogenes . |
= = Treatment = = |
First @-@ line treatment of AML consists primarily of chemotherapy , and is divided into two phases : induction and postremission ( or consolidation ) therapy . The goal of induction therapy is to achieve a complete remission by reducing the number of leukemic cells to an undetectable level ; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure . Hematopoietic stem cell transplantation is usually considered if induction chemotherapy fails or after a person relapses , although transplantation is also sometimes used as front @-@ line therapy for people with high @-@ risk disease . Efforts to use tyrosine kinase inhibitors in AML continue . |
= = = Induction = = = |
All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine ( ara @-@ C ) and an anthracycline ( most often daunorubicin ) . This induction chemotherapy regimen is known as " 7 + 3 " ( or " 3 + 7 " ) , because the cytarabine is given as a continuous IV infusion for seven consecutive days while the anthracycline is given for three consecutive days as an IV push . Up to 70 % of people with AML will achieve a remission with this protocol . Other alternative induction regimens , including high @-@ dose cytarabine alone , FLAG @-@ like regimens or investigational agents , may also be used . Because of the toxic effects of therapy , including myelosuppression and an increased risk of infection , induction chemotherapy may not be offered to the very elderly , and the options may include less intense chemotherapy or palliative care . |
The M3 subtype of AML , also known as acute promyelocytic leukemia ( APL ) , is almost universally treated with the drug all @-@ trans @-@ retinoic acid ( ATRA ) in addition to induction chemotherapy , usually an anthracycline . Care must be taken to prevent disseminated intravascular coagulation ( DIC ) , complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation . APL is eminently curable , with well @-@ documented treatment protocols . |
The goal of the induction phase is to reach a complete remission . Complete remission does not mean the disease has been cured ; rather , it signifies no disease can be detected with available diagnostic methods . Complete remission is obtained in about 50 % – 75 % of newly diagnosed adults , although this may vary based on the prognostic factors described above . The length of remission depends on the prognostic features of the original leukemia . In general , all remissions will fail without additional consolidation therapy . |
= = = Consolidation = = = |
Even after complete remission is achieved , leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques . If no further postremission or consolidation therapy is given , almost all people with AML will eventually relapse . Therefore , more therapy is necessary to eliminate nondetectable disease and prevent relapse — that is , to achieve a cure . |
The specific type of postremission therapy is individualized based on a person 's prognostic factors ( see above ) and general health . For good @-@ prognosis leukemias ( i.e. inv ( 16 ) , t ( 8 ; 21 ) , and t ( 15 ; 17 ) ) , people will typically undergo an additional three to five courses of intensive chemotherapy , known as consolidation chemotherapy . For people at high risk of relapse ( e.g. those with high @-@ risk cytogenetics , underlying MDS , or therapy @-@ related AML ) , allogeneic stem cell transplantation is usually recommended if the person is able to tolerate a transplant and has a suitable donor . The best postremission therapy for intermediate @-@ risk AML ( normal cytogenetics or cytogenetic changes not falling into good @-@ risk or high @-@ risk groups ) is less clear and depends on the specific situation , including the age and overall health of the person , the person 's values , and whether a suitable stem cell donor is available . |
For people who are not eligible for a stem cell transplant , immunotherapy with a combination of histamine dihydrochloride ( Ceplene ) and interleukin 2 ( Proleukin ) after the completion of consolidation has been shown to reduce the absolute relapse risk by 14 % , translating to a 50 % increase in the likelihood of maintained remission . |
= = = Relapsed AML = = = |
For people with relapsed AML , the only proven potentially curative therapy is a hematopoietic stem cell transplant , if one has not already been performed . In 2000 , the monoclonal antibody @-@ linked cytotoxic agent gemtuzumab ozogamicin ( Mylotarg ) was approved in the United States for people aged more than 60 years with relapsed AML who are not candidates for high @-@ dose chemotherapy . This drug was voluntarily withdrawn from the market by its manufacturer , Pfizer in 2010 . |
Since treatment options for relapsed AML are so limited , palliative care or enrolment in a clinical trial may be offered . |
For relapsed acute promyelocytic leukemia ( APL ) , arsenic trioxide is approved by the US FDA . Like ATRA , arsenic trioxide does not work with other subtypes of AML . |
= = Prognosis = = |
Acute myeloid leukemia is a curable disease ; the chance of cure for a specific person depends on a number of prognostic factors . |
= = = Cytogenetics = = = |
The single most important prognostic factor in AML is cytogenetics , or the chromosomal structure of the leukemic cell . Certain cytogenetic abnormalities are associated with very good outcomes ( for example , the ( 15 ; 17 ) translocation in acute promyelocytic leukemia ) . About half of people with AML have " normal " cytogenetics ; they fall into an intermediate risk group . A number of other cytogenetic abnormalities are known to associate with a poor prognosis and a high risk of relapse after treatment . |
The first publication to address cytogenetics and prognosis was the MRC trial of 1998 : |
Later , the Southwest Oncology Group and Eastern Cooperative Oncology Group and , later still , Cancer and Leukemia Group B published other , mostly overlapping lists of cytogenetics prognostication in leukemia . |
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