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Hairy Cell Leukemia

HCL

Hairy cell leukemia (HLC) is a rare, chronic form of B-lymphocytic leukemia.

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Presentation

Patients usually present on diagnosis with pancytopenia, splenomegaly, and circulating hairy cells [4]. All the signs and symptoms of hairy cell leukemia are the result of the proliferation of the abnormal white blood cells. All of the symptoms are reversible by reducing the number of malignant cells [5].

Signs and symptoms include the following [5] [7]:

The cause of hairy cell leukemia is not known, however exposure to toxic chemicals, radiation, and wood dust have been implicated. The mechanism involved in the development of the abnormal hairy leukocytes is as yet unknown.

Splenomegaly
  • Also these cytokines may play a role in the development of hairy cell leukemia.Key words: hairy cell leukemia -  sarcoidosis - massive splenomegaly.[ncbi.nlm.nih.gov]
  • It typically affects middle-aged to elderly male who present with pancytopenia and massive splenomegaly. Lymphadenopathy is usually not seen.[ncbi.nlm.nih.gov]
  • We present the case of a 67-year-old Taiwanese male with HCL-v who had leukocytosis and splenomegaly. His hairy leukemic cells were weakly positive for TRAP and expressed CDllc and CD103 but not CD25.[ncbi.nlm.nih.gov]
  • In most cases splenomegaly is a presenting sign. The goal of therapy in hairy cell leukemia is to decrease the risk of infection and other serious complications.[symptoma.com]
  • A 47-year-old woman with pancytopenia, excessive systemic lymphadenopathy and splenomegaly was referred to our hospital.[ncbi.nlm.nih.gov]
Massive Splenomegaly
  • Also these cytokines may play a role in the development of hairy cell leukemia.Key words: hairy cell leukemia -  sarcoidosis - massive splenomegaly.[ncbi.nlm.nih.gov]
  • It typically affects middle-aged to elderly male who present with pancytopenia and massive splenomegaly. Lymphadenopathy is usually not seen.[ncbi.nlm.nih.gov]
  • Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly.[ncbi.nlm.nih.gov]
  • Definition / general Rare chronic leukemia that commonly presents with massive splenomegaly, with tumor cells containing hair-like projections Terminology Formerly known as leukemic reticuloendotheliosis Clinical features Mean age 52 years, range 20 -[pathologyoutlines.com]
  • The decision to treat is based on symptomatic cytopenias (low blood counts), massive splenomegaly (enlarged spleen), or the presence of other complications.[lymphomation.org]
Abdominal Lymphadenopathy
  • Rarely there is marked abdominal lymphadenopathy due to infiltration by large hairy cells. Recurrent opportunistic infections, vasculitis and immune dysfunction are common.[e-immunohistochemistry.info]
  • The frequency and significance of intra-abdominal lymphadenopathy have not been extensively defined, although one report suggested that lymphadenopathy correlated with overall survival. 8 Multiple investigators have found that age and hemoglobin level[bloodjournal.org]
  • ., et at Incidence and significance of abdominal lymphadenopathy in hairy-cell leukaemia (abstract). Blood, 1993;82.2273. 16. Seshadri, R. Brown, E. and Zipursky, A. Leuksemic reticuloendotheliosia. A failure of monocyte prodoction.[jpma.org.pk]
Generalized Lymphadenopathy
  • Hepatomegaly was seen in 28% cases; less than that reported in other studies. [11] , [12] Though uncommon, lymphadenopathy was seen in six cases, two patients had abdominal nodes detected on CT scan, while one patient had generalized lymphadenopathy,[ijpmonline.org]
Lymphocyte Disorder
  • Hairy cell leukemia: a B-lymphocytic disorder derived from splenic marginal zone lymphocytes? Blut 1985; 50:191–194. 27 . Chung SS, Kim E, Park JH, et al. Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia.[journals.lww.com]
