Lecture 11.1 - Neoplasia 4 PDF

Incidence of different malignant neoplasms: ◦The global cancer burden is estimated to have risen to 18.1 million new cases and 9.6 million deaths in 2018. 1 in 5 men and 1 in 6 women worldwide develop cancer during their lifetime, and one in 8 men and one in 11 women die from the...

Incidence of different malignant neoplasms: ◦The global cancer burden is estimated to have risen to 18.1 million new cases and 9.6 million deaths in 2018. 1 in 5 men and 1 in 6 women worldwide develop cancer during their lifetime, and one in 8 men and one in 11 women die from the disease. ◦For comparison, there were over 14 million new cases of cancer worldwide in 2012 and 8.2 million deaths, making it the world's most lethal disease ‣ Cancer is a global epidemic and a leading cause of death worldwide ‣ Worldwide, cancer now causes more deaths than HIV/AIDS, tuberculosis and malaria combined ‣ More than 70% of all cancer deaths occur in low and middle income countries Predicting outcome: ◦Determining which individuals will have a favourable outcome for malignant neoplasms is far from exact. Factors to consider include age and general health status, the tumour site, the tumour type, the grade (i.e. differentiation), the tumour stage and the availability of effective treatments ‣ Age ‣ Health ‣ Status ‣ Site ‣ Type ‣ Grade ‣ Stage ‣ Treatment Tumour stage as a measure of malignant neoplasm's overall burden: ◦Based upon the size and extent of metastatic spread of the lesion ◦Tumour-node-metastasis (TNM) system used for most cancers ‣ Size, in cm, of the tumour (T) ‣ Involvement of lymph nodes (N) ‣ Presence or absence of distant metastasis (M) Staging - "T":  Staging - "N": Staging - "M": For any given cancer TNM staging system converts into stage I to IV: Staging for lymphoma: Dukes staging for colorectal carcinoma:  Grading: ◦Degree of differentiation exhibited by cells ◦How closely cells resemble normal tissue structure ◦Grade I - low grade, well differentiated ◦Grade II - moderately differentiated ◦Grade III - poorly differentiated ◦Grade IV - undifferentiated (anaplastic) Grading for breast carcinoma: Cancer treatments: ◦Surgery ◦Chemotherapy ◦Radiotherapy ◦Molecular targeted therapies Cure rate comparisons: Surgery: ◦Removal of body tissue ◦One of main treatments for cancer ◦49% of those 'cured' of cancer are treated by surgery ◦The best treatment for cancers that have not spread, leading to better prognosis ‣ Diagnosis -> curative treatment -> adjuvant treatment ‣ Diagnosis -> neoadjuvant treatment -> curative treatment ◦Adjuvant treatment is given after surgical removal of a primary tumour to eliminate subclinical disease. Neoadjuvant treatment is given to reduce the size of a primary tumour prior to surgical excision Chemotherapy: ◦Use of drugs for treatment  ◦Cytotoxic chemotherapy ◦11% of those 'cured' of cancer are treated by chemotherapy ◦Several classes: ‣ Antimetabolites mimic normal substrates involved in DNA replication, e.g. Fluorouracil. ‣ Alkylating and platinum-based drugs, e.g. cyclophosphamide and cisplatin, cross-link the two strands of the DNA helix. ‣ Antibiotics act in several different ways, e.g. doxorubicin inhibits DNA topoisomerase, which is needed for DNA synthesis, while bleomycin causes double-stranded DNA breaks. ‣ Plant-derived drugs include vincristine, which blocks microtubule assembly and interferes with mitotic spindle formation. Giving cytotoxic drugs: ◦Different ways of delivering cytotoxics: ◦Single agent - tends to cause side-effects ◦Combination - lower doses less side-effects ◦Continuous infusion ◦Intermittent - enables cell recovery ◦High dose - used to destroy bone marrow ◦Immediate side effects: ‣ Pain at the injection site ‣ Sensation of cold during administration ‣ Itching - along or near path of vein ‣ Hypersensitivity reaction ‣ Allergic reaction ‣ Leakage of drug into the tissues ◦Medium-term side effects: ‣ Hair loss ‣ Low blood count ‣ Nausea, vomiting ‣ Loss of appetite ‣ Sore mouth ‣ Flu-like symptoms ‣ Tiredness, weakness ‣ Diarrhoea, constipation ‣ Blood in urine ‣ Discoloured urine Radiotherapy: ◦Radiotherapy is the use of high energy X-rays and similar rays (such as electrons) to cause damage to cells, which then makes it difficult for them to replicate ◦Single dose or daily rose ◦Daily treatments where total dose is split into fractions to preserve normal tissue and reduce side effects of treatment. Affects both normal and cancer cells ◦Aim to preserve normal cells and damage only cancer cells ◦Normal tissue repairs more effectively ◦An area treated with radiotherapy usually receives a lifetime dose  ◦Side effects: ‣ Fatigue ‣ Malnutrition ‣ Weight loss ‣ Skin: redness/sunburn-like symptoms ‣ Head and neck: irritation of mucosal lining, dryness, ulceration ‣ Chest: heartburn-like symptoms if oesophagus is affected ‣ Upper abdomen: nausea and vomiting ‣ Lower abdomen: cramps, diarrhoea and urinary problems ◦Both radio and chemo target ALL proliferating cells Glioma survival: DNA breaks: ◦When gold NP is close to DNA, it amplifies the effects of radiation and causes more damage ◦Why gold or platinum?: ‣ Potential to increase the dose by: Photoactivation Stable scaffolds Size easy to control Water soluble Stable to radiation Versatile surface chemistry Inert and non-toxic Approved for clinical applications (colloidal gold) ◦But how do we get gold close enough to DNA inside tumour cells? Creating peptide-coated gold designer nanoparticle: ◦NPs are stable and biocompatible ◦Get the gold close to DNA ◦Maximise the DNA damage inflicted in tumour cells after radiation  ◦Can be used to target GBM cells preferentially Target molecular therapies: Precision medicine: ◦Cancers classified by molecular abnormalities and site of origin ◦Exceptional success when treatment is matched to a driver mutation Mab's and Inib's: ◦Rituximab is a monoclonal antibody. It targets a protein called CD20 on the surface of the leukaemia and lymphoma cells. Rituximab sticks to all the CD20 proteins it finds. Then the cells of the immune system pick out the marked cells and kill them. ◦Trastuzumab is a type of targeted cancer drug called a monoclonal antibody. It works by attaching to HER2 so it stops the cancer cells from growing and dividing. (Some breast and stomach cancers have large amounts of human epidermal growth factor receptor 2 (HER2). They are called HER2 positive cancers. HER2 makes the cancer cells grow and divide). ◦Imatinib is a type of cancer growth blocker called a tyrosine kinase inhibitor (TKI). Tyrosine kinases are proteins that cells use to signal to each other to grow. They act as chemical messengers. There are a number of different tyrosine kinases and blocking them stops the cancer cells growing. Imatinib targets different tyrosine kinases, depending on the type of cancer.  When it works, it works beautifully: Rise of new immunotherapy: Tumour markers monitoring: ◦Various substances are released by cancer cells into the circulation. Although some have a role in diagnosis, in general they are most useful for monitoring tumour burden during treatment and follow up. Tumour markers include hormones (e.g. human chorionic gonadotrophin released by testicular tumours), ‘oncofetal’ antigens (e.g. alpha fetoprotein released by hepatocellular carcinoma), specific proteins (e.g. prostate-specific antigen released by prostate carcinoma) and mucins/glycoproteins (e.g. CA-125 released by ovarian cancer). Cancer screening - looking for early signs: Covid 19 pandemic impact: ◦Three million people in the UK have missed out on cancer screenings since the start of the pandemic (2020). ◦This has resulted in about 350,000 people not being referred to hospital for urgent checks (Cancer Research UK). ◦NHS figures show about 31,000 fewer patients across the UK started treatment for cancer between April and July 2020 compared with the same time last year, a reduction of 26 per cent.