Paraneoplastic cerebellar degeneration: Difference between revisions

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Revision as of 18:35, 13 April 2016

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Synonyms and keywords: Cerebellar ataxia due to neoplasia;

Overview

Paraneoplastic cerebellar degeneration (PCD) is a rare paraneoplastic syndrome associated with lung, ovarian, breast, Hodgkin’s lymphoma, and other types of tumors. Paraneoplastic cerebellar degeneration occurs in less than 1 to 3% of cancer patients. The pathogenesis of paraneoplastic cerebellar degeneration is due to an autoimmune reaction targeted against components of the central nervous system. The presence of anti-Purkinje cell is triggered by tumor cells, that normally express a Purkinje neuronal protein termed CDR2 antibodies. The antibodies that have been associated with the development of paraneoplastic cerebellar degeneration, include: anti-P/Q type calcium channel antibodies, anti-Tr antibodies, anti-Ri (ANNA-2), anti-CV2, antibodies to Ma proteins, and antibodies to the Zic4. Paraneoplastic cerebellar degeneration is more commonly observed among patients between 40 to 60 years old. Paraneoplastic cerebellar degeneration affects females more commonly than males. The majority of patients with paraneoplastic cerebellar degeneration are typically symptomatic. Early clinical features include dizziness, nausea, and vomiting. The diagnosis of paraneoplastic cerebellar degeneration is made with the following criteria: positive antibody-mediated immune response, diffuse cerebellar atrophy in imaging findings, and positive medical history for cancer. Common medical therapies for paraneoplastic cerebellar degeneration, include: intravenous immunoglobulins, cyclophosphamide, and methylprednisolone.

Historical Perspective

Paraneoplastic cerebellar degeneration was first described in early 1980.

Classification

Paraneoplastic cerebellar degeneration according to the presence or absence of an antibody, into several categories.

Pathophysiology

The pathogenesis of paraneoplastic cerebellar degeneration is characterized by the presence of anti-Purkinje cell antibodies.
The pathogenesis of paraneoplastic cerebellar degeneration is due to an autoimmune reaction targeted against components of the central nervous system.
The pathophysiology mechanism of paraneoplastic cerebellar degeneration is triggered by tumor cells, that normally express a protein (Purkinje neuronal protein termed cdr2). This protein is believed to trigger an anti-tumor immune and anti-neuronal immune response.
The antibodies that have been associated with the development of paraneoplastic cerebellar degeneration, include:

Anti-P/Q type calcium channel antibodies
Anti-Tr antibodies
Anti-Ri (ANNA-2)
Anti-CV2
Antibodies to Ma proteins
Antibodies to the Zic4

Causes

Causes of paraneoplastic cerebellar degeneration, include:

Lung cancer
Ovarian cancer
Breast cancer
Hodgkin's lymphoma

Differentiating Paraneoplastic Cerebellar Degeneration from other Diseases

Paraneoplastic cerebellar degeneration must be differentiated from other diseases that cause ataxia, dizziness, and nausea such as:

Epidemiology and Demographics

Paraneoplastic cerebellar degeneration affects is approximately 1-3% of all cancer patients.

Age

Paraneoplastic cerebellar degeneration is more commonly observed among patients between 40 to 60 years old.
Paraneoplastic cerebellar degeneration is more commonly observed among middle aged adults

Gender

Paraneoplastic cerebellar degeneration affects females more commonly than males.

Race

There is no racial predilection for paraneoplastic cerebellar degeneration.

Risk Factors

There are no known risk factors for paraneoplastic cerebellar degeneration.

Natural History, Complications and Prognosis

The majority of patients with paraneoplastic cerebellar degeneration are typically symptomatic.
Early clinical features include dizziness, nausea, and vomiting.
If left untreated, the majority of patients with paraneoplastic cerebellar degeneration may progress to develop severe disability with inability to walk
Common complications of paraneoplastic cerebellar degeneration, include:
Prognosis is generally poor, and the median survival rate of patients with paraneoplastic cerebellar degeneration is approximately 13 months.

Diagnosis

Diagnostic Criteria

The diagnosis of paraneoplastic cerebellar degeneration is made with the following criteria:

Positive antibody-mediated immune response
Diffuse cerebellar atrophy in imaging findings
Positive medical history for cancer.