Anemia
  • Hairy cell leukemia (HCL) is occasionally misdiagnosed as aplastic anemia when only a few leukemic cells are present in the circulation.[ncbi.nlm.nih.gov]
  • If the patient has significant cytopenia and its related problems: anemia, infections or bleeding, and/or significant splenomegaly, treatment should be started immediately.[symptoma.com]
  • The differential diagnosis of leukemia includes other neoplastic hematopoietic disorders, such as lymphoma, myelodysplastic syndromes, multiple myeloma, aplastic anemia, severe megaloblastic anemia, severe lymphocytosis, severe monocytosis, and bone marrow[ncbi.nlm.nih.gov]
  • We are reporting a 4-year-old child who was received for investigation for persistent anemia, prolonged fever, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Hairy cell leukemia typically presents with pancytopenia and often mimics aplastic anemia.[ncbi.nlm.nih.gov]
Fatigue
  • Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections.[ncbi.nlm.nih.gov]
  • During interferon-α therapy she developed multiple subcutaneous swellings, accompanied by fever and fatigue. A skin biopsy revealed lobular, T-cell lymphocytic panniculitis.[ncbi.nlm.nih.gov]
  • Twenty-five years later, the patient presented with weight loss, fatigue, and a large PET-avid mass surrounding the head of the pancreas.[ncbi.nlm.nih.gov]
  • A 65 years old man was admitted with multiple lymphadenopathy, weight loss, night sweats and fatigue for 2 months. He had been treated for bladder cancer 2 years ago. Leukocyte count was 37.9 x10(9)/l. Peripheral blood smear had 91% lymphocytes.[ncbi.nlm.nih.gov]
  • The low blood counts caused by hairy cell leukemia can lead to: Infections Fatigue Excessive bleeding Call your provider if you have major bleeding.[medlineplus.gov]
Weight Loss
  • Twenty-five years later, the patient presented with weight loss, fatigue, and a large PET-avid mass surrounding the head of the pancreas.[ncbi.nlm.nih.gov]
  • A 65 years old man was admitted with multiple lymphadenopathy, weight loss, night sweats and fatigue for 2 months. He had been treated for bladder cancer 2 years ago. Leukocyte count was 37.9 x10(9)/l. Peripheral blood smear had 91% lymphocytes.[ncbi.nlm.nih.gov]
  • Weight Loss Surgery is a Big Decision Our specialists provide the expertise and support you need to reach your weight loss goals.[uhhospitals.org]
  • A 36-year-old man presented with abdominal discomfort, frequent gum bleeding and significant weight loss for 2 months.[ncbi.nlm.nih.gov]
  • Some hairy cell leukemia symptoms include the following: an uncomfortable or "full" feeling in the upper left part of the abdomen, easy bruising, fatigue, weakness, unexpected weight loss, and recurring infections with fever and chills.[cancercenter.com]
Lymphadenopathy
  • A 47-year-old woman with pancytopenia, excessive systemic lymphadenopathy and splenomegaly was referred to our hospital.[ncbi.nlm.nih.gov]
  • Lymphadenopathy is usually not seen.[ncbi.nlm.nih.gov]
  • Although considered uncommon, a number of unusual clinical presentations have been noted in the literature, including the presence of peripheral lymphadenopathy, lytic bone lesions, skin involvement, organ involvement, and central nervous system involvement[ncbi.nlm.nih.gov]
  • This chronic lymphoproliferative disorder is not typically associated with lymphadenopathy or mass lesions. We report a case of HCL first treated by splenectomy, followed by several years of interferon therapy.[ncbi.nlm.nih.gov]
  • A 65 years old man was admitted with multiple lymphadenopathy, weight loss, night sweats and fatigue for 2 months. He had been treated for bladder cancer 2 years ago. Leukocyte count was 37.9 x10(9)/l. Peripheral blood smear had 91% lymphocytes.[ncbi.nlm.nih.gov]
