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Phase 2A > Miscellaneous > Flashcards

Miscellaneous Flashcards

1
Q

what is the epidemiology of HIV/AIDS?

A
  • in general more men are infected than women - could be due to the fact that HIV is spread very well by anal intercourse which is very prevalent in male to male sexual activity
  • of those diagnosed in the UK, 30% are women
  • sub-Saharan Africa remains the most seriously affected
  • homosexual (male sex with men (MSM)) and culturally diverse heterosexual population from sub-Saharan Africa are the two largest groups of people living with HIV
  • there is increasing HIV transmission in eastern Europe and Middle East where homosexuality is less accepted and driven underground
  • majority of all new infections world-wide are 15-24 year olds
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2
Q

who is most at risk for HIV/AIDS?

A
  • men who have sex with men (unprotected - higher risk)
  • heterosexual women (unprotected - higher risk)
  • IV drug users
  • commercial sex workers
  • heterosexual men
  • truck drivers (tend to use sex industry more)
  • migrant workers (tend to use sex industry more)
  • uncircumcised men
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3
Q

what are the routes of administration of HIV/AIDS?

A
  • sexual intercourse (vaginal and anal)
  • mother to child transmission
  • contaminated blood, blood products and organ donation
  • contaminated needles
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4
Q

what are features of sexual intercourse (vaginal and anal) as a route of acquisition of HIV/AIDS?

A
  • world-wide, sexual intercourse accounts for the vast majority of infections
  • coexistent STIs especially those causing genital ulceration enhance transmission
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5
Q

what are features of mother-to-child transmission as a route of acquisition of HIV/AIDS?

A

can occur in utero although the majority of infections take place perinatally or via breast milk

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6
Q

what are features of contaminated blood, blood products and organ donation as a route of acquisition of HIV/AIDS?

A

risk is minimal in developed countries since the introduction of screening

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7
Q

what are features of contaminated needles as a route of acquisition of HIV/AIDS?

A

major route of transmission of HIV among IV drug users who

share needles and syringes

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8
Q

what type of virus is HIV?

A

part of the lentivirus group of the retrovirus family

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9
Q

what does the HIV envelope contain?

A

HIV envelope contains RNA, capsid (encases the genetic material of the virus) and reverse transcriptase

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10
Q

what is the action of reverse transcriptase?

A
  • has the enzyme reverse transcriptase which allows viral RNA to be transcribed into DNA and thence incorporated into the host cell genome using the enzyme integrase
  • since reverse transcription is highly error-prone and due to the high rate of viral turnover this leads to considerable genetic variation and a diversity of viral subtypes or clades
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11
Q

what are the different groups of HIV?

A
  • group M (major)
  • group N (new)
  • group O (outlying)
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12
Q

what are features of group M HIV? where are its subtypes most common?

A

• most common
• have subtypes or clades ranging from A-K
• subtype A is most common in West and Central Africa
• subtype B is most common in Europe, North America and
Australia
• subtype C is most common in Southern Africa

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13
Q

where does HIV enter the body?

A

virus enters via mucosa - vagina, rectum or intestines (at delivery or via breastfeeding in infants)

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14
Q

how does HIV spread within the body?

A
  • local infection within a mucosal macrophage or dendritic cell is established
    and then spreads to other cells
  • as these are antigen presenting cells, some will migrate to local lymph nodes to present antigen to T cells - where infection of T helper cells occurs
  • HIV targets CD4 T helper cells
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15
Q

what is the function of CD4 T helper cells?

A
  • CD4 T helper cells act as the bodies coordinators in the specific/acquired immune response
  • they are responsible for organising, recruiting and facilitating the maturation of B-antibody producing cells and CD8 T killer cells
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16
Q

what happens on presentation of antigen to CD4 cells?

A

CD4 cells mature into two types of T helper cell

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17
Q

what is the function of T helper 1 cells?

A
  • produces specific interleukins (IL4, 5, 10, 13) that cause the maturation of B lymphocytes into plasma cells
  • the plasma cells then produce specific antibodies e.g. IgG etc. against the specific antigen - allows for a more prolonged and effective antibody response
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18
Q

what is the function of T helper 2 cells?

A
  • produces interferon alpha and TNF
  • these cytokines activate further CD8 cells, turning them into Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells
  • CTLs then produce then enzyme perforin that directly kills cells with the antigen on or in
  • note: IFN alpha is an important cytokine in the bodies defence against TB
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19
Q

what is the HIV envelope glycoprotein?

A

gp120

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20
Q

what does HIV bind to?

A

binds, via its gp120 envelope glycoprotein, to CD4 receptors on:

  • helper T lymphocytes
  • monocytes
  • macrophages
  • neural cells
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21
Q

what is responsible for HIV entry into cells?

A

interaction between CD4 and HIV glycoprotein gp120 together with host chemokine CCR5 or CXCR4 co-receptors is responsible for HIV entry into cells

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22
Q

what is gp160 made of?

A

gp120 and gp41

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23
Q

what is the mechanism of viral replication within CD4 T helper cells?

