AIDS-Associated Lymphoproliferative Disorders

AIDS-Associated Lymphoproliferative Disorders

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Sexual Health
Diseases & Conditions
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Contributed byKrish Tangella MD, MBAApr 28, 2018

What are the other Names for this Condition? (Also known as/Synonyms)

  • AIDS-Associated LPDs

What is AIDS-Associated Lymphoproliferative Disorders? (Definition/Background Information)

  • AIDS-Associated Lymphoproliferative Disorders are a range of disorders that occur in a background of AIDS or HIV infection. It has been observed that around 1 in 10-20 individuals with AIDS have this condition
  • Lymphoproliferative disorders (LPDs) are disorders in which there is uncontrolled production of (excess) lymphocytes due to various reasons; chiefly from an immune-compromised state of the individual
  • There are a variety of lymphomas that can arise in a HIV-positive individual. These are typically aggressive and mostly arise from B-cells. AIDS-Associated Lymphoproliferative Disorders affect many organs such as the lymph nodes, bone marrow, liver, GI tract, brain, lung, and skin
  • The most common AIDS-Associated Lymphoproliferative Disorders include:
    • Burkitt lymphoma (BL): Studies have shown that BL is 1000 times more common in HIV-positive individuals compared to the general population
    • Diffuse large B-cell lymphoma (DLBCL)
    • Primary effusion lymphoma (PEL)
    • Plasmablastic lymphoma
    • Primary CNS lymphoma
  • The specific cause of AIDS-Associated Lymphoproliferative Disorders is unknown. The presence of AIDS is a key risk factor associated with this condition
  • Manifestation of signs and symptoms occur due to AIDS and the organs and body systems involved due to lymphoproliferative disorders. It can also include enlarged lymph nodes, chronic infections, unexplained weight loss, severe fatigue, and anemia
  • The treatment is targeted at the whole body and systemic therapy, such as chemotherapy, may be provided. Treatment of AIDS is undertaken through HAART and antiretroviral therapy
  • The prognosis of AIDS-Associated Lymphoproliferative Disorders is generally poor, due to an aggressive nature of the condition, poor immune system of the patient, and complete involvement of the body systems and organs. However, early administration of HAART for AIDS has positively influenced the survival rate

General information on lymphoma and lymphocytes:

  • Lymphoma is a type of cancer stemming from uncontrollably dividing lymphocytes (type of white blood cells). There are two types of lymphomas:
    • Hodgkin lymphoma
    • Non-Hodgkin lymphoma
  • Lymphocytes are the main white blood cells found in the lymph, which is the fluid of the lymphatic system; just as blood is the fluid of the circulatory system. Lymphocytes are made in bone marrow, and can develop into either B-cells or T-cells
  • Lymph results from filtration of blood as it travels to and from tissues. Lymph is colorless because it lacks red blood cells; instead, it contains lymphocytes. It is central to the immune system
  • There are 3 different kinds of lymphocytes:
    • T-lymphocytes or T cells: They help combat infections and abnormalities within the cells (cell-mediated immunity). They fight viruses and cancerous cells
    • B-lymphocytes or B cells: They produce antibodies that are bodily defense proteins, which target foreign invaders outside the cells (humoral immunity). They fight bacterial cells, cell fragments, and other immunogenic elements
    • Natural killer cells or NK cells: They perform diverse functions related to both cell-mediated and humoral immunity. They also scout for cancer cells, a process called immune surveillance

Who gets AIDS-Associated Lymphoproliferative Disorders? (Age and Sex Distribution)

  • AIDS-Associated Lymphoproliferative Disorders occur in about 5-10% of AIDS patients
  • AIDS is more common in younger adults than other age groups due to their risky behaviors, such as multiple partners, usage of injectable drugs, etc.
  • The condition affects both males and females
  • All races and ethnic groups can be affected

What are the Risk Factors for AIDS-Associated Lymphoproliferative Disorders? (Predisposing Factors)

  • The primary risk factor for AIDS-Associated Lymphoproliferative Disorders is HIV infection resulting in AIDS. This leads to poor immune system in the affected individual

International Prognostic Index: According to some scientists, the International Prognostic Index may not be very helpful in evaluating AIDS-Associated LPDs. However, some scientists believe that it is helpful in some cases, to determine the prognosis.

