lecture 5 Flashcards
What are the most common B/T-cell related cancers?
- non hodgkin lymphoma (2620m/2070f cases in 2012)
- myeloma (C90) (895m/650f)
- chronic lymphocytic leukaemia (C91.1) (765 men)
What is a lymphoma?
- a malignancy of lymphocytes
- presents as a solid tumour of lymphoid cells, e.g. enlargement of lymph nodes
- two basic categories of lymphoma:
- Hodgkin’s lymphoma: diagnosed by the presence off a type of cell called the Reed-Sternberg cell
- Non-Hodgkin’s lymphomas: a large, diverse group of B cell or T cell lymphomas
- Both have indolent (slow-growing) and aggressive subtypes, that behave and respond differently
- some B cell types include: Burkitt lymphoma, Diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma
What is the greatest risk factor for non-hodgkin lymphoma?
- age is the greatest risk factor, as most cases arise in people 60+ years of age
- very rare in people younger than 50
What is leukaemia?
- cancer that starts in blood-forming tissue such as bone marrow and causes large numbers of malignant cells to be produced and enter the bloodstream
- B cel, T cell or myeloid cell leukaemias: prevalance, ~8-14/100,000 (depending on race)
- B cell types include:
- Acute lymphocytic leukaemia (ALL): a childhood peak incidence at 2-5 years and another in old age
- Chronic lymphocytic leukaemia (CLL): the most common type of lymphoid leukaemia is B cell-CLL, mostly adults, >50 years old, males
What is myeloma/multiple myeloma?
- cancer of plasma cells ( = antibody secreting cells)
- prevalence ~4-10/100,000 (depending on race)
- often preceded by an asymptomatic, premalignant stage of clonal plasma cell proliferation: “monoclonal gammopathy of undetermined significance” (MGUS)
- MGUS is present in more than 3% of the population >50 years of age, and progresses to myelome at ~1%/year
What has the classification of B cells historically been based on?
Physical observations:
- patient’s condition
- histology of tumour or involved tissues (including blood)
- karyotype of tumour cells - chromosome number and structure (are there translocations?)
- abormal accumulation of clones of cells
- more recently, flow cytometry using mAbs that recognise surface molecules (CDs) on malignant cells
- even more recently diagnosing tumours by sequencing them
What are Reed-Sternberg cells?
mysterious but diagnostic giant cells found in biopsies from individuals with Hodgkin’s lymphoma, with markers of both myeloid or lymphoid cells
What is the common pathogenesis of B cell cancers?
- malignant cells crowd out normal cells in limited “niches”, such as the bone marrow
- this severely limits the function of normal haematopoietic cells such as RBC and WBC that are essential to life, thereby causing infection, anaemia, platelet deficiencies, bleeding problems, and respiratory failure
What is a diagnostic feature of myeloma patients?
- normal serum Ig concentration is ~10-15mg/ml
- myeloma patients have clonal “paraprotein”, in serum and urine, often»_space; 30 mg/ml, with free light chains “Bence Jones proteins” (Ig lambda and kappa)
How do myeloma cells destroy bone marrow?
Normal plasma cells like to go back and sit in the bone marrow and produce antibody in a benign way for decades.
Myeloma bind to stromal cells in the bone marrow –> an imbalance between factors that control bone homeostasis:
- growth factor RANK-L (bone resorbing) is overproduced
- growth factor OGP (bone-forming) is diminished (osteogenic growth peptide)
- results in osteoclastogenesis and osteolysis
What are the diagnostic criteria for multiple myeloma?
- clonal plasma cells >10% on bone marrow biopsy
- a monoclonal antibody in either serum or urine
- end organ damage:
- bone lesions and fractures
- hypercalcemia
- renal insufficiency
- anaemia
- frequent severe infection
What are the current therapies for patients with Non-Hodgkin lymphoma?
- chemotherapy (systemic): general toxins that kill rapidly dividing cells - CHOP
- standard care for decades - Antibody - Rituxan - R-chop
- monoclonal antibody
- made in a lab
- injected into patients
- specific for B cells
- targets both cancerous and normal B cells for destruction by the patients own IS - Radiation - limited
- Bone marrow transplantation - if things are really dire, all blood cells killed off and replaced by normal, healthy donor stem cells to give them effectively a new IS, which will provide protection against infection, and in many cases will also fight the cancer cell, which it will see as foreign
What is CHOP?
- the chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. Consists of: Cyclophosphamide Hydroxydaunorubicin Oncovin Prednisone
What is an example of targeted therapies to suit multiple myeloma?
First choice therapies include thalidomide and lenalidomide (a derivative)
- thalidomide reasonably effective: targets the energy production of cells
- plasma cells are sensitive to this: they need a lot of energy, are producing a lot of proteins
- other treatments include melphalan, corticosteroids, autologous transplantation, bortezimib
- none of these are curative - there is no cure, simply managing the disease so that symptoms don’t get too severe
What is Bortezimib?
- a drug used in the treatment of MM
- a boronic acid dipeptide
- Inhibits the 26S proteosome - a large protease complex that collaborates with the ubiquitin system to mark proteins for degradation including key regulatory proteins and transcription factors including NFkB (also their activation relies on proteasomal degradation of some component of them)
- Plasma cells (and myeloma cells) are protein secreting factories - handling large quantities of immunoglobulin - so are especially sensitive to this drug
- NFkB is required for expression of the survival genes on which MM rely
- no better molecular therapies - yet
- proteasomes are present in every cell so it is important to try and get the dosage right, so that it is mostly the myeloma cells that are effected
- has a lot of side effects