A
  • glycoproteins on the HIV molecule (gp160 made up of gp120 and gp41) allow it to attach and fuse onto the CD4 and CCR5 receptors
  • the viral capsid then enters and enzymes and nucleic acids are uncoated and released
  • using reverse transcriptase the single stranded RNA is converted into double stranded DNA
  • viral DNA is then integrated into the host cells own DNA by integrase enzyme
  • when the infected cell divides the viral DNA is read and transcribed and long chains of viral proteins are made
  • viral RNA is spliced and protein chains are cleaved and reassembled by the protease enzyme into individual proteins that combine to form a working virus
  • budding occurs where the immature virus pushes out of the cell taking with it some cell membrane of the T helper cell
  • immature virus breaks free to undergo more maturation and is then able to infect other CD4 cells
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24
Q

where do infected T cells go once they have been infected by HIV?

A
  • infected T cells then leave the lymph node and infection spills into the blood stream resulting in viraemia and the exponential rise in T cell infection occurs
  • replication of HIV in the CD4 T cells results in cell death
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25
Q

what is a key consequence of viraemia?

A

a key consequence of the viraemia is uncontrolled activation of CD4 T cells
- activated CD4 T cells, unless they receive a non-specific co-stimulatory
signal (usually CD28 (on T cell) binding to CD80 or CD86 on the stimulator), will
undergo activation induced cell death (apoptosis) via Fas ligand upregulation which then bind to Fas receptors leading to the activation of
caspases (cell death enzyme) which then triggers apoptosis and cell death

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26
Q

what happens to infected CD4 T cells?

A

targeted by an immune response

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27
Q

how are infected CD4 T cells targeted by humoral immunity?

A

neutralising antibodies against primary isolates are of a low magnitude however due to the fact that the viral envelope glycoprotein is poorly immunogenicity and shows genetic diversity

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28
Q

how are infected CD4 T cells targeted by cell-mediated immunity?

A
  • CD8 cytotoxic T lymphocytes (CTL) play a role in the early decline in virus but are incomplete
  • HIV escapes from CTL responses through mutations
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29
Q

what are other aspects of immune dysfunction due to HIV infection?

A
  • CD8 T cells show enhanced activation and decreased cytolytic and non-cytolytic function
  • B cells show enhanced activation but decreased proliferation resulting in increased non-specific but decreased specific antibody production
  • decreased natural killer (NK), neutrophil and macrophage function
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30
Q

what does the resulting cell-mediated immunodeficiency due to HIV lead to?

A

the resulting cell-mediated immunodeficiency leaves the host open to infections with intracellular pathogens, while coexisting antibody
abnormalities predispose to infections with capsulated bacteria e.g. Streptococcus pneumoniae and Haemophilus influenzae

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31
Q

what does early T-cell activation in HIV infection lead to?

A

T-cell activation occurs from the earliest stages of infections and leads to an
increase in the number is susceptible CD4-bearing target cells that can become infected and destroyed

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32
Q

what does T cell deficiency increase susceptibility to?

A
  • viruses such as Herpes virus-CMV
  • bacteria such as intracellular mycobacteria and salmonella
  • fungi e.g. Yeasts - Candida spp
  • parasites such as spore forming cryptosporidia
  • malignancies especially Epstein-Barr virus associated lymphoma
  • autoimmune disease; rheumatologic or dermatologic due to loss of T-cell regulatory cells
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33
Q

when does someone have AIDS?

A
  • given CD4 T cells’ central role in coordinating adaptive immune responses, it follows that their depletion by HIV infection leads to increased immunosuppression which after a long latent period results in increased infections and other complications i.e Acquired Immune Deficiency (AIDS)
  • when the individual has a CD4 count of less than 200 cells per mm3 they are at risk of infections and are said to have AIDS
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34
Q

what is the natural history of HIV infection?

A
  • acute primary infection (seroconversion); 2-6 weeks
  • asymptomatic phase/clinical latency; years
  • early symptomatic HIV
  • AIDS
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35
Q

what occurs in acute primary infection (seroconversion); 2-6 weeks?

A
  • transient immunosuppression and fall in CD4 count, followed by
    a gradual rise
  • acute rise in viral load, then fall to ‘set point’
  • accompanied by a transient illness 2-6 weeks after exposure with abrupt onset of non-specific symptoms
  • symptoms can be severe for 2 weeks
  • illness lasts up to 3 weeks and recovery is usually complete
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36
Q

what non-specific symptoms are seen in acute primary infection (seroconversion)?

A 
• fever
• malaise
• myalgia (muscle pain)
• pharyngitis (sore throat)
• maculopapular rash
• significant weight loss can
occur
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37
Q

what occurs in the asymptomatic phase/clinical latency of HIV?

A
  • progressive loss of CD4 T cells resulting in poor immunity
  • asymptomatic so can unknowingly spread infection
  • 30% may have persistent generalised lymphadenopathy defined as nodes greater than 1cm diameter and at more than 2 extra-inguinal sites persisting for 3 months or longer
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38
Q

what occurs in early symptomatic HIV?

A

associated with a rise in viral load and a fall in CD4 count and development of symptoms and signs due to direct HIV effects and immunosuppression

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39
Q

what are examples of early symptomatic conditions in HIV?

A 
• fever (high temperature)
• night sweats
• diarrhoea
• weight loss
• minor opportunistic infections:
- oral candida
- herpes zoster (shingles)
- recurrent herpes simplex
• this collection of symptoms is known as AIDS-related complex
(ARC)
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40
Q

what occurs in AIDS?

A
  • symptoms of immune deficiency with a CD4 below 200

- as CD4 decreases so does immune function - below 250 see signs of infection

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41
Q

what are the timescales of HIV/AIDS?