The International Prognostic Index, for aggressive non-Hodgkin lymphoma, lists a few factors that determine the overall risk:

  • Age over 60 years
  • Elevated level of serum lactate dehydrogenase - LDH (a type of enzyme)
  • Performance status, i.e. the overall health condition of the individual, which could range from being fully active (low risk) to being completely disabled (very high risk)
  • Individual, who have already suffered from lymphoma, or other types of blood cancers, may have a relapse or a recurrence
  • Presence of an immunodeficiency syndrome, like AIDS, is a high-risk factor
  • Those infected with Epstein-Barr virus are also prone to the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of AIDS-Associated Lymphoproliferative Disorders? (Etiology)

Lymphocytes are a type of white blood cells that are responsible for providing immunity in the human body. B-cells and T-cells are the two different types of lymphocytes. When under certain circumstances, the lymphocytes grow and multiply abnormally, it leads to a condition called as lymphoma, which is a most common type of cancer. There are 2 types of lymphoma:

  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma

The definitive cause of AIDS-Associated Lymphoproliferative Disorders is currently unknown and is under research.

  • Some researchers believe that decreased immunity caused by AIDS (or advanced HIV infection) increases the chance of lymphocytes to become malignant
  • Nevertheless, according to current studies, HIV is not directly responsible for the formation of malignant cells

Also, there may be certain genetic defects, such as translocation, which is a juxtaposition of regions of the chromosomes. This may result in:

  • Change of regulatory elements of certain cancer-causing genes called as oncogenes, which can lead to increased production of their mRNA (overexpression), thus increasing their protein levels
  • Exchange of protein coding regions of gene, giving rise to new proteins that can stimulate the inappropriate growth of cells

It is believed that the abnormal development of lymphocytes gives rise to cancerous cells leading to the formation of this condition. Nevertheless, how this occurs and the factors that cause it remain under investigation.

What are the Signs and Symptoms of AIDS-Associated Lymphoproliferative Disorders?

The signs and symptoms of AIDS-Associated Lymphoproliferative Disorders may be subdivided into 2 categories - the one caused by AIDS and the other due to presence of the lymphoma. The exact signs and symptoms vary from one individual to another and depend on each individual’s specific circumstances and health parameters. Many individuals may have a combination of both.

The signs and symptoms associated with AIDS may include:

  • Presence of a variety of opportunistic infections (that could be viral, fungal, or bacterial) not normally observed in healthy individuals. These may include:
    • Pneumonia
    • Sinusitis
    • Skin infection
    • Tuberculosis
    • Yeast infection or thrush
    • Meningitis
    • Hepatitis
  • Severe loss of strength in different muscles in the body
  • Low lymphocyte count, established by a blood test
  • Peripheral neuropathy
  • Arthritis
  • Progressive multifocal leukoencephalopathy causing difficulty in speech, paralysis, and other symptoms
  • Certain cancers that may develop due to poor immunity such as Kaposi’s sarcoma or primary CNS lymphoma

The general signs and symptoms associated with lymphoproliferative disorders could include:

  • Enlarged lymph nodes; about 1 in 3 patients have involvement of the lymph nodes
  • Unintentional weight loss; changes in appetite
  • Fatigue and weakness, headache
  • High temperatures and excessive night sweats (may be recurrent)
  • Anemia (low red blood cell count)
  • Trouble breathing
  • Low blood pressure
  • Back pain
  • Swelling of the legs
  • Abdominal pain and swelling; constipation
  • Frequent urination

Depending upon the specific organ or area involved, the signs and symptoms may include:

  • There may be associated autoimmune disorders, which can cause joint and muscle pain, heat intolerance, recurrent rashes, abdominal pain, and a general feeling of illness
  • If the brain is involved, then neurological symptoms such as the following may be observed:
    • Confusion
    • Tinnitus (ringing in the ears)
    • Hearing and visual impairment
  • If the gastrointestinal (GI) tract is involved, then GI tract symptoms such as the following may be observed:
    • Ulcers
    • Diarrhea
    • Inflammation
    • GI bleeding
  • Liver and spleen enlargement
  • Joint inflammation and fluid accumulation (edema) can occur, if the joints are affected
  • The tumor can affect the bones and result in easy fractures
  • Presence of skin lesions on the body that can ulcerate and bleed

Note: There could be an involvement of several organs, such as the gastrointestinal tract, brain, bone marrow, liver, lung, and skin, along with their associated signs and symptoms.

How is AIDS-Associated Lymphoproliferative Disorders Diagnosed?