Recurrent Infection
  • Patients require treatment when they have significant cytopenia or recurrent infections.[ncbi.nlm.nih.gov]
  • Treatment may be advised for HCL patients with low blood cell counts, recurrent infections, or an enlarged spleen or lymph nodes. Treatment is most often with chemo using one of the purine analog drugs -- either cladribine (2-CdA) or pentostatin.[cancer.org]
  • These include weight loss , fatigue , easy bruising, anemia and recurrent infections. Treatment of hairy cell leukemia involves chemotherapy , immunotherapy , surgery and targeted therapy. Accurate diagnosis is critical for effective treatment.[medindia.net]
  • Complications include recurrent infections, bleeding, anemia and splenic rupture. Etiology Etiology is unknown.[orpha.net]
Hepatomegaly
  • Hepatomegaly and liver dysfunction may be found in 20% of patients. Approximately 30% of patients diagnosed with hairy cell leukemia develop secondary cancers during or following treatment for the disease.[symptoma.com]
  • No hepatomegaly or lymphadenopathy was detected.[ncbi.nlm.nih.gov]
  • Hepatomegaly with mild liver dysfunction is found in 20% of cases and lymphadenopathy is found in 10% of cases. Complications include recurrent infections, bleeding, anemia and splenic rupture. Etiology Etiology is unknown.[orpha.net]
  • […] with filamentous, hair-like projections tartrate-resistant acid phosphatase (TRAP ) Presentation Symptoms pancytopenia from infiltration of bone marrow fatigue infections bleeding anemia Physical exam splenomegaly from infiltration of spleen may see hepatomegaly[step2.medbullets.com]
  • Physical examination revealed splenomegaly in most patients (92%) and hepatomegaly in a minority (28%).[ijpmonline.org]
Hepatosplenomegaly
  • Abdominal discomfort is a common symptom, resulting from hepatosplenomegaly. Splenomegaly is present in virtually all cases, and is classed as massive in more than 80% of cases.[orpha.net]
  • The major clinical manifestations of malaise, hepatosplenomegaly, anemia, and leukocytosis are related to abnormal, excessive, unrestrained overgrowth of granulocytes in the bone marrow.[medical-dictionary.thefreedictionary.com]
  • The criteria for CR were similar in both treatment cohorts and included : ( a ) absolute granulocyte count 1,500/μl, hemoglobin 12 g/dl, and platelet count 100,000/μl; ( b ) absence of adenopathy or hepatosplenomegaly; and ( c ) complete absence of hairy[clincancerres.aacrjournals.org]
Purpura
  • Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia purpura (ITP) can also be observed. 7 Indicators to initiate therapy include fatigue and weakness that interfere with quality of life, symptomatic organomegaly, frequent infections, and signs[hematologyandoncology.net]
  • Severe immune thrombocytopenic purpura and hemolytic anaemia in a hairy-cell leukaemia patient . Eur J Haematol 1995; 54 : 127–129. 7. Mainwaring CJ , Walewska R , Snowden J , Winfield DA , Ng JP , Chan-Lam D et al .[nature.com]
  • Hemorrhagic manifestations, such as purpura and echymoses, caused by severe thrombocytopenia with peripheral blood plasma platelet counts of less than 80,000/mm 3 , are found in about 20% of patients (2) .[scielo.br]
Cutaneous Manifestation
  • However, data regarding the treatment of these cutaneous manifestations are lacking, given the rarity of the concomitance of HCL and vasculitic syndromes.[ncbi.nlm.nih.gov]
  • In addition, patients may present with cutaneous manifestations, such as herpes zoster, cellulitis, abscess, pyoderma, dermatophytosis, leukemia cutis, ecchymosis, and purpura. 7 Laboratory findings may reveal leukopenia, neutropenia, monocytopenia, anemia[hematologyandoncology.net]