A
  • HIV→ AIDS: 8 years
  • ARC →AIDS: 2 years
  • AIDS → death: 2 years (without HAART)
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42
Q

what are AIDS defining infections?

A
  • candidiasis oesophageal/lung (fungal infection)
  • extra-pulmonary cryptococcosis
  • cryptosporidiosis for more than 1 month
  • mycobacterium TB
  • persistent herpes simplex (cold sores)
  • Pneumocystis jiroveci (carinii) pneumonia
  • recurrent bacterial pneumonia
  • cytomegalovirus (CMV) in any organ except liver, spleen and lymph nodes
  • recurrent salmonella septicaemia
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43
Q

what are AIDS defining neoplasms?

A
  • invasive cervical carcinoma
  • Kaposi’s carcinoma
  • primary CNS lymphoma
  • non-hodgkin’s lymphoma
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44
Q

what is done for a patient with fever, rash and non-specific symptoms for suspected HIV?

A
  • take a sexual history (enquire about protection)
  • think of HIV seroconversion illness (acute)
  • tell lab to check for antigen
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45
Q

when should HIV be thought of in diagnosis?

A
  • patient with fever, rash and non-specific symptoms
  • if you see high protein but low albumin on bloods - this is a sign of something going around blood, could be antibodies but must rule out HIV
  • think of testing for HIV when faced with recurrent shingles and candidiasis and any of conditions above
  • if taking O2 sats and see normal sats at rest (98%) but then sharp drop in sats after walking (79%) then think pneumocystis pneumonia - HIV related condition so test for it
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46
Q

what are the two markers used to monitor HIV infection?

A
  • CD4 T cell count/μl
  • HIV viral load (RNA copies/ml)
  • both are important in prognosis
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47
Q

what methods are used to diagnose HIV?

A
  • CD4 cell count and HIV viral load
  • detection of IgG antibody to envelope contents
  • detection of IgG antibody to p24 (anti-p24)
  • genome detection assays
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48
Q

how is detection of IgG antibody to envelope contents used to diagnose HIV infection?

A

• based on enzyme-linked immunosorbent assay (ELISA) technique, which may be confirmed with Western blot assays
• up to 3 months (on average 6 weeks) may elapse from initial infection to antibody detection (serological latency)
• will see a positive result in HIV infection
• these antibodies to HIV have no protective function and persist for life, as will all IgG antibodies, and the anti-HIV antibodies will cross the placenta
• all babies born to HIV-positive women will thus have the antibody at birth
- in this situation anti-HIV antibody is not a reliable marker of active infection; instead use nucleic acid-based assays

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49
Q

how can detection of IgG antibody to p24 (anti-p24) be used to diagnose HIV?

A
  • can be detected from the earliest weeks of infection and through the asymptomatic phase
  • it is frequently lost as the disease progresses
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50
Q

how can genome detection assays be used to diagnose HIV?

A
  • nucleic acid-based assays that amplify and test for components of the HIV genome
  • used to aid the diagnosis of HIV in the babies of HIV-positive mothers or in conditions where serological tests may be inadequate such as in early infection when antibody may not be present
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51
Q

when should HAART be started?

A

before CD4 count is less than 200

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52
Q

what is HAART?

A

highly active antiretroviral therapy
• ideally start before CD4 count is less than 200
• use more than 3 drugs to minimise replication and cross-resistance:
- 2 NRTI + 1 NNRTI
- 2 NRTI + 1PI
• negotiate strict adherence
• aim is to reduce viral load to less than 50 copies/ml and increase CD4 count

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53
Q

what is the aim of HAART?

A

to reduce viral load to less than 50 copies/ml and increase CD4 count

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54
Q

what is the mechanism of action of nucleoside reverse transcriptase inhibitors (NRTI) in HAART?

A

inhibit the synthesis of DNA by reverse transcription and also act as DNA chain terminators

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55
Q

what are some examples of nucleoside reverse transcriptase inhibitors (NRTI)?

A
  • abacavir
  • didanosine
  • emtricitabine
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56
Q

what are some side effects of nucleoside reverse transcriptase inhibitors (NRTI)?

A
  • nausea
  • mitochondrial dysfunction
  • lactic acidosis
  • pancreatitis (didanosine)
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57
Q

what is the mechanism of action of non-nucleoside reverse transcriptase inhibitors (NNRTI) in HAART?

A

bind directly to, and inhibit reverse transcriptase

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58
Q

what are some examples of non-nucleoside reverse transcriptase inhibitors (NNRTI)?

A
  • efavirenz
  • etravirine
  • nevirapine
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59
Q

what are side effects of non-nucleoside reverse transcriptase inhibitors?

A
  • rash
  • elevation of liver enzymes
  • hallucinations
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60
Q

what is the mechanism of action of protease inhibitors in HAART?

A

act competitively on HIV enzyme involved in production of functional viral proteins and enzymes

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61
Q

what are examples of protease inhibitors?

A
  • atazanavir
  • darunavir
  • indinavir
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62
Q

what are side effects of protease inhibitors?

A
  • hyperlipidaemia
  • GI intolerance
  • lipodystrophy
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63
Q

what is the mechanism of action of fusion inhibitors in HAART?

A

inhibits fusion of HIV with target cells

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64
Q

what is an example of a fusion inhibitor?

A

enfuvirtide

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65
Q

what are side effects of fusion inhibitors?

A

reactions at sub-cutaneous injection sites

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66
Q

what is the mechanism of action of integrase inhibitors in HAART?