The following methods may aid in the study-diagnosis of AIDS-Associated Lymphoproliferative Disorders:

  • A thorough physical examination and a complete medical history
  • The presence of HIV infection can be diagnosed through blood tests including:
    • HIV ELISA (enzyme-linked  immunosorbent assay)
    • Western blot test
    • CD4 lymphocyte count
    • HIV RNA level (viral load test)
  • Blood tests to detect the presence of lymphoma in the body that include:
    • Complete blood cell count (CBC) blood test
    • Chemistry panel
    • Serum calcium levels
    • Serum lactodehydrogenase (LDH) level: High LDH levels may be seen
    • Serum albumin levels
    • Blood urea nitrogen (BUN)
    • Absolute lymphocyte count on peripheral blood
  • Since the lymphoma involves the lymph nodes, biopsies of enlarged lymph nodes are taken and examined in a lab to determine if the cells are malignant or benign. The biopsies may be performed under general or local anesthesia. Normally, the entire lymph node is removed to help determine the subtype of lymphoma
  • A biopsy may be obtained from the affected area (such as from the skin)
    • A biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
    • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
    • Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, flow cytometric analysis and very rarely, electron microscopic studies, to assist in the diagnosis
  • Radiological imaging may be performed to determine the extent of lymphoma in the body including:
    • X-ray of the affected region
    • Ultrasound scan of the affected region
    • Computerized tomography (CT) scan of the affected region
    • Vascular radiological studies
    • Whole body bone scan
    • Whole body CT-PET scans to determine how far the lymphoma has spread, by checking the size and metabolic rate (a reflection of uncontrolled growth) of lymph nodes, throughout the body. This can also help determine, if the cancer has spread to other organ systems
    • Brain MRIs are used if neurological symptoms are present, which can help determine if the cancer has spread to the brain, or to tissues that cover the brain
  • Bone marrow aspiration and biopsy is performed and sent to a laboratory for a pathological examination, to determine if the bone marrow is involved. Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, histochemical stains, molecular testing, and very rarely electron microscopic studies. However, a bone marrow biopsy is not needed in the early stages of the condition
  • Flow cytometry (analysis of blood and/or tissue) to identify cells as they flow through an instrument, called a flow cytometer. Flow cytometry measures the number and percentage of cells in a blood sample, and cell characteristics such as size, shape, and the presence of biomarkers on the cell surface. This method helps to sub-classify the condition and also to detect residual levels of disease after treatment. This tool can help in diagnosing relapse and restart treatment as needed
  • Fluorescence in situ hybridization (FISH): It is a test performed on the blood or bone marrow cells to detect chromosome changes (cytogenetic analysis) in blood cancer cells. The test helps in identifying genetic abnormalities that may not be evident with an examination of cells under a microscope
  • Immunophenotyping to identify a specific type of cell in a sample, which can help determine the best treatment course to be followed
  • Polymerase chain reaction (PCR): It is used to measure the presence of certain biomarkers in blood or bone marrow cells. The test is ultrasensitive and detects extremely low amounts of biomarkers remaining in blood, which can be missed by cytogenetic methods, such as FISH, karyotype, or flow cytometry. PCR allows a more sensitive follow-up of patients in remission and can help determine whether additional treatment is necessary
  • Tests to examine central nervous system (CNS) involvement, if any
  • GI endoscopy: It may be performed to assess the extent of tumor spread
  • Multigated acquisition (MUGA) scan or echocardiography to identify cardiotoxicity as a result of chemotherapy
  • Liver function test (LFT) and liver biopsy
  • Pulmonary function test (PFT)
  • Exploratory laparoscopy (diagnostic laparoscopy) may be required, if gastrointestinal symptoms are present. In this procedure, the abdomen is examined using a minimally-invasive technique, and a tissue biopsy and tissue for culture obtained. Minimally-invasive approaches help decrease complications and the length of stay at the hospital. A diagnostic laparoscopy is also helpful in staging of the tumor. Nevertheless, this procedure is not very much used

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of AIDS-Associated Lymphoproliferative Disorders?

The complications of AIDS-Associated Lymphoproliferative Disorders may be due to AIDS or lymphoproliferative disorders or a combination of both. It could involve the following:

The complications due to AIDS may include:

  • Dementia, polyneuropathy
  • Coronary artery disease
  • Stroke
  • Cancer
  • Severe and recurrent infections
  • Treatment-related complications may include Cushing’s disease, metabolic syndrome, and abnormal fat deposition

The complications due to lymphoproliferative disorders may include:

  • Involvement of local and distant organs and loss of function of the organ/area to which the cancer has spread
  • Weakened immune system (or immunosuppression) that can become more severe during treatment. Due to this, individuals are more vulnerable to infections; there is an increased risk of developing serious complications from such infections
  • If the condition spreads to the brain and central nervous system, it can give rise to:
    • Inflammation of the meninges or brain (that can be lethal)
    • Vision changes
    • Facial numbness
  • If the abdomen is affected, it can cause intestinal obstruction that results in urine outflow obstruction and kidney damage
  • Blood loss may occur due to frequent or heavy bleeding, giving rise to severe anemia
  • The leukemic cells can overgrow and cause clogging of vessels resulting in stroke, or blurring of vision

