Oncology and Haematology

Question 1

a) What is the most common Melanoma?
b) What is the most common melanoma in blacks, Asians, and Hispanics? What is it’s appearance and most common location? (pictured)
c) Describe 3 characteristics of a nodular melanoma
d) Describe Lentigo maligna melanoma
e) Describe dysplastic naevi

Answer 1

a) Superficial Spreading Melanoma
b) Acral lentiginous melanoma. An enlarging hyperpigmented macule or plaque on the palms/soles
c) Rapidly growing, often ulcerated or crusted black nodule.
d) Occurs on sun-exposed skin, often large, hyperpigmented macule or plaque with irregular borders and variable pigmentation (pictured).
e) Benign, irregularly pigmented and shaped with some atypical cellular features (frequently associated with familial melanoma).

Question 2

a) Where are melanocytes derived and where do they migrate to?

Answer 2

a) Melanocytes originate from neural crest cells and migrate to the skin, meninges, mucous membranes (nasal cavity, paranasal sinus, oral cavity, GIT, CNS, vulva/vagina, and uveal tract of the eye), upper oesophagus, and eyes.

NB: Melanocytes can undergo malignant transformation at all of these sites, however the most common is the skin.

Question 3

a) What are the strongest risk factors for developing melanoma?
b) The presence of how many naevi infers an increased risk?
c) What percentage of melanomas arise from naevi?
d) What is the lifetime risk for an individula with clinically atypical moles and a strong family hx of melanoma?

Answer 3

a) Presence of multiple benign or atypical naevi and a family or personal hx of melanoma
b) The presence of >40 melanocytic naevi, common or dysplastic, is a marker for increased risk.
c) ~25% of melanomas are histologically associated with naevi, but the majority arise de novo
d) ~50% lifetime risk. Warrants close f/u with dermatologist.

Question 4

a) What are the size classifications of melanocytic naevi? and what size poses the highest risk?
b) What is the liklihood of congenital melanocytic naevi developing into melanoma? What is the best management option for these naevi?

Answer 4

a) Small (<1.5cm), medium (1.5-20cm), and giant (>20cm). Gant melanocytic naevus (bathing trunk naevus) has the highest risk, prophylactic excision early in life is often prudent.
b) Risk for a typical naevus is low, ~0.03% (1 in 3164) for men and 0.009% (1 in 10,800) for women. Management is controversial as surgery cannot remove all at risk naevus, therefore excision is primarily based on histologic findings from biopsies of clinically stypical naevi.

Question 5

a) After diagnosis of melanoma, what is the individuals lifetime risk in comparison to the general population, and how long should surveillance continue?
b) What is the risk of melanoma for patients with a family history, and what are the true signs of familial melanoma?

Answer 5

a) LIfetime risk is 10x greater than the general population and surveillance should be lifelong.
b) First-degree relatives have 2x greater risk of developing melanoma. (NB: Only 5-10% of melnomas are truly familial). In familial melanoma, patients tend to be younger at Dx, lesions are thinner, and multiple primary melanomas are common.

Question 6

a) What percentage of melanomas are due to germline mutations in the cell cycle?
b) What locus & chromosome mutations/deletion is involved in most cutaneous melanoma?
c) What two tumour-suppressor proteins does this locus encode?
d) What is the function of the above 2 tumour supporessor proteins, and what is the end result if CDKN2A is deleted?

Answer 6

a) 20-40% of hereditary melanoma (0.2-2% of all melanoma).
b) 70% of all cutaneous melanoma have mutations or deletions affecting CDKN2A locus on chromosome 9p21
c) p16 and ARF (p14ARF)
d) p16 protein inhibits CDK4/6-mediated phosphorylation and inactivation of the retinoblastoma (RB) protein, whereas ARF inhibits MDM2 ubiquitin-mediated degradation of p53. If CDKN2A is deleted, this results in inactivation of two critical tumor-suppressor pathways, RB and p53, which control entry of cells into the cell cycle.

Question 7

a) What other cancer is associated with CDKN2A mutations?
b) What is another high risk locus and chromosome associated with melanoma suseptibility? What is it’s role?
c) What pathway do they inactivate?
d) What 2 rarer germline mutations predispose to both familial and sporadic melanomas?

Answer 7

a) Pancreatic cancer
b) CDK4, on chromosome 12q13. It encodes the kinase inhibited by p16
c) Inactivate RB pathway.

NB: CDK4 mutations are much rarer than CDKN2A mutations.

d) Melanoma lineage-specific oncogene microphthalmia-associated transcription factor (MITF) and telomerase reverse transcriptase (TERT) mutations predispose to both familial and sporadic melanomas.

