Non-Hodgkin lymphoma - Biomed PDF

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Summary

Non-Hodgkin lymphoma Definition and PathogenesisNon-Hodgkin's lymphoma is cancer that originates in your lymphatic system, the disease- fighting network spread throughout your body. In non-Hodgkin's lymphoma, tumours develop from lymphocytes — a type of white blood cell. Non-Hodgkin lymphoma is cau...

Description

Non-Hodgkin lymphoma  Definition and Pathogenesis Non-Hodgkin's lymphoma is cancer that originates in your lymphatic system, the diseasefighting network spread throughout your body. In non-Hodgkin's lymphoma, tumours develop from lymphocytes — a type of white blood cell. Non-Hodgkin lymphoma is caused by a change (mutation) in the DNA of a type of white blood cell called lymphocytes. Non Hodgkin lymphoma originates 85% from B cells but 15% also originates from T cell or NK cells Subtypes of Non- Hodgkin’s lymphoma: -

Diffuse large B-cell lymphoma (DLBCL): This is also known as high grade and is the most common form of lymphoma. About 30% of NHL in the United States is this type. It is an aggressive form of NHL that involves organs other than the lymph nodes about 40% of the time. About 2 out of 3 people with DLBCL are cured with chemotherapy given in combination with rituximab (Rituxan). Radiation therapy is also used for some patients, especially if the lymphoma is found in a limited area.

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Follicular lymphoma: known as low grade 20% of people with NHL have this subtype. It usually begins in the lymph nodes, is most often indolent, and grows very slowly. People with early, stage I follicular lymphoma may be cured with radiation therapy. For some, bone marrow/stem cell transplantation may cure the disease. Patients with follicular lymphoma may receive a combination of chemotherapy; monoclonal antibodies, a type of targeted therapy; and/or radiation therapy. Low grad has a characteristic of being indolent, it response well to treatment but very difficult to cure.

 Pathology: - There is cytogenetic abnormalities in IgG genes due to translocation in chromosome 2, 14 and 22 being overexpressed. E.g. follicular lymphoma where there is translocation t (14;18)q(32;q21) which continuously express BCL2 - B cells of patients with non-Hodgkin's lymphoma (B-NHL) harbour specific chromosomal translocations, including t (14; 18), the most common aberration found in this disease. The translocation involves the immunoglobulin (Ig) heavy-chain joining (JH) region gene on chromosome 14 and the BCL2 gene on chromosome 18, resulting in dysregulated expression of the BCL2 gene. The t (14; 18) translocation has been thought to occur in the pre-B-cell stage, during the first event of Ig gene rearrangement.  Clinical manifestations Clinical manifestations of Non-Hodgkin’s lymphoma are: -

Superficial lymphadenopathy (painless enlargement) Sore throat Other constitutional symptoms like night sweat, body temperature of above 38°C Infections Splenomegaly and enlarged liver

 Diagnostic work up - Biopsy of the lymph nodes or other involved tissue Assist by -

Flow cytometry Fluorescence in situ hybridization (FISH) Polymerase Chain Reaction (PCR)

Stages of Non-Hodgkin's lymphoma include: Stage 1 – the cancer is limited to 1 group of lymph nodes, such as your neck, armpit or groin nodes, either above or below your diaphragm (the sheet of muscle underneath the lungs) Stage 2 – 2 or more lymph node groups are affected, both either above or below, but just on one side of, the diaphragm Stage 3 – the cancer has spread to lymph node groups on both sides of the diaphragm, above and below Stage 4 – the lymphoma has spread beyond the lymphatic system and is now present in both lymph nodes and organs or bone marrow

 Treatments The general treatment is a combination of chemotherapy with monoclonal antibody (mAb) Chemotherapy -

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) FAD (fludarabine, doxorubicin and dexamethasone) FMD (fludarabine, mitoxantrone and dexamethasone)

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For some types of non-Hodgkin lymphoma, you may have a type of medication called a monoclonal antibody. These medications attach themselves to both healthy and cancerous cells, and signal to the immune system to attack and kill the cells.

Monoclonal Antibody (mAb) -

Rituximab Ofatumumab Obitunuzumab

Side effects of rituximab can include: -

Tiredness Nausea Night sweats Itchy rash Hair loss

CLUSTER 5 - LECTURE 3: MULTIPLE MYELOMAS  Definition and Pathogenesis Multiple myeloma is a type of blood cancer that affects plasma cells. In multiple myeloma, malignant plasma cells accumulate in the bone marrow (the soft, spongy tissue at the centre of your bones), crowding out the normal plasma cells that help fight infection. These malignant plasma cells then produce an abnormal antibody called M protein, which offers no benefit to the body and may cause tumours, kidney damage, bone destruction, and impaired immune function. The hallmark characteristic of multiple myeloma is a high level of M protein in the blood. Pathogenesis