Workup

Patients may be asymptomatic and the disease is only identified when a complete blood count is done for an unrelated complaint [7]. Most symptomatic patients present with complaints of fatigue, bruising, and abdominal pain. Other patients are seen initially for infections due to cytopenia [7].

Hairy cell leukemia is suspected initially when the abnormal hairy cells are present in the peripheral blood. Diagnosis is confirmed by demonstration of hairy cells in biopsy specimens from the bone marrow or spleen or in peripheral blood [9]. Bone marrow aspiration and the presence of the abnormal cells is the least invasive means of making a definitive diagnosis [1]. However, bone marrow aspiration is often impossible because of fibrosis of the marrow. Bone marrow biopsy is then the method of choice and the final step in confirming the diagnosis [1].

Diagnostic tests include [7]:

  • Peripheral blood smear
  • Bone marrow biopsy
  • Immunohistology to exclude other B-cell leukemia
  • Monoclonal antibody panel
  • Computed tomography of splenomegaly and hepatomegaly

The most consistent laboratory finding is cytopenia, usually affecting all three types of blood cells: red cells, white cells, and platelets [7]. Physical examination may show significant signs of anemiapale skin and mucosa, elevated pulse and respiratory rate, fatigue and exercise intolerance. In most cases splenomegaly is a presenting sign.

Decreased Platelet Count
Staphylococcus Aureus
  • In our case, the skin lesion was surgically removed and then left to heal by secondary intention due to the presence of bacterial infection by Staphylococcus aureus and Streptococcus pyogenes.[ncbi.nlm.nih.gov]
Dry Tap Bone Marrow
  • Practitioners should beware of erroneous diagnosis of aplastic anemia owing to a dry-tap bone marrow aspirate with hypocellular bone marrow.[online.epocrates.com]

Treatment

The goal of therapy in hairy cell leukemia is to decrease the risk of infection and other serious complications [10]. Hairy cell leukemia is diagnosed based on the presence of the characteristic malignant white blood cells called hairy cells in the bone marrow. It is important to exclude other leukemia which present the same but require different treatment.

Once the diagnosis has been made the first determination to be made is if treatment is required at the time. Since all treatment modalities are associated with some side effects deferring treatment until the patient is symptomatic seems appropriate [6] [7]. If the patient has significant cytopenia and its related problems: anemia, infections or bleeding, and/or significant splenomegaly, treatment should be started immediately [7]. 

Currently the initial treatment of choice are Purine analogues (nucleosides) and/or Interferon A. Both are effective treatment regimes, but nucleosides are the first line of treatment because they have a higher complete remission rate [6] [9]. However, there are still instances where Interferon therapy is indicated [9] [11] [12].

Splenectomy was the recommended treatment for hairy cell leukemia until the mid-1980s. The efficacy of splenectomy on survival of patients has not been demonstrated [10]. In the past three decades, three very effective therapies have been approved for use with this disease: Interferon Alfa, pentostatin, and cladribine [4]. Splenectomy is rarely performed currently except in cases of profound splenomegaly or excessive blood burden [4] [11] [12].

Pentostatin and cladribine are the two most commonly used Purine analogues [7] [9] [11] [12]. Studies have shown that a single courses of cladribine orpentostatin administered to patients with hairy cell leukemia have high response rates with a majority of patients achieving complete responses. Most patients then go on to long-lasting complete remissions. These rates have been recorded as high as 90-95%. Patients, approximately 30%, who relapse, may be re-treated successfully with repeat treatment [4] [9] [11] [12].

Alpha-interferon has a complete remission rate of 86 % [9]. Interferon Alfa alone or in conjunction with one of the Purine analogues is indicated in patients with infections at diagnosis. Studies indicate that its inclusion in the treatment regime may increase the survival rate patients with advanced diesease. How this works is unclear [10].

Growth factors such as Granulocyte colony-stimulating factor (G-CSF) may be used in hairy cell leukemia to treat severe neutropenia. It can be given before, during and/or after treatment with a Purine analogue. Its routine use is not recommended [7].

Long-term follow-up with repeat bone marrow biopsy is necessary in order to detect relapse or residual disease early [1]. Relapse has been reported in about 30% of patients. These cases respond well to retreatment with the drugs used in initial therapy (92%) [8].

Prognosis

Follow-up studies have shown a complete remission rate of approximately 95% and a partial response rate of 5%. These rates were often achieved after a single course of treatment [4]. About 37% of treated patients experienced relapse after their first course of treatment. The time to relapse had a median of 42 months [4].

There is no clear guidelines to predict the progress of the disease. Since hairy cell leukemia primarily affects bone marrow and spleen and progresses slowly, prognosis depends on status of both these organs [7].

The response to purine analogue therapy is also a predictor of patient outcome. Those achieving complete remission did better than those with only partial response.  For this reasons, the goal of treatment is achieve a complete remission [7].

The complications of hairy cell leukemia are primarily responsible for the morbidity and mortality associated with the disease. These complications include:

Complications associated with hairy cell leukemia are due to interruption in the production of normal blood cells. Anemia occurs with low red cell production. Decreased white cell production increases the risk of infection. Low platelet counts result in bleeding or excessive bruising. Abdominal pain and potential splenic rupture are complications resulting from splenomegaly which is present in almost all cases. Hepatomegaly and liver dysfunction may be found in 20% of patients [1] [2].

Approximately 30% of patients diagnosed with hairy cell leukemia develop secondary cancers during or following treatment for the disease [4].

Etiology

The symptoms seen in hairy cell leukemia are due to the proliferation of malignant B cell leukocytes that infiltrate the cells of bone marrow, resulting in bone marrow failure [1] [4].

All leukemias result from the proliferation immature of blood cell that are not functional. They do not then allow adequate production of normal erythrocytes, lymphocytes, granulocytes, and platelets. This pancytopenia results in severe anemia, life-threatening infection, bleeding, and the possibility of secondary malignancies [5]. Hairy cell leukemia was first described by Bouroncle, et al. in 1958 [9]. Hairy cell leukemia differs from other in two aspects: the presence of the distinctive hairy cells and the fact that it is the most treatable of all the blood malignancies [6].

The progression varies from patient to patient. Some patients may need no treatment; the majority (> 90 %) have complete remissions; some have chronic symptoms for many years; while still others die early from complications [5].

Epidemiology

The annual incidence has been estimated to be approximately 1 in 500,000. It is a rare disorder accounting for only 2% of all leukemia cases. It affects men five times more often than women (5:1 incidence) and occurs most commonly in middle-age or older adults (average age of onset is 50 years) [7].

Race

Hairy cell leukemia is seen more often in Caucasians and Ashkenazi Jewish males. It is rare in those of Japanese and African descent [8].

Sex

Hairy cell leukemia occurs most often in males, with a male-female ratio of 5 to 1 [8].

Age

Hairy cell leukemia occurs most often in middle-aged men, with a median age of 52 years [8].

Sex distribution
Age distribution

Pathophysiology

HCL is a rare, highly treatable, chronic B-cell leukemia. They disorder is distinguished by the presences of malignant white blood cells called hairy cells because of their characteristic appearance. These cells also possess a rare acid phosphatase enzyme (tartrate-resistant acid phosphatase (TRAP)) which acts as a useful marker for the disease [1] [6].

The abnormal cells proliferative slowly, so that symptomatology results from an abnormally prolonged cell survival rate [12]. The effect of the accumulation of hairy cells on the other blood cell types is pancytopenia. The etiology of this is unclear [6].

The distinctive biological features include [6]: 

  • Monocytopenia
  • Distinctive tissue distribution
  • Distinctive patterns of tissue remodeling

In hairy cell leukemia all types of blood cells are affected resulting in:

Unlike other lymphoid disorders, hairy cell leukemia has distinctive tissue distribution [6]:

  • Hairy cells do not infiltrate lymph nodes.
  • The spleen is more often involved and the pattern of splenic involvement is distinctive.
  • Hairy cells also accumulate in the liver, without hepatomegaly

Hairy cell leukemia also has a distinctive pattern of bone marrow fibrosis

Prevention

Since the cause of hairy cell leukemia is not known, ways to prevent the disease are not clear. Some toxic chemicals and radiation have been implicated in the incidence of the disorder. Avoidance of these environmental substances may prevent the disease. 

Summary

Hairy cell leukemia (HLC) is a chronic form of B-lymphocytic leukemia in which the predominant feature is the presence of characteristic malignant white blood cells [1] [2]. These cells are named hairy cells because of protrusions on the surface of the cells that appear hair like [1]. These malignant cells infiltrate the bone marrow, spleen, peripheral blood, and, occasionally, the liver [3]. The primary symptoms are anemia, pancytopenia, and splenomegaly [4].

Hairy cell leukemia is a rare disorder, accounting for only 2% of all cases of leukemia [1] [4]. It is a very treatable form of blood malignancy. Its diagnosis and differentiation from other forms of leukemia is of prime importance so that appropriate treatment is instituted as soon as possible.