Symptoms

Symptoms of paraneoplastic cerebellar degeneration may include the following:

Dysarthria
Truncal, limb and gait ataxia
Vertigo
Nausea
Vomiting
Diplopia
Slurred speech
Dysphagia
Nystagmus

Physical Examination

Patients with paraneoplastic cerebellar degeneration usually appear confused, or lethargic.
Neurological examination may be remarkable for:

Hyperactive reflexes
Gait disturbance
Babinski sign
Speech disturbance
Lack of coordination
Nystagmus

Laboratory Findings

There are no specific laboratory findings associated with paraneoplastic cerebellar degeneration.
Laboratory testing may include thyroid function tests, vitamin levels, and antibody titers (anti-gliadin, or anti-GAD antibodies)

Imaging Findings

Magnetic resonance imaging is the imaging modality of choice for paraneoplastic cerebellar degeneration.
On MRI, findings of paraneoplastic cerebellar degeneration, include:

Diffuse cerebellar atrophy
No atrophy of the cerebral cortex, midbrain, pons, or medulla

Other Diagnostic Studies

Paraneoplastic cerebellar degeneration may also be diagnosed using PET scan.
Findings on PET scan are often unspecific, but may include hypermetabolism.

Treatment

Medical Therapy

The mainstay of therapy for paraneoplastic cerebellar degeneration is supportive care.
Common medical therapies for paraneoplastic cerebellar degeneration, include:

Intravenous immunoglobulins
Cyclophosphamide
Methylprednisolone

Surgery

Surgery is not recommended for patients with paraneoplastic cerebellar degeneration.

Prevention

There are no primary preventive measures available for paraneoplastic cerebellar degeneration.