A

prevents the insertion of HIV DNA into the human genome

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67
Q

what is an example of an integrase inhibitor?

A

raltegravir

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68
Q

what are some side effects of integrase inhibitors?

A
  • GI side-effects
  • headache
  • myopathy
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69
Q

what are some drugs that are used to treat HIV?

A
  • nucleoside reverse transcriptase inhibitors
  • non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors
  • fusion inhibitors
  • integrase inhibitors
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70
Q

what are some sanctuary sites for HIV?

A
  • genital tract
  • central nervous system
  • GI system
  • bone marrow
  • macrophages and microglia
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71
Q

how can HIV be prevented?

A
  • Education on transmission
  • increase use of contraception
  • reduce sexual violence since violence increases risk of mucosal surface breach
  • male circumcision reduces risk of transmission by 60%
  • give IV drug users clean needles
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72
Q

what is amyloidosis?

A

a group of disorders of protein metabolism, in which there is extracellular
deposition of an insoluble fibrillar protein called amyloid which is resistant to degradation

73
Q

what are examples of amyloidosis occurring in disease?

A

• localised amyloidosis deposition occurs in the brain of patients with Alzheimer’s
• local amyloid deposition is also a feature of DMT2 and long-term haemodialysis
(deposition is in the joints of patients)

74
Q

what is the epidemiology of amyloidosis?

A
  • rare disease
  • although systemic amyloidosis continues to be fatal and is responsible for
    about 1 in 1,500 deaths per year in the UK
  • can be acquired or inherited and may be localised or systemic
75
Q

how is amyloidosis classified?

A

classification is based on the nature of the precursor plasma proteins (at least 20) that form the fibrillar deposits

76
Q

what is AL amyloid/primary amyloidosis?

A

• L of AL stands for light-chain
• abnormal plasma cells in the bone marrow produce light chain amyloid protein
• these light chains are normally part of healthy immunoglobulins and thus the proteins are referred to as amyloidogenic monoclonal
immunoglobulin fibrillar light chain proteins
• these proteins then get deposited and result in organ failure and death
• associated with myeloma (15%) and Non-Hodgkin’s lymphoma

77
Q

what causes clinical features in primary amyloidosis?

A

clinical features are as a result of amyloid deposits affecting the normal structures and function of the affected tissue

78
Q

what is the clinical presentation of primary amyloidosis in the kidneys?

A

glomerular lesions resulting in proteinuria and nephrotic

syndrome

79
Q

what is the clinical presentation of primary amyloidosis in the heart?

A

• restrictive cardiomyopathy - looks like sparkling on
echocardiogram
• arrhythmias
• angina

80
Q

what is the clinical presentation of primary amyloidosis in the nerves?

A

peripheral and autonomic neuropathy and carpal tunnel

syndrome

81
Q

what is the clinical presentation of primary amyloidosis in the GI tract?

A

macroglossia (big tongue), malabsorption and weight loss, perforation, haemorrhage, obstruction and hepatomegaly

82
Q

what is the clinical presentation of primary amyloidosis in the vascular system?

A

purpura - especially periorbital (characteristic feature)

83
Q

what is the treatment of primary amyloidosis?

A
  • optimise nutrition

- alkylating agent + corticosteroid e.g. oral melphalan + prednisolone

84
Q

what is the mechanism of action of melphalan?

A

melphalan works by damaging DNA within plasma cells (which produce the monoclonal immunoglobulin light chains) thereby preventing cell division and thus reducing amyloid deposition

85
Q

what is AA amyloidosis/secondary amyloidosis?

A

here amyloid is derived from serum amyloid A, an acute phase protein - it is therefore related to chronic inflammatory disorders and chronic infection

86
Q

what disorders is AA amyloidosis/secondary amyloidosis associated with?

A
  • rheumatoid arthritis
  • UC/Crohn’s
  • familial mediterranean fever
  • chronic infections e.g. TB, bronchiectasis and osteomyelitis
87
Q

what is the clinical presentation of secondary amyloidosis?

A
  • it affects the kidneys, liver and spleen
  • may present with:
    • proteinuria
    • nephrotic syndrome
    • hepatosplenomegaly
    • macroglossia (large tongue) is not seen
    • cardiac involvement is rare
88
Q

what is the treatment of secondary amyloidosis?

A

treat underlying cause

89
Q

what is ATTR familial amyloidosis?

A
  • autosomal dominant
  • usually caused by mutations in transthyretin (a liver transport protein which transports thyroxine and retinol binding protein) where the mutant protein forms amyloid fibrils
  • usually starts in middle age
90
Q

what are types of amyloidosis?

A
  • light chain (AL)
  • inflammation (AA)
  • dialysis (Abeta2M)
  • hereditary and old age (ATTR)
91
Q

what is the clinical presentation of ATTR familial amyloidosis?

A
  • sensory or autonomic neuropathy
  • cardiomyopathy
  • renal involvement
92
Q

what is the treatment of ATTR familial amyloidosis?

A

liver transplant can cure

93
Q

how is amyloidosis diagnosed?

A

diagnosis is made with biopsy of affected tissue:
• the rectum or subcutaneous fat are relatively non-invasive sites for biopsy and are positive in 80%
• biopsy is positive if there is congo red staining with red-green birefringence under polarised light microscopy

94
Q

how is biopsy used to diagnose amyloidosis? what would a positive result look like?