Question 8

a) What inherited gene associated with increased melanoma susceptibility is associated with red hair?
b) What stimulates MC1R and what is it’s function?
c) How is MC1R associated with red hair?

Answer 8

a) Melanocortin-1 receptor (MC1R) gene

b) Solar radiation stimulates the production of melanocortin (α-melanocyte-stimulating hormone [α-MSH]), the ligand for MC1R, which is a G-protein-coupled receptor that signals via cyclic AMP and regulates the amount and type of pigment produced.
c) MC1R is highly polymorphic, with 80 variants. Those that result in partial loss of signaling lead to the production of red/yellow pheomelanins, which are not sun-protective and produce red hair (rather than brown/black eumelanins that are photoprotective).

Question 9

a) What is the phenotypical appearance and skin risks in relation to Red Hair Colour (RHC)?
b) What is the risk of pheomelanin vs eumelanin?
c) What are some other more common, low-penetrance polymorphisms that affect melanoma susceptibility?

Answer 9

a) Fair skin, red hair, freckles, increased sun sensitivity, and increased risk of melanoma.

b) Increased pheomelanin production in patients with inactivating polymorphisms of MC1R also provides a UV-independent carcinogenic risk of melanomagenesis via oxidative damage and reduced DNA damage repair.
c) Genes related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor.

Question 10

a) What are the primary prevention methods for melanoma?
b) What are the secondary prevention methods for melanoma?
c) What is tertiary prevention of melanoma?

Answer 10

a) Regular use of broad-spectrum sunscreens that block UVA and UVB with (SPF)> 30 and protective clothing. Avoidance of sunburns, tanning beds, and midday sun exposure is recommended.
b) Education-patients should be taught to recognise the clinical features of melanoma, screening-full body skin exam (may be at increased intervals depending on risk factors), and early detection e.g. biopsy.
c) Lifetime surveillance with full body skin exams by a deramtologist.

Question 11

a) What is the ABCDEs approach to identifying melanoma?

Answer 11

a) Asymmetry; border irregularity; color variation (benign lesions usually have uniform light or dark pigment); diameter >6 mm; and evolving (change in size/shape/color/elevation or new symptoms e.g bleeding, itching, crusting).

NB: Naevus that appears atypical and different from the rest of the naevi on that individual (an “ugly duckling”) should be considered suspicious.

Question 12

a) What are the optimal factors involved in a full skin check?

Answer 12

a) -Examination of the entire skin surface including scalp, mucous membranes and nails
- Bright room illumination
- Hand lens with low-level magnification with polarised light (may allow more precise visualisation of patterns of pigmentation possible for the naked eye)
- Resources to biopsy suspicious lesions
- Chart or photography for suspicious lesions

Question 13

a) What margins are suggested for an excisional biopsy?
b) What are the types of biopsy?
c) What is the aim of biopsy and what are the limitations of Shave biopsies?
d) What should the biopsy report include?
e) What is the breslow thickness?
f) What other options are there to distinguish challenging benign naevi from melanomas?

Answer 13

a) 1-3mm margin for excisional biopsy
b) Fusiform (ellipse excision), Tangential (shave), Incisional (incomplete excision) NB: Incisional biopsy does not appear to facilitate spread of melanoma.
c) The aim of the biopsy is to assess the deep and peripheral margins and to perform immunohistochemistry. Shave/tangential biopsies are an acceptable alternative (if the suspicion of malignancy is low), however it may be difficult to get to the deepest margin.
d) Breslow thickness, mitotic rate, presence/absence of ulceration and lymphatic invasion, microsatellitosis and peripheral and deep margin status.
e) Breslow thickness is the greatest thickness of a primary cutaneous melanoma measured on the slide from the top of the epidermal granular layer, or from the ulcer base, to the bottom of the tumor.
f) Fluorescence in situ hybridization (FISH) with multiple probes and comparative genome hybridization (CGH) can be helpful.

Question 14

a) What are the 5 major types of cutaneous melanoma?
b) What types have a period of radial growth, where size increases but it does not penetrate? NB: This is the time melanoma is most likely to be cured with surgical excision.
c) What type of cutaneous melanoma does not have a radial growth phase?
d) Describe the characteristics of desmoplastic melanoma?

Answer 14

a) Superficial spreading melanoma, Lentigo melanoma maligna, acral lentinginous melanoma, nodular melnoma and Desmoplastic melanoma.
b) Superficial spreading melanoma, Lentigo melanoma maligna & acral lentinginous melanoma.
c) Nodular melanoma. Usually presents as a deeply invasive lesion that is capable of early metastasis.
d) Desmoplastic melanoma is associated with a fibrotic response, neural invasion, and greater tendency for local recurrence.