There may be complications related to chemotherapy used in treating the condition, which may include:

  • Side effects such as dizziness, vomiting, appetite loss, mouth ulcers, and hair loss
  • By damaging healthy cells, the individual is more open or vulnerable to secondary infections
  • The treatment can also cause infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy
  • Tumor lysis syndrome: This can occur due to chemotherapy treatment and can result in kidney failure, if not recognized promptly

How is AIDS-Associated Lymphoproliferative Disorders Treated?

AIDS-Associated Lymphoproliferative Disorders are a group of aggressive cancers that require prompt treatment for systemic signs and symptoms following its diagnosis. Once a definitive diagnosis has been made, staging is used to describe how far the cancer has spread. The stage can help describe:

  • How many lymph nodes are affected
  • Their locations in the body
  • And, if other organs are being affected

Staging is important because different treatment regimens are necessary, depending on the progression of the lymphoma. These may be classified as:

  • Stage 1: Only one group of lymph nodes in one location is affected
  • Stage 2: Lymph nodes in multiple locations that are all above or below the diaphragm are affected
  • Stage 3: Lymph nodes in multiple locations, both above and below the diaphragm are affected
  • Stage 4:  Lymph nodes located throughout the body, the bone marrow, and other organs are affected

Treatment for HIV infection and AIDS may be undertaken through the following measures:

  • Antiretroviral therapy to suppress the multiplication of the virus in the body
  • HAART or highly-active antiretroviral therapy: It employs a combination of two different classes of anti-retroviral medications. HAART has proven to be very effective in addressing this immunodeficiency disorder caused by a virus

Systemic therapy is generally required for malignant and advanced stage tumors. A combination of treatment measures may be effectively used to treat the condition. It may include the following:

  • Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells and can be used in patients, for all stages of the cancer
    • There can be severe side effects including fatigue, nausea, hair loss, anemia, high risk of infection, and drug-specific reactions
    • Many T-cell lymphomas can be resistant to chemotherapy. It can also damage healthy cells
    • Chemotherapy can be administered as a pill, liquid, shot, or intravenously

Note: Men and women in child-bearing age would greatly benefit from counseling regarding fertility issues. Some chemotherapy agents can cause infertility in both men and women. There can be permanent damage to the testicles and ovaries, harming their ability to produce sperms or ova. In men, sperm banking can be considered before initiating therapy. In women, in many cases, due to urgency of starting chemotherapy, it is often difficult to perform ovum banking. However, if there is sufficient time prior to chemotherapy, ovum banking may be performed. The healthcare provider may help assess the risk-benefit analysis, depending upon each individual’s specific circumstances.

  • Radiation: Radiation therapy is the use of high-energy radiation waves to kill cancer cells, by destroying their DNA
    • This treatment modality is generally used for early stage lymphomas. It is most commonly used in combination with chemotherapy
    • The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body
    • The side effects of radiation therapy include nausea, vomiting, fatigue, pain, risk of cancer later in life, and risk of heart disease
    • Radiation can damage healthy cells in addition to cancer cells, causing further complications
  • Intrathecal chemotherapy, if there is an involvement of the brain
  • Supportive treatment: Steroids, blood transfusions, anti-nausea medications, and antibiotics, may be used as supportive therapy. In combination with other treatment measures, these can help combat the symptoms of immunodeficiency, on a case-by-case basis

If AIDS-Associated Lymphoproliferative Disorders are not fully responsive to treatment, or if the chance of recurrence is high, then bone marrow transplantation or stem cell transplantation can be considered depending on each individual’s specific circumstances. Generally, these procedures may be undertaken if the patient is relatively younger.

  • Bone marrow transplantation: Typically systemic cases may be treated by administering high doses of chemotherapy or radiotherapy. But, high doses of chemotherapy drugs will also damage the bone marrow, preventing it from making any blood cells. Hence, before starting high-dose chemotherapy, the physicians may take out some of the patient’s bone marrow and freeze/preserve it. Collecting the bone marrow is called a bone marrow harvest. The bone marrow is then stored. After high dose chemotherapy or radiation, the bone marrow is thawed and injected back into patient through a drip (transfusion). This is called an autologous bone marrow transplant. Sometimes bone marrow donated by another matching person (usually a brother or sister) is used, if the condition recurs following transplant using one’s own cell. This is called as allogeneic bone marrow transplant
  • Stem cell transplantation: This procedure is similar to bone marrow transplantation and involves the transplantation of healthy blood-forming stem cells into the body. The procedure is also called hematopoietic progenitor cell transplantation. Stem cells can be collected from the bone marrow, circulating (peripheral) blood, and umbilical cord blood. It may either involve an autologous stem cell transplantation, where stem cells are harvested from individuals before treatment and transplanted back into the patient after treatment, or involve an allogeneic stem cell transplantation, where stem cells donated by another matching person (usually a brother or sister) is used, if the condition recurs after stem cell transplant using one’s own cell. This is called as allogeneic stem cell transplant