A
  • the rectum or subcutaneous fat are relatively non-invasive sites for biopsy and are positive in 80%
  • biopsy is positive if there is congo red staining with red-green birefringence under polarised light microscopy
95
Q

what is the prognosis of amyloidosis?

A
  • median survival is 1-2 years

- patients with myeloma and amyloidosis have a shorter survival than those with myeloma alone

96
Q

what is the epidemiology of breast cancer?

A

breast cancer is by far the most common cancer in women and the second most common cause of death in the UK

97
Q

what does the majority of breast cancer arise from?

A

the majority of breast cancer arises from either:

  • the epithelial lining of ducts and are called ductal
  • from the epithelium of the terminal ducts of the lobules and are called lobular
98
Q

what is the genetic component of familial breast cancer?

A
  • around 5-10% of breast cancers are due to mutation in BRCA1 (long-arm of
    chromosome 17) or BRCA2 (long-arm of chromosome 13)
  • both BRCA1 (higher risk) and BRCA2 are tumour suppression genes that act
    as inhibitors of cellular growth
  • carrying a BRCA1 mutation confers a 65% lifetime risk of developing breast cancer
  • for BRCA2 the risk of breast cancer is 45% - thus BRCA2 confers less risk than BRCA1
  • there is a stronger incidence of BRCA1 mutation than BRCA2
99
Q

where are BRCA1 and BRCA2 located?

A 
BRCA1 = long arm of chromosome 17
BRCA2 = long arm of chromosome 13
100
Q

what is the epidemiology of breast cancer?

A
  • affects 1 in 9 women
  • rare in men - around 1% of all breast cancers
  • risk increases with age; less than 5% below 35 yrs
  • most common histological subtype is infiltrating ductal carcinoma (IDC) - 70%
  • lobular carcinoma accounts for 10-15% of breast cancers
  • medullary cancers (5%) tend to affect younger patient
  • colloid/mucoid cancers (2%) tend to affect the elderly
101
Q

what is the most common histological subtype of breast cancer?

A

infiltrating ductal carcinoma (70%)

102
Q

what are risk factors for breast cancer?

A
  • risk increases with age
  • family history of breast cancer in a first-degree relative
  • BRCA1 (65% risk) or BRCA2 (45% risk) mutation
  • never having borne a child (nulliparity) or first child after age 30 yrs
  • not having breast-fed (breast-feeding is protective)
  • early menarche (started periods early) and late menopause
  • radiation to chest
  • hormone replacement therapy (HRT) with oestrogen and progesterone
  • combined oral contraceptive pill
  • obesity
  • past breast cancer
103
Q

what is the clinical presentation of breast cancer?

A

most women with symptomatic rather than screen-detected breast cancer present with painless, increasing mass that may also be associated with:
• nipple discharge
• skin tethering
• ulceration
• in inflammatory cancers there may also be oedema and erythema

104
Q

what are differential diagnoses of breast cancer?

A

benign breast disease:

  • fibroadenoma
  • breast cysts
  • intraductal papilloma
105
Q

what is the clinical presentation of fibroadenoma?

A
  • usually present < 30yrs (peak - 20-24yrs) but can occur up to menopause
  • most common type of breast lesion
  • benign overgrowth of collagenous mesenchyme of one breast lobule
  • present as firm, non-tender, highly mobile palpable lumps
  • may be multiple
  • 1/3 regress, 1/3 get stay the same, 1/3 get bigger
106
Q

what is the treatment of fibroadenoma?

A
  • observation and reassurance
  • ultrasound if in doubt +/- fine needle aspiration
  • surgical excision if large enough
107
Q

what are features of breast cysts?

A
  • more common between the ages 35-60 yrs - especially around menopause
  • palpable, benign, fluid-filled rounded lumps that are not fixed to surrounding tissue
  • occasionally they are painful
108
Q

what is the treatment of breast cysts?

A

diagnosis is confirmed with aspiration

109
Q

what are features of intraductal papilloma?

A
  • benign, warty lesion usually located just behind the areola
  • present as a small lump and a sticky, possibly blood-stained discharge may be noticed
  • women aged in their 40s are more likely to have just one but younger women may have multiple lesions
  • triple assessment is required in a specialist breast clinic, with examination, imaging and biopsy
110
Q

how is breast cancer diagnosed?

A
  • triple assessment
  • ask direct questions e.g. past lumps?, family history?, pain?, nipple discharge?, skin changes?, change in size related to menstrual cycle?
  • consider metastatic disease; weight loss, breathlessness, back pain or abdominal mass?
  • check oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status since this will affect treatment
    options
  • expression of HER2 is an adverse factor for small, otherwise good-prognosis tumours - since tumour is more likely to grow and divide!
111
Q

how is triple assessment used to diagnose breast cancer?

A
  • clinical examination
  • radiology
  • histology and cytology
112
Q

how is radiotherapy used to diagnose breast cancer?

A
  • ultrasound for < 35yrs

- mammography (breast X-ray) and ultrasound > 35 yrs

113
Q

how is histology and cytology used to diagnose breast cancer?

A
  • fine-needle aspiration

- ultrasound guided core biopsy

114
Q

what are the results of fine-needle aspiration in an assessment of breasts for breast cancer?

A

if there is a cystic lump:

  • clear fluid found = discard fluid and reassure
  • bloody fluid found = send for cytology
115
Q

what are the results of ultrasound guided core biopsy in an assessment of breasts for breast cancer?