NB: Melanomas can also be amelanotic, which are Dx microscopically.

NB: Although these subtypes are clinically distinct, this classification has minimal prognostic value and is not part of staging.

Question 15

a) Melanomagenesis (pathogenesis of melanomas) arises from environmental and genetic components. Describe the environmental component and how this affects the skin
b) How is UVR exposure implicated in Melanomas?

Answer 15

a) Major effect of UV solar radiation is to cause genetic changes in the skin. However, it also impairs cutaneous immune function, increases production of growth factors, and induces the formation of DNA-damaging reactive oxygen species that affect keratinocytes and melanocytes.
b) Melanomas arising in chronic sun-damaged skin harbor substantially more mutations than melanomas from non-sun-damaged skin. The majority (76% primary tumors and 84% of metastatic melanomas) exhibit a mutation signature indicating UVR exposure.

Question 16

a) Describe driver mutations
b) Describe the major driver mutations involved in melanoma
c) Describe the 3 main features of the malignant phenotype
d) Name the most prevalent significant mutated genes in melanoma?

Answer 16

a) A mutation that is causally implicated in oncogenesis by virtue of a conferred growth advantage on the cancer cell. Driver mutations often affect pathways that promote cell proliferation or inhibit normal pathways of apoptosis in response to DNA repair.

b) **MAP kinase and PI3K/AKT pathways: Promote proliferation and inhibit apoptosis, respectively, are subject to mutations in melanoma.
- ERK: extracellular signal-regulated kinase
- MEK: Mitogen-activated protein kinase
- NF-1: Neurofibromatosis type 1 gene
- PTEN: Phosphatase and tensin homolog.
c) Invasion, metastasis, and angiogenesis.
d) BRAF, RAS, NF-1, and triple-WT (wild-type)

Question 17

a) Describe mutations that alone, are not necessarily associated with melanoma. Describe their frequency and what other mutations they’re often associated with to cause melanoma.
b) Describe BRAF mutation in melanoma

Answer 17

a) N-RAS is mutated in ∼20% of melanomas, and somatic activating BRAF mutations are found in most benign naevi and 40–50% of cutaneous melanomas. Neither mutation by itself appears to be sufficient to cause melanoma; they often are accompanied by other mutations, such as TERT.
b) Point mutation (valine-to-glutamate amino acid substitution (V600E)) present in most melanomas that arise on sites of intermittent sun exposure. Most important with therapeutic decision making in patients with advanced melanoma.

Question 18

a) Describe how mutations in AKT (primarily AKT3) and PTEN (phosphatase and tensin homolog) can come about in melanoma.
b) What can be the sequence of events after the above mutations occur?
c) What can occur with mutation in NF1?

Answer 18

a) AKT can be amplified and PTEN may be deleted or undergo epigenetic silencing.
b) The above leads to activation of PI3K/AKT pathway and enhanced cell survival by antagonizing the intrinsic pathway of apoptosis. Loss of PTEN and mutation of AKT3 both prolong cell survival through inactivation of BAD, BCL-2-antagonist of cell death, and activation of the forkhead transcription factor FOXO1, which leads to synthesis of prosurvival genes.
c) Mutation of NF-1 affects both MAP kinase and PI3K/AKT pathways. These two signaling pathways enhance tumorigenesis, chemoresistance, migration, and cell cycle dysregulation.

Question 19

a) What is needed to ensure complete melanoma staging?

Answer 19

a) -Microscopic evaluation of skin lesion including regional lymph nodes obtained during excisiona and sentinel node biopsy.
- Complete history, with attention to symptoms that may suggest metastatic disease (malaise, weight loss, headaches, visual changes, and pain)
- Physical exam directed to the site of primary melanoma e.g. looking for persistent disease or for dermal or subcut nodules that could represent satellite or in-transit metastasis, and to regional draining lymph nodes, CNS, liver and lungs.
- FBE, metabolic panel, LDH. e.g. microcytic anaemia may indicate bowel mets, and elevated LDH should prompt a extensive evaluation, incl CT &/or PET.

NB: At initial presentation, >80% of patients will have disease confined to the skin and a negative history and physical examination, in which imaging is not indicated.

Question 20

a) For clinically localised melanoma, what is the best treatment option?
b) Inclusion of what tissue allows the best assessment by pathologist?
c) What topical treatment option is available for lentigo maligna (i.e superficial melanoma)?
d) What is the MOA for this medication?

Answer 20

a) Wide local excision with a margin of normal skin is necessary to remove all malignant cells and minimize possible local recurrence. For a lesion >2mm, 2cm margin is