Malignant disease is common and is the second most common cause of death after cardiovascular disease. Most tumours arise from genetic muta-tions within a single population of precursor stem cells and over subsequent cell divisions there is an accumulation of further abnormalities. The genes most commonly affected are those that control cell cycle check points, DNA repair and DNA damage recognition, apoptosis, differentiation and growth signalling. Gene mutations may be:
■ Germline - e.g. mutations in BRCA1 and BRCA2 account for most cases of familial breast cancer. The protein product of these mutated genes is unable to bind to the DNA repair enzyme Rad51 to make it functional in repairing DNA breaks.
■ Somatic - in response to environmental carcinogens, e.g. smoking.
The diagnosis of malignancy is made by:
■ Screening in an asymptomatic person with the aim of detecting cancer at an earlier stage than symptomatic presentation and hopefully a better outcome. This is by population screening or individual screening of at-risk individuals. In the UK, population screening programmes are established for breast, cervical and colon cancer. Individual screening programmes are established for persons with a higher than average risk, usually because of family history, e.g. colonoscopy in persons with a family history of colon cancer at a young age.
■ Surveillance in a patient with a disease that places them at higher risk of developing malignancy, e.g. liver ultrasound and measurement of serum a-fetoprotein in a patient with cirrhosis with the aim of detecting hepato-cellular carcinoma at an earlier stage than symptomatic presentation.
■ Investigation in a symptomatic patient. Symptoms are the result of:
■ The primary tumour
Table 6.1 Serum tumour markers
Hepatocellular carcinoma and non-seminomatous germ cell tumour of the gonads
β-human chorionic gonadotrophin (β-hCG)
Choriocarcinomas, germ cell tumours (testicular) and lung cancer
Prostate-speciAc antigen (PSA)
Carcinoembryonic antigen (CEA)
Colorectal cancer. May also be raised in other gastrointestinal malignancies
Ovarian cancer. May also be raised in breast, cervical, endometrial and gastrointestinal malignancies
Upper gastrointestinal malignancies
Many cancers including mesothelioma
■ Paraneoplastic symptoms. These are a consequence of the cancer but are not due to the local presence of the cancer and may be medi-ated by hormones or cytokines secreted by the cancer (e.g. ectopic adrenocorticotropic hormone [ACTH] secretion in small cell lung cancer) or an immune response directed against the cancer e.g. dermatomyositis
■ Non-specific effects such as weight loss, tiredness and lethargy. Investigations
■ To confirm the presence of malignancy in a patient with suspicious symptoms of signs. This is by radiological imaging (with the specific test depending on the site) and biopsy of a suspicious lesion (e.g. at endo-scopy) with histological examination and tissue tumour markers. Serum tumour markers (Table 6.1) are intracellular proteins or cell surface glycoproteins released into the circulation and may be present in higher than usual concentration in patients with cancer. In many cases they are requested inappropriately as most tumour markers are neither sensi-tive nor specific for a particular malignancy and can also be raised in benign conditions. They are mainly used in monitoring response to treatment.
■ To stage the cancer once diagnosed. Staging the cancer will divide the patients into groups of different prognosis which can guide treatment selection. The staging systems vary according to tumour type and may be site specific (see Hodgkin's lymphoma) or the TNM (tumour, node, metastasis) classification which can be adapted for application to most common cancers.
■ To assess a patients suitability for treatment, e.g. full cardiac and respira-tory work-up before liver transplantation for hepatocellular carcinoma.
The management of patients with cancer must be coordinated by a multi-disciplinary team (MDT) which includes, depending on tumour type, a surgeon, oncologist, radiologist, histopathologist, physician, specialist nurse and sometimes other healthcare workers, e.g. dietician. Discussion with the patient about the treatment plan at each step will allow them to make a fully informed choice about their management.
In some solid tumours, treatment (chemotherapy, radiotherapy or hormone) is given after the primary treatment, e.g. surgical resection, where dissemi-nation is undetectable but patients are at risk of micromelaslases. This is called adjuvant therapy. Neoadjuvant therapy is given before the primary treatment to shrink the tumour to improve the efficacy of the local excision and to treat micrometastases as soon as possible. If effective, these treat-ments should lead to an increased chance of cure or overall disease-free survival.