A

if there is a residual mass or solid lump:

  • if malignant = plan treatment
  • if clear fluid found = discard fluid and reassure
116
Q

what questions should be asked in breast cancer diagnosis?

A

ask direct questions e.g. past lumps?, family history?, pain?, nipple discharge?, skin changes?, change in size related to menstrual cycle?

117
Q

what receptors should be checked in breast cancer diagnosis?

A
  • check oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status since this will affect treatment
    options
  • expression of HER2 is an adverse factor for small, otherwise good-prognosis tumours - since tumour is more likely to grow and divide!
118
Q

how is breast cancer staged?

A

CXR, MRI, CT, liver ultrasound, bone scan, liver function tests and Ca2+ for
staging

119
Q

what is stage 1 breast cancer/

A

confined to breast, mobile

120
Q

what is stage 2 breast cancer?

A

growth confined to breast, mobile, lymph nodes in ipsilateral axilla

121
Q

what is stage 3 breast cancer?

A
  • tumour fixed to muscle (but not chest wall), ipsilateral lymph nodes matted and may be fixed
  • skin involvement is larger than tumour
122
Q

what is stage 4 breast cancer?

A
  • complete fixation of tumour to chest wall

* distant metastases

123
Q

what is the TNM staging of breast cancer?

A
  • T1 < 2cm
  • T2 - 2-5 cm
  • T3 > 5cm
  • T4 - fixed to chest wall
  • N1 - mobile ipsilateral nodes
  • N2 - fixed nodes
  • M1 - distant metastases
124
Q

what is surgical treatment of stage 1-2 breast cancer?

A
  • removal of tumour by wide local excision (WLE) or mastectomy
  • +/- breast reconstruction
    • axillary node sampling/surgical clearance
125
Q

how is radiotherapy used to treat stage 1-2 breast cancer? what are its side effects?

A
  • recommended for all patients with invasive cancer after WLE
  • side effects: pneumonitis, pericarditis & rib fracture
126
Q

how is chemotherapy used to treat stage 1-2 breast cancer?

A

alongside surgery e.g. epirubicin + CMF (cyclophosphamide + methotrexate + fluorouracil (5-FU))

127
Q

how is endocrine therapy used to treat stage 1-2 breast cancer?

A

aims to reduce oestrogen activity (to reduce tumour growth) and is used in oestrogen receptor (ER) or progesterone receptor (PR) positive disease

128
Q

what endocrine therapy is only used post-menopause?

A
  • oestrogen receptor blocker e.g. oral tamoxifen

- aromatase inhibitors that target peripheral oestrogen synthesis e.g. oral anastrozole

129
Q

what are side effects of oestrogen receptor blockers?

A

hot flushes, weight gain, mood changes, vaginal discharge, thromboembolism

130
Q

what are side effects of aromatase inhibitors that target peripheral oestrogen synthesis?

A

hot flushes, vaginal dryness, arthralgia, skin rash, osteoporosis

131
Q

what endocrine therapy is used if premenopausal and ER positive?

A
  • ovarian ablation via surgery/radiotherapy - to stop oestrogen synthesis
  • GnRH (gonadotropin-releasing hormone) analogues e.g. oral goserelin
132
Q

what is the treatment of stage 3-4 breast cancer?

A

• radiotherapy to bony lesions:
give bisphosphonates e.g. oral alendronate to reduce fracture risk and pain
• oral tamoxifen is used in ER positive - if there is relapse after initial success then consider chemotherapy
• use oral trastuzumab for HER2 positive tumours
• CNS surgery for solitary and easily accessible metastases; if not then radiotherapy

133
Q

how can breast cancer be prevented?

A
  • promote awareness

- screening - 2-view mammography every 3yrs for women aged 47-73 yrs

134
Q

what is lymphoedema? what is its clinical presentation?

A

• a chronic, non-pitting oedema caused by lymphatic insufficiency i.e. failure of
lymphatic drainage
• most commonly affects the legs and tends to progress with age
• the legs can become enormous and prevent normal shoes being worn
• chronic disease may cause a secondary ‘cobblestone’ thickening of the skin

135
Q

what causes primary lymphoedema?

A
  • presents early in life

* due to an inherited deficiency of lymphatic vessels e.g. Milroy’s disease

136
Q

what causes secondary lymphoedema?

A

due to obstruction of lymphatic vessels e.g. :

  • filarial infection - caused by parasitic worms that occurs the lymphatic system thereby causing obstruction in drainage
  • malignant disease - causes damage/obstruction to lymphatics
  • trauma
  • radiotherapy - causes damage to lymphatics
  • surgery - causes damage to lymphatics
137
Q

what is treatment of lymphoedema?

A
  • compression stockings
  • physical massage
  • for filariasis infection give oral diethylcarbamazine
  • if there is recurrent cellulitis, long-term antibiotics are advisable, as each episode of cellulitis will further damage the lymph vessels
  • surgery should be avoided
138
Q

what is given for filariasis infection in lymphoedema?

A

oral diethylcarbamazine

139
Q

what is the action and side effects of oral diethylcarbamazine?

A
  • kills worms and microfilariae
  • serious allergic responses may occur as the parasites are killed
  • side effects: facial swelling, headaches and lethargy
140
Q

what is given if there is recurrent cellulitis in lymphoedema?