References

@@ Line 1: / Line 1: @@
-{{Infobox disease |
-  Name           = Paraneoplastic cerebellar degeneration |
-  Image          = |
-  Caption        = |
-  DiseasesDB     = 33977 |
-  ICD10          = {{ICD10|G|13|0|g|10}} |
-  ICD9           = {{ICD9|334.9}} |
-  ICDO           = |
-  OMIM           = |
-  MedlinePlus    = |
-  eMedicineSubj  = neuro |
-  eMedicineTopic = 299 |
-  MeshID          = D020362 |
-}}
 __NOTOC__
-{{CMG}}
+{{SI}}
+{{CMG}} {{AE}} {{MV}}
+{{SK}} Cerebellar ataxia due to neoplasia;
+==Overview==
+'''Paraneoplastic cerebellar degeneration''' (PCD) is a rare [[paraneoplastic syndrome]] associated with [[lung]], [[ovarian]], [[breast]], [[Hodgkin’s lymphoma]], and other types of tumors. Paraneoplastic cerebellar degeneration occurs in less than 1 to 3% of cancer patients. The pathogenesis of paraneoplastic cerebellar degeneration is due to an autoimmune reaction targeted against components of the central nervous system.  The presence of anti-Purkinje cell is triggered by tumor cells, that normally express a Purkinje neuronal protein termed CDR2 antibodies. The antibodies that have been associated with the development of paraneoplastic cerebellar degeneration, include: anti-P/Q type calcium channel antibodies, anti-Tr antibodies, anti-Ri (ANNA-2), anti-CV2, antibodies to Ma proteins, and antibodies to the Zic4.  Paraneoplastic cerebellar degeneration is more commonly observed among patients between 40 to 60 years old. Paraneoplastic cerebellar degeneration affects females more commonly than males. The majority of patients with paraneoplastic cerebellar degeneration are typically symptomatic.  Early clinical features include dizziness, nausea, and vomiting. The diagnosis of paraneoplastic cerebellar degeneration is made with the following criteria: positive antibody-mediated immune response, diffuse cerebellar atrophy in imaging findings, and positive medical history for cancer. Common medical therapies for paraneoplastic cerebellar degeneration, include:  intravenous immunoglobulins, cyclophosphamide, and methylprednisolone.
+==Historical Perspective==
+*Paraneoplastic cerebellar degeneration was first described in early 1980.
+==Classification==
+Paraneoplastic cerebellar degeneration according to the presence or absence of an antibody, into several categories.
+==Pathophysiology==
+*The pathogenesis of paraneoplastic cerebellar degeneration is characterized by the presence of anti-Purkinje cell antibodies.
+*The pathogenesis of paraneoplastic cerebellar degeneration is due to an autoimmune reaction targeted against components of the central nervous system.
+*The pathophysiology mechanism of paraneoplastic cerebellar degeneration is triggered by tumor cells, that normally express a protein (Purkinje neuronal protein termed cdr2). This protein is believed to trigger an anti-tumor immune and anti-neuronal immune response.
+*The antibodies that have been associated with the development of paraneoplastic cerebellar degeneration, include:
+:*Anti-P/Q type calcium channel antibodies
+:*Anti-Tr antibodies
+:*Anti-Ri (ANNA-2)
+:*Anti-CV2
+:*Antibodies to Ma proteins
+:*Antibodies to the Zic4
+==Causes==
+* Causes of paraneoplastic cerebellar degeneration, include:
+:*Lung cancer
+:*Ovarian cancer
+:*Breast cancer
+:*Hodgkin's lymphoma
+==Differentiating Paraneoplastic Cerebellar Degeneration from other Diseases==
+*Paraneoplastic cerebellar degeneration must be differentiated from other diseases that cause ataxia, dizziness, and nausea such as:
-{{SK}} Cerebellar ataxia due to neoplasia
+==Epidemiology and Demographics==
+* Paraneoplastic cerebellar degeneration affects is approximately 1-3% of all cancer patients.
-==Overview==
+===Age===
-'''Paraneoplastic cerebellar degeneration''' (PCD) is a [[paraneoplastic syndrome]] associated with [[lung]], [[ovarian]], [[breast]], [[Hodgkin’s lymphoma]]<ref name=terrance>{{cite journal|last=O'Brien|first=Terrence J.|author2=Pasaliaris, Bill |author3=D'Apince, Anthony |author4= Byrne, Edward |title=Anti-Yo positive paraneoplastic cerebellar degeneration: a report of three cases and review of the literature|journal=Journal of Clinical Neuroscience|year=1995|volume=2|issue=4|pages=316–320|doi=10.1016/0967-5868(95)90052-7}}</ref>  and other [[cancer]]s. PCD is a rare condition that occurs in less than 1% of cancer patients<ref name=terrance /><ref name=Abdul>{{cite journal|last=Rana|first=Abdul, Oayyu|author2=Ranna, A.N. |author3=Adul, Ashfique |title=Acute ataxia due to anti-Yo antibody paraneoplastic cerebellar degeneration 4 months prior to diagnosis of uterine carcinoma|journal=Acta Neurologica Belgica|year=2012}}</ref><ref name=Finsterer>{{cite journal|last=Finsterer|first=Josef|author2=Voigtlander, Till |author3=Grisold, Wolfgang |title=Deterioration of anti-Yo-associated paraneoplastic cerebellar degeneration|journal=Journal of the Neurological Sciences|year=2011|volume=308|pages=139–141|doi=10.1016/j.jns.2011.06.051}}</ref> and usually occurs in middle-aged women.
+*Paraneoplastic cerebellar degeneration is more commonly observed among patients between 40 to 60 years old.
+*Paraneoplastic cerebellar degeneration is more commonly observed among middle aged adults
+===Gender===
+*Paraneoplastic cerebellar degeneration affects females more commonly than males.
+===Race===
+*There is no racial predilection for paraneoplastic cerebellar degeneration.
+==Risk Factors==
+*There are no known risk factors for paraneoplastic cerebellar degeneration.
+== Natural History, Complications and Prognosis==
+*The majority of patients with paraneoplastic cerebellar degeneration are typically symptomatic.
+*Early clinical features include dizziness, nausea, and vomiting.
+*If left untreated,  the majority of patients with paraneoplastic cerebellar degeneration may progress to develop severe disability with inability to walk
+*Common complications of paraneoplastic cerebellar degeneration, include:
+*Prognosis is generally poor, and the median survival rate of patients with paraneoplastic cerebellar degeneration is approximately 13 months.
+== Diagnosis ==
+===Diagnostic Criteria===
+*The diagnosis of paraneoplastic cerebellar degeneration is made with the following criteria:
+:*Positive antibody-mediated immune response
+:*Diffuse cerebellar atrophy in imaging findings
+:*Positive medical history for cancer.
-As is the case with other [[paraneoplastic syndromes]],<ref>[http://books.google.com/books?id=TGFmbuOFot0C&dq=darnell+posner&source=gbs_navlinks_s Paraneoplastic Syndromes, 2011, Darnell & Posner]</ref> PCD is believed to be due to an [[autoimmune]] reaction targeted against components of the [[central nervous system]] (in PCD, this is specifically  [[Purkinje cells]]<ref>{{citation |journal=Annals of Neurology |author=Jaeckle,K.A., Graus,F., Houghton,A., Cardon-Cardo,C., Nielsen,S.L., Posner,J.B. |title=Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen |volume=18|issue=5 |pages=592–600 |year=1985 |pmid=2416270 |doi=10.1002/ana.410180513}}</ref> in the cerebellum,<ref name=Brock>{{cite journal|last=Phuphanich|first=Surasak|author2=Brock |author3=Charles |title=Neurologic improvement after high-dose intravenous immunoglobulin therapy in patients with paraneoplastic cerebellar degeneration associated with anti-Purkinje cell antibody|journal=Journal of Neuro-oncology|year=2007|volume=81|pages=67–69|doi=10.1007/s11060-006-9198-x}}</ref> sometimes  accompanied  by  a  proliferation  of  Berg- mann [[astrocytes]] and [[microglia]] in the molecular layer of the cerebellum and a loss of granule cells<ref name=Brock /><ref name=anderson>{{cite journal|last=Anderson|first=NE|author2=Rosenblum, MK |author3=Posner, JB |title=Paraneoplastic cerebellar degeneration: clinical-immunological correlations|journal=Annals of Neurology|year=1988|volume=24|issue=5|pages=559–567|doi=10.1002/ana.410240413}}</ref> ).  It is thought to be triggered when tumor cells (in PCD, most commonly ovarian or breast cancer<ref>{{citation |journal=Neurology |author=Peterson,K., Rosenblum, J.K., Kotanides,H., Posner,J.B. |title=Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients |volume=42|issue=10 |pages=1931–1937 |year=1992 |pmid= 1407575 |doi=10.1212/wnl.42.10.1931}}</ref><ref>Sillevis Smith et al, Chapter 97</ref>) express a protein normally expressed in the brain (in PCD, this is the Purkinje neuronal protein termed cdr2).  This is believed to trigger an anti-tumor immune response that may be clinically significant, but also an anti-neuronal immune response.<ref>{{citation |journal=Current Opinion in Immunology |author=Roberts,W.K., Darnell,R.B. |title=Neuroimmunology of the paraneoplastic neurological degenerations |volume=16|issue=5 |pages=616–622 |year=2004 |pmid= 15342008 |doi=10.1016/j.coi.2004.07.009}}</ref>  PCD patients harbor an anti-neuronal antibody known as anti-Yo (named after the first two letters of the index patient).  PCD may be associated with onconeural antibodies directed against other intracellular antigens or against cell surface<ref name=Finsterer />  and with other tumors. When associated with small cell lung cancer, it is antibody termed "anti-Hu" (more commonly associated with paraneoplastic subacute sensory neuropathy and/or [[limbic encephalitis]]). The immune cells cross the blood–brain barrier, resulting in an autoimmune attack of Purkinje cells throughout the cerebellar cortex.<ref name=Abdul /> Radiologic imaging occasionally reveals cerebellar atrophy. Other paraneoplastic antibodies may be associated with PCD symptoms, including anti-Tr and antibodies to glutamate receptor. Occasionally myoclonia and opsoclonus may occur.<ref name=Brock />
+=== Symptoms ===
+*Symptoms of paraneoplastic cerebellar degeneration may include the following:
+:*Dysarthria
+:*Truncal, limb and gait ataxia
+:*Vertigo
+:*Nausea
+:*Vomiting
+:*Diplopia
+:*Slurred speech
+:*Dysphagia
+:*Nystagmus