The etiology of hairy cell leukemia is not known. But exposure to chemicals and radiation has been implicated. The highest incidence of Hairy cell leukemia is seen in middle-aged men [3]. It is five times as prevalent in men as in women [3] [4]. With chemotherapy complete remission occurs in about 90% of patients. The disease may be mild and slowly progressive so that patients do not need treatment. Complications include recurrent and life threatening infections, severe anemia, bleeding, and ruptured spleen.

Patient Information

What is hairy cell leukemia?

Hairy cell leukemia is a rare, highly treatable form of leukemia, blood cell cancer. Leukemia is a blood disorder where abnormal white blood cells are produced instead of normal cells. The malignant cells in this disease are called hairy cells because of the hair-like protrusions on the surface of the cell. In hairy cell leukemia the abnormal cells also interfere with the production of all blood cell types, red blood cells, white blood cells, and platelets.

What are the symptoms?

The symptoms are the result of the suppression of normal blood cells. They include:

What causes hairy cell leukemia?

The cause of hairy cell leukemia is not known. Exposure to toxic chemicals and radiation have been suspected but not proven to cause the disease.

Who gets hairy cell leukemia?

Anyone can get hairy cell leukemia, however it occurs most often in middle aged or elderly Caucasian men. The mean age at diagnosis is 50 years. The incidence in men is 5 times as high as in women.

How is it diagnosed?

Diagnosis is based on the results of the physical examination, blood tests, bone marrow biopsy and CT scan. The initial suspicion may occur with a routine blood test. Confirmation is based on the presence of characteristic malignant white blood cells called hairy cells in the bone marrow.

How is hairy cell leukemia treated?

Hairy Cell leukemia can be treated with intravenous medications that interfere with the production of the abnormal cells. Complete remission occurs in nearly 90% of patients. Usually only one course of treatment is necessary. However relapse occurs in approximately 30% of patients. Relapse can be treated with another course of treatment with a 90% success rate.

What are the complications?

The complications of hairy cell leukemia are due to the decrease in the production of normal blood cells. They include:

References

Article

  1. Lee WF, Beckstead JH. Hairy Cell Leukemia with Bone Marrow Hypoplasia. American Cancer Society. 0008-543X/82/ 1 1 1512207 pp.2207-2210.
  2. Said JW, Pinkus GS. Immunologic characterization and ultrastructural correlations for 125 Cases of B- and T-cell leukemias: Studies of chronic and acute lymphocytic prolymphocytic lymphosarcoma. American Cancer Society.  0008-543X/81/1215/pp. 2630-2643.
  3. Henderson ES, Han T. Current therapy of acute and chronic   leukemiain adults. Cancer Journal For Clinicians. Vol 36. No 6 Novemberdecember1986, 322-351.
  4. Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol. Mar 1 2003;21(5):891-6.
  5. Vardiman JW, Harris NL, Brunning. Classification of the myeloid neoplasms. The World Health Organization (WHO) October 1, 2002; Blood: 100 (7).
  6. Cawley JC. Hairy-cell leukaemia: biology and management.  British Journal of Haematology, 1999, 106, 2-8.
  7. Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D.  Revised guidelines for the diagnosis and management of hairycell leukaemia and hairy cell leukaemia variant.British Journal of Haematology, 156, 186–195
  8. Cannon T, Mobarek D, Wegge J, Tabbara IA. Hairy cell leukemia:current concepts. Cancer Invest. Oct 2008;26(8):860
  9. Jaiyesimi IA, Kantarjian HM, Estey EH. Advances in therapy for Hairy Cell Leukemia. CANCER July 2, 2993, Volume 72, No. 1, 5=17.
  10. Glaspy JA, Jacobs AD, Golde DW. Evolving Therapy of Hairy Cell Leukemia. Cancer 59:652-657, 1987.
  11. Zinzani PZ,  Magagnoli M, Bendandi M, Tani M, Stefoni V, Cellini C, Poggi C, Piccioli M, Pileri S, Tura S. Malignant Lymphomas : Longterm follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine. Haematologica 2000; 85:922-925.
  12. Ng JP, Nolan B, Chan-Lam D, Coup AJ, McKenna D. Successful treatment of aplastic variant of hairy-cell leukaemia with deoxycoformycin. Hematology. Aug 2002;7(4):259-62.  

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Last updated: 2018-06-22 04:58