A

if there is recurrent cellulitis, long-term antibiotics are advisable, as each episode of cellulitis will further damage the lymph vessels
• e.g. prophylaxis low-dose antibiotics e.g. oral phenoxymethylpenicillin twice daily

141
Q

what causes carbon monoxide poisoning?

A

• CO poisoning is usually the result of inhalation of smoke, car exhaust or fumes from improperly maintained and ventilated heating systems
• also, the inhalation of methylene chloride (found in paint strippers) may also lead
to CO poisoning as methylene chloride is metabolised in the liver to CO

142
Q

what is the pathophysiology of carbon monoxide poisoning?

A

• carbon monoxide has a 200 times greater affinity for the oxygen-binding sites on
haemoglobin than oxygen and forms carboxyhaemoglobin (COHb)
• thereby reducing the amount of oxygen that combines with haemoglobin and thus the oxygen-carrying capacity of Hb
• in response, the remaining haem groups (of which there are 4) increase their affinity for O2 which decreases the unloading of O2 from haemoglobin in the tissues

143
Q

what is the effect of carbon monoxide poisoning on the oxygen-haemoglobin dissociation curve?

A

shifts it to the left

144
Q

what is the clinical presentation of carbon monoxide poisoning?

A
  • symptoms of mild to moderate exposure to CO may be mistaken for a viral
    illness
  • despite the hypoxaemia the skin is pink/pale and NOT blue
  • vomiting, increased pulse and tachypnoea
  • headache, mental impairment and in severe cases (when COHb > 50%),
    convulsions, coma and cardiac arrest
  • metabolic acidosis, myocardial ischaemia, hypertonia, extensor plantar
    responses, retinal haemorrhages and papilloedema also occur
145
Q

what is the diagnosis of carbon monoxide poisoning?

A
  • do not use pulse oximetry which looks at SpO2 (oxygen blood saturation) since this will be normal as O2 is still in blood but it has just been displaced and is thus not bound to Hb
  • use ABG that looks for SaO2 (oxygen haemoglobin saturation), haemoglobin
    and COHb
146
Q

why should pulse oximetry not be used to diagnose carbon monoxide poisoning?

A

do not use pulse oximetry which looks at SpO2 (oxygen blood saturation) since this will be normal as O2 is still in blood but it has just been displaced and is thus not bound to Hb

147
Q

how is ABG used to diagnose carbon monoxide poisoning? what are the results?

A

use ABG that looks for SaO2 (oxygen haemoglobin saturation), haemoglobin
and COHb:
• venous COHb > 3% in non smokers and > 10% in smokers confirms exposure to CO
• COHb should be < 5% in healthy people

148
Q

what is the treatment of carbon monoxide poisoning?

A
  • remove patient from CO source
  • give 100% O2 until COHb < 10%:
    • metabolic acidosis will usually respond to correction of hypoxia
  • hyperbaric O2 treatment hastens CO elimination and is indicated if the victim has been unconscious, has cardiovascular dysfunction or has a blood COHb concentration > 25%
  • if there is severe CO poisoning there may be cerebral oedema as the cranial vessels vasodilate to compensate for hypoxia: give IV mannitol to reduce ICP
149
Q

what are features of opioid drugs? what are some examples?

A

opioid drugs e.g. diamorphine (heroin), codeine and buprenorphine produce
physical dependancy, such that an acute withdrawal syndrome develops (‘cold
turkey’) if the drugs are stopped

150
Q

what are the withdrawal symptoms of opioids? how can they be reduced?

A

these severe withdrawal symptoms (profuse sweating, tachycardia, dilated pupils,
leg cramps, diarrhoea and vomiting) may be reduced by giving methadone, which is a
pharmaceutical preparation of an opioid

151
Q

what is the clinical presentation of opioid overdose?

A
  • pinpoint pupils
  • reduced respiratory rate (not seen in buprenorphine overdose as this is only a
    partial opioid agonist)
  • coma
  • in severe cases there may be hypothermia, hypoglycaemia and convulsions
152
Q

what is the treatment of opioid overdose?

A

give an opioid antagonist e.g. IV nalozone every 2 minutes until breathing is adequate (since naloxone has a very short half-life) - infusion over time may be necessary to outrun the opiod that caused the overdose since the
duration of naloxone is often less than the drug taken in overdose

153
Q

what is an opioid antagonist?

A

naloxone

154
Q

what are features of insecticide overdose? what is their effect on the body?

A
  • organophosphorus (OP) insecticides are used widely throughout the world and are a common cause of poisoning
  • intoxication may follow ingestion, inhalation or dermal absorption
  • OP insecticides inhibit acetylcholinesterase
  • thereby resulting in the accumulation of acetylcholine (ACh) at central and peripheral cholinergic nerve endings - including the neuromuscular junctions
155
Q

what is the clinical presentation of insecticide overdose?

A
  • SLUD response: salivation, lacrimation (tears), urination, diarrhoea
  • anxiety and restlessness which is typically followed by nausea, vomiting, abdominal colic, diarrhoea (especially if exposure is by ingestion), sweating and chest tightness
  • also look for small pupils, muscle fasciculation, coma, respiratory distress and bradycardia
156
Q

what is SLUD in relation to insecticide overdose?

A

Salivation
Lacrimation (tears)
Urination
Diarrhoea

157
Q

what is the diagnosis of insecticide overdose?

A

confirmed by measuring the erythrocyte acetylcholinesterase activity

158
Q

what is the treatment of insecticide overdose? what is given to symptomatic patients?