-Neurological symptoms present insidiously and progress rapidly for about 6 months to a severely disabled state followed by a variable plateau period that can last for months to years.<ref name=terrance /><ref name=Abdul /><ref name=Brock /> The clinical [[cerebellar ataxia]] evident in patients with PCD are caused by Purkinje neuronal loss in the cerebellum. It is manifested by [[dysarthria]], truncal, limb and gait [[ataxia]], [[vertigo]], nausea, vomiting, [[diplopia]]<ref name=terrance /><ref name=Brock /> and [[nystagmus]].  Neurological symptoms precede the diagnosis of the underlying cancer in about 60% of cases.<ref name=Finsterer /><ref name=Frings>{{cite journal|last=Frings|first=Markus|coauthors=Antoch, Gerald; Knorn, Phillipp; Freudenberg, Lutz; Bier, Ulrich; Timmann, Dagar, Timmann; Maschke, Matthias|title=Strategies in detection of the  primary tumour in anti-Yo associated paraneoplastic cerebellar degeneration|journal=Journal of Neurology|year=2005|volume=252|pages=197–201|doi=10.1007/s00415-005-0635-0}}</ref> A cure of the cancer underlying PCD usually does not affect neurological symptoms, as cerebellar dysfunction stabilizes in the early stage after symptom onset before the cancer treatment has been initiated.<ref name=Takeda>{{cite journal|last=Takeda|first=Akihrio|author2=Manabe, Shuichi |author3=Mitsui, Takashi |author4= Nakamura, Hiromi |title=Laparoscopic management of fallopian tube carcinoma with paraneoplastic cerebellar degeneration|journal=Gyneological Surgery|year=2007|volume=4|pages=131–134|doi=10.1007/s10397-006-0228-7}}</ref> There may be a role for high dose gammaglobulin therapy in the treatment PCD, but due to the rare occurrence of this disease, controlled trials of this therapy may be difﬁcult.<ref name=Brock />
+=== Physical Examination ===
+*Patients with paraneoplastic cerebellar degeneration usually appear confused, or lethargic.
+*Neurological examination may be remarkable for:
+:*Hyperactive reflexes
+:*Gait disturbance
+:*Babinski sign
+:*Speech disturbance
+:*Lack of coordination
+:*Nystagmus
-==Pathophysiology==
+=== Laboratory Findings ===
-The anti-Purkinje cell antibodies originally described in PCD led to the hypothesis that the antibody might be pathogenic, much as earlier studies had demonstrated pathogenicity of anti-acetylcholine receptor antibodies in [[myasthenia gravis]].  However, when the antibody was used to clone the cDNA encoding the cdr2 antigen, it was found to be an intracellular protein.  This led to the suggestion<ref>{{citation |journal=Proc Natl Acad Sci U S A |author=Darnell,R.B. |title=Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain |volume=93|issue=10 |pages=4529–4536 |year=1996 |pmid= 8643438 |pmc=39311 |doi=10.1073/pnas.93.10.4529}}</ref> that there might be a cell-mediated component (T cell) in disease pathogenesis.  cdr2 antigen-specific CD8+ T cells were subsequently described<ref>{{citation |journal=Ann Neurol |author=Albert,M.L., Austin,L.M., Darnell,R.B. |title=Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration |volume=47|issue=1 |pages=9–17 |year=2000 |pmid= 10632096 |doi=10.1002/1531-8249(200001)47:1<9::aid-ana5>3.3.co;2-9}}</ref> in all PCD patients,<ref>{{citation |journal=Ann Neurol |author=Darnell,R.B., Albert,M.L. |title=cdr2-specific CTLs are detected in the blood of all patients with paraneoplastic cerebellar degeneration analyzed |volume=48|issue=2 |pages=270–271 |year=2000 |pmid= 10939585 |doi=10.1002/1531-8249(200008)48:2<270::aid-ana25>3.3.co;2-p}}</ref> making them a hallmark of the disease, and likely components in both the anti-tumor immune response and in the neuronal degeneration.
+*There are no specific laboratory findings associated with paraneoplastic cerebellar degeneration.
+*Laboratory testing may include thyroid function tests, vitamin levels,  and antibody titers (anti-gliadin, or anti-GAD antibodies)
-==References==
+===Imaging Findings===
-{{Reflist|2}}
+*Magnetic resonance imaging is the imaging modality of choice for paraneoplastic cerebellar degeneration.
+*On MRI, findings of paraneoplastic cerebellar degeneration, include:
+:* Diffuse cerebellar atrophy
+:* No atrophy of the cerebral cortex, midbrain, pons, or medulla
-==External links==
+=== Other Diagnostic Studies ===
-*[http://www.antibodypatterns.com/yo.php Antibody associated with cerebellar degeneration]
+*Paraneoplastic cerebellar degeneration may also be diagnosed using PET scan.
+*Findings on PET scan are often unspecific, but may include hypermetabolism.
+== Treatment ==
+=== Medical Therapy ===
+*The mainstay of therapy for paraneoplastic cerebellar degeneration is supportive care.
+*Common medical therapies for paraneoplastic cerebellar degeneration, include:
+:*Intravenous immunoglobulins
+:*Cyclophosphamide
+:*Methylprednisolone
-{{Paraneoplastic syndromes}}
+=== Surgery ===
+*Surgery is not recommended for patients with paraneoplastic cerebellar degeneration.
-[[Category:Paraneoplastic syndromes]]
+=== Prevention ===
+*There are no primary preventive measures available for paraneoplastic cerebellar degeneration.
+==References==
+{{Reflist|2}}
+[[Category: Oncology]]