MM begins as monoclonal gammopathy of undetermined significance (MGUS), progresses to smoldering (asymptomatic) myeloma and finally becomes overt (symptomatic) myeloma, resulting in BM infiltration and osteolytic lesions. During MM progression the normal equilibrium between osteoblastic (bone building) and osteoclastic (bone breakdown and resorption) activity is skewed toward net bone loss. MM-induced osteolysis releases growth factors embedded inside the bone matrix, fuelling MM progression and expansion in the BM niche and resulting in greater osteoclastic activity in a process known as the vicious cycle. During this MM-induced cycle, osteoclastic bone breakdown releases bone-embedded growth factors to promote tumour growth which, in turn, stimulates greater osteoclast activity. The cause for Multiple Myeloma is generally unknown but some risk factors are: -

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Monoclonal gammopathy of undetermined significance (MGUS) which increases the risk of developing multiple myeloma. MGUS transforms to multiple myeloma at the rate of 1% to 2% per year. Smoldering multiple myeloma increases the risk of developing multiple myeloma. Individuals diagnosed with this premalignant disorder develop multiple myeloma at a rate of 10% per year for the first 5 years.

Normal plasma cell get mutated and becomes a myeloma cell. It induces cyclin D2. the cell then proliferates

continuously into the cell cycle which increase survival proliferation and increase the blood vessel around it.

 Clinical manifestations Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember some of the common symptoms of multiple myeloma is CRAB: C = Calcium (elevated) known as hypercalcaemia R = renal failure: due deposition of Ab in the kidneys A = anaemia: decreased level of RBC and the individual looks pale and fatigue B = bone disease: -

Bone pain, especially in your spine or chest Nausea Constipation Loss of appetite Mental fogginess or confusion Fatigue Frequent infections Weight loss Weakness or numbness in your legs Excessive thirst

 Diagnostic work up - Blood tests: Myeloma cells often secrete the antibody monoclonal immunoglobulin, known as M protein. M protein levels in a patient's blood is used to determine the extent of the disease and to monitor the effectiveness of treatment. The levels of serum albumin and serum beta-2 microglobulin (β2-M) are also measured using blood tests. Serum albumin is a blood protein made by the liver that is necessary for maintaining proper blood volume and general health. - Urine tests: Immunoglobulin levels are measured to help check the amount of antibody levels in the blood. These antibodies are immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM). In multiple myeloma, when the cancer protein level is up, the normal antibody levels are down. The amount of free light chains in the blood can be measured before the blood is filtered by the kidneys. This test is called a serum free light chain assay. - Radiological tests: Imaging tests may be recommended to detect bone problems associated with multiple myeloma. Tests may include an X-ray, MRI, CT or positron emission tomography (PET). Diagnostic Criteria: The diagnostic criteria is classified in two groups Major Criteria: -

The patient will need to show plasmacytoma (tumour involved in the plasma cell) in the biopsy tissue

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The must be above 30% of plasma cell in the patient’s bone marrow There is an antibody spike on electrophoresis.  The patient has IgG more than 3.5g/dl  IgA more than 2g/dl  Free light chain about 1g/dl in the urine sample.

Minor Criteria: -

Bone marrow plasma cells 10-30% Ab spike but less than above Lytic bone lesions Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

 Medicines There are seven (7) different types of drugs used to Multiple Myeloma Bortezomib Effect -

delay the growth of the tumour by inhibiting mammalian 26S proteasome

Food interaction -

Citrus fruits/Vitamin C -> Ascorbic Acid may diminish the therapeutic effect of Bortezomib Green Tea - Green Tea may diminish the antineoplastic effect of Bortezomib

Cyclophosphamide Effect: -

inhibits the growth of the tumour by adding alkyl group to DNA which inhibits replication

Food interaction -

Drink liberally- 2 to 3 litres/day Take with food to reduce irritation

Dexamethasone and Prednisone Effect: -

inhibits the growth of the tumour bind to DNA -> modification of transcription Phospholipase A2 inhibitory protein -> anti inflammatory

Lenalidomide Effect:

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inhibits the growth of the tumour by inhibiting COX-2 expression

Food interaction -

When given with a fatty meal, the extent of absorption is reduced

Thalidomide Effect: -

inhibits the growth of the tumour which suppresses VEGF inhibitor

Food interaction N/A  Melphalan Effect: -

delay the growth of the tumour by the attachment of alkyl groups to DNA bases : DNA damage via the formation of cross-links : mispairing of the nucleotides leading to mutation

Food interaction -

Take on an empty stomach. Food decreases bioavailability by approximately 30%. Increase liquid intake

 Disease management - When we look at the patient, it’s been confirmed that the patient might have Multiple Myeloma. - You then look at whether the patient has CRAB or not. - If they don’t it means that the patient has asymptomatic myeloma so they require no treatment. It they have CRAB, it means that they have symptomatic myeloma and they will require treatment.

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Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Anaemia (haemoglobin...