A
  • wear gloves and remove soiled clothes and wash skin - for mild cases is this is all that is required
  • give IV atropine every 10 minutes until skin is dry, pulse > 70 bpm and the pupils are dilated
  • symptomatic patients may be given IV pralidoxime chloride to reactivate inhibited acetylcholinesterase
  • most patients recover in 2-3 weeks
159
Q

how can cocaine be taken?

A

injection, inhalation (crack) or ingestion

160
Q

when are effects of cocaine overdose experienced? how long can they last for?

A

• effects are experienced almost immediately and stimulate the CNS producing
euphoria, agitation, hypertension and tachycardia
• effects resolve in about 20 minutes but may last up to 90 mins

161
Q

what is the mechanism of action of cocaine?

A

blocks reuptake of biogenic amines:
- inhibition of dopamine reuptake is responsible for the psychomotor agitation
that commonly accompanies cocaine use
- blockade of noradrenaline reuptake produces tachycardia
- inhibition of serotonin reuptake induces hallucinations

powerful local anaesthetic and vasoconstrictor

162
Q

what is the clinical presentation of cocaine overdose?

A
  • after the initial euphoria, cocaine overdose produces agitation, tachycardia,
    hypertension, sweating, hallucinations, convulsions, metabolic acidosis, hyperthermia, rhabdomyolysis (breakdown of skeletal muscle) and ventricular arrhythmias
  • dissection of the aorta, myocarditis, myocardial infarction, dilated
    cardiomyopathy, subarachnoid haemorrhage and cerebral haemorrhage or
    infarction may occur
  • cocaine overdose should always be considered in a young person presenting with a stroke or MI due to cocaine’s vasoconstrictor effects
163
Q

what is the treatment of cocaine overdose?

A
  • IV diazepam to control agitation and convulsions
  • active external cooling should be employed for hyperthermia
  • hypertension and tachycardia should respond to sedation and cooling
    • if hypertension persists then give IV GTN until BP is
    controlled
  • calcium-channel blockers e.g. verapamil or nifedipine are an alternative second-line therapy
  • beta-adrenoceptor blockers are contraindicated as they may worsen hypertension!!!
164
Q

what drug is contraindicated in cocaine overdose? why?

A

beta-adrenoceptor blockers are contraindicated as they may worsen hypertension!

165
Q

what are sarcomas? where do they develop? what is their origin?

A

• a group of rare solid tumours of connective tissues - more than 50 different
histological subtypes are known
• these cancers develop in the muscle, bone, nerves, cartilage, tendons, blood
vessels and fatty and fibrous tissues
• mesodermal origin

166
Q

what is the epidemiology of sarcomas?

A
  • account for 1% of all adult tumours

- soft tissue sarcoma (STS) is more common than bone sarcoma

167
Q

what are the two main types of sarcomas?

A
  • soft tissue sarcoma (80%)

- bone sarcoma (20%)

168
Q

what is the epidemiology of soft tissue sarcomas?

A
  • majority of sarcomas
  • can affect any part of the body
  • more common in middle age and elderly
169
Q

what are examples of soft tissue sarcomas?

A
  • leiomyosarcoma - the most common STS
  • GI stromal tumours (GIST):
    • common type - develops from GI tract
  • other examples include; angiosarcoma, liposarcoma and gastrointestinal stromal tumours (GIST)
170
Q

what are red flags for soft tissue sarcomas?

A

a lump is more likely to be sarcoma if it:
• is big (more than 5cm across) or getting bigger
• is deep in the body tissues
• is painful
• occurs when you are older

171
Q

what is the clinical presentation of soft tissue sarcomas?

A
  • lump that’s painless at first
  • pain and soreness as the lump grows and presses against nerves and muscles
  • a leiomyosarcoma in the womb may cause bleeding other than when patient is having a period or after menopause
  • most sarcomas metastasise to the lung initially
172
Q

how are soft tissue sarcomas diagnosed?

A
  • MRI and core needle biopsy

- CT thorax for lung metastases

173
Q

what is the treatment of soft tissue sarcoma?

A
  • surgical resection + chemotherapy +/- radiotherapy

- chemotherapy +/- radiotherapy if unresectable

174
Q

what is the epidemiology of bone sarcoma?

A
  • only affect less than 500 people in the UK each year - very rare form of cancer
  • more common in those under 20
175
Q

what are examples of bone sarcomas?

A
  • osteosarcoma:
    • the most primary malignant bone tumour
    • occurs predominantly in those under 20 and in 80% is in the long bones
  • other examples include; Ewing’s sarcoma, chondrosarcoma and spindle cell sarcomas
176
Q

what are red flags for bone sarcoma?

A
  • pain
  • non mechanical bone pain
  • night pain
  • palpable bony mass
  • if patient presents with these then investigate - start with X-ray
  • average duration of symptoms is 3 months
  • bone destruction, new bone formation, periosteal swelling and soft tissue swelling suggest tumour
177
Q

what is the clinical presentation of bone sarcoma?

A
  • non mechanical bone pain that is still present when lying still
  • swelling
  • feeling tired
  • pyrexia
  • weight loss
178
Q

what is the diagnosis of bone sarcoma?

A
  • X-ray, CT or MRI

- bone scans and biopsy

179
Q

what is the treatment of bone sarcoma?

A
  • wide surgical resection and reconstruction

- chemotherapy +/- radiotherapy

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