Note: Allogeneic bone marrow and allogeneic stem cell transplants may have more side effects and complications, and this treatment may not be suitable for every individual. If allogeneic transplants come from a healthy donor with no malignant cells, then the chances of recurrence of the condition may be reduced.

  • In order to prevent infections because the immune system is weakened by AIDS-Associated LPDs or by its treatment, the patient is kept in an isolated ward and treated with appropriate antibiotics
  • Nowadays, targeted therapies are being developed, that can selectively kill the lymphoma/leukemia cells. Many of them are in the stage of clinical trials
  • Clinical trials: There may be some newer treatment options, currently on clinical trials, which can be considered for some patients depending on their respective risk factors

Your healthcare provider will determine the best course of treatment depending on your individual circumstances. Also, follow-up care with regular screening and check-ups are important post-treatment.

How can AIDS-Associated Lymphoproliferative Disorders be Prevented?

AIDS-Associated Lymphoproliferative Disorders are influenced by the presence of AIDS. Following longstanding HIV infection that develops to AIDS, an individual becomes vulnerable to various infections and cancers including lymphoproliferative disorders.

Hence, by preventing HIV infection and AIDS, one can avoid the associated disorders. This can involve the following measures:

  • Safe sex practices including the use of latex condoms with a water-soluble lubricant, every time during sex
  • Maintaining long-term monogamous relationships and avoiding multiple sexual partners
  • Avoiding needle sharing practices, especially with individuals who have a habit of intravenous drug abuse
  • Routine HIV testing and counseling for individuals between the ages of 15 and 65 years
  • Routine HIV testing in expectant mother
  • Routine screening of blood and organ donors, transfusion products, etc.
  • HIV-positive individuals should be encouraged to talk about their status to their partners
  • HIV-positive mothers should avoid breastfeeding their baby to prevent transmission
  • HIV-positive individuals can decrease the transmission to uninfected partners, if they are on antiretroviral therapy
  • In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, etc. should be well-documented and follow-up measures initiated

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, are mandatory. Often several years of active vigilance are crucial and necessary.

What is the Prognosis of AIDS-Associated Lymphoproliferative Disorders? (Outcomes/Resolutions)

  • AIDS-Associated Lymphoproliferative Disorders are malignant cancers with generally high mortality rates. However, their incidence has decreased after the development of antiretroviral treatment
  • The prognosis depends upon the administration of highly-active antiretroviral therapy (HAART). This treatment regimen has greatly increased the survival outcome. A complete remission is possible if timely HAART treatment is given
  • The prognosis is generally poor with respect to the following factors:
    • In the absence of HAART treatment
    • In IV drug users
    • Individuals with less CD4 count have poorer prognosis than those with greater CD4 count
  • AIDS-Associated LPD outcomes also depend upon the subtype of lymphoma associated with the condition. Generally, diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma (PEL) have poorer prognosis than other subtypes
  • The prognosis depends upon a set of several factors, which include:
    • Stage of tumor: With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
    • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
    • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
    • Degree of immunosuppression: The higher the degree of immunosuppression, the poorer is the prognosis
    • The size of the tumor: Individuals with small-sized tumors fare better than those with large-sized tumors
    • Individuals with bulky disease have a poorer prognosis: At the time of diagnosis, most patients have high tumor burden (bulky disease)
    • Involvement of vital organs may complicate the condition
    • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
    • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
    • Progression of the condition makes the outcome worse (progressive condition)
  • An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
  • The combination chemotherapy drugs used, may have some severe side effects (such as cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor
  • Progression to bone marrow failure is usually associated with short survival

Additional and Relevant Useful Information of AIDS-Associated Lymphoproliferative Disorders:

  • Treatment for AIDS-Associated Lymphoproliferative Disorders can cause physical and emotional distress; supportive care and encouragement, help positively and can bring a measure of relief to the patients

The following article link will help you understand leukemia and lymphoma (blood cancer):

http://www.dovemed.com/diseases-conditions/leukemia-and-lymphoma/

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