There are many chemotherapy drugs in common use. These drugs directly damage DNA and/or RNA and kill cells by promoting apoptosis and some-times cell necrosis. They therefore affect not only tumour cells, but also the rapidly dividing normal cells of the bone marrow, gastrointestinal tract and germinal epithelium.
Side-effects include bone marrow suppression (leading to anaemia, thrombocytopenia and neutropenia [p. 205]), mucositis (causing mouth ulceration), loss of hair (alopecia) and sterility (which can be irreversible). To minimize these side-effects, chemotherapy is given at intervals to allow some recovery of normal cell function between cycles. Nausea and vomiting may be severe with some drugs, such as cisplatin, and are related to the direct actions of cytotoxic agents on the brainstem chemoreceptor trigger zone. Antiemetics such as metoclopramide (p. 136) and domperidone (p. 136) are used initially, but the serotonin 5-HT3 antagonists (ondansetron and graniset-ron) combined with dexamethasone are used for severe vomiting. Chemo-therapy drugs may themselves cause cancer, particularly acute leukaemia presenting years after treatment. There are additional side-effects that are specific to one class of drug, e.g. cardiotoxicity with the anthracyclines such as doxorubicin and neurotoxicity and nephrotoxicity with cisplatin.
Radiation induces strand breaks in DNA and apoptosis. The complications of radiotherapy depend on the radiosensitivity of normal tissue in the path of the radiation field. There may be damage to the skin (erythema and desquamation), gut (nausea, mucosal ulceration and diarrhoea), testes (steril-ity) and bone marrow (anaemia, leucopenia). General side-effects are leth-argy and loss of energy.
This is used in the treatment of breast and prostate cancer to block the effects of oestrogens and androgens which may act as growth factors. Tamoxifen is a mixed agonist and antagonist of oestrogen on the oestrogen receptor and is used as an adjuvant therapy in breast cancer and in advanced metastatic breast disease. Aromatase inhibitors, e.g. anastrozole, letrozole and exemes-tane, block the conversion of androgens (synthesized by the adrenal glands) to estrone in the subcutaneous fat of post-menopausal women. They have greater efficacy than tamoxifen in the treatment of metastatic breast cancer and equal efficacy in the adjuvant setting. Gonadotropin-releasing hormone (GnRH) agonists, e.g. goserelin, which lower levels of circulating androgens and androgen receptor blockers, e.g. flutamide, are both used in the treat-ment of prostate cancer.
This group includes a range of protein molecules, from small peptide chem-okines and larger cytokines to complex antibody molecules, made available by genetic engineering.
■ Interferons such as interferon alfa have many actions in treatment of malignant disease, with both antiproliferative activity and stimulation of humoral and cell-mediated immune responses to the tumour.
■ Interleukins have widespread activity in coordinating cellular activity in many organs. Interleukin 2 is used in renal cell carcinoma and melanoma.
■ Tyrosine kinase inhibitors (imatinib, sunitinib, sorafenib) have diverse effects on cell growth, differentiation and metabolism.
■ Anti-growth factor agents e.g. bevacizumab (antivascular endothelial growth factor receptor) and cetuximab (antiepidermal growth factor receptor) are added to chemotherapy to improve response.
■ Anti-CD20 (rituximab) inhibits CD20 on B cells, which normally plays a role in the development and differentiation of B cells into plasma cells. Anti-CD52 (alemtuzumab) inhibits CD52 expressed on T and B lym-phocytes and monocytes.
■ Haemopoietic growth factors such as erythropoietin and granulocyte colony-stimulating factor (G-CSF) are used to treat anaemia or to reduce the duration of neutropenia following chemotherapy.
1. Ethics and communication
2. Infectious diseases
3. Gastroenterology and nutrition
4. Liver, biliary tract and pancreatic disease
Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER DISEASE IN PREGNANCY
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS
5. Haematological disease
Assessment and treatment of suspected neutropenic sepsis
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
6. Malignant disease
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
8. Water, electrolytes and acid–base balance
WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
9. Renal disease
INVESTIGATION OF RENAL DISEASE
URINARY TRACT INFECTION
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
10. Cardiovascular disease
COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
ISCHAEMIC HEART DISEASE
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
ARTERIAL AND VENOUS DISEASE
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS
11. Respiratory disease
12. Intensive care medicine
13. Drug therapy, poisoning, and alcohol misuse
14. Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
15. Diabetes mellitus and other disorders of metabolism
16. The special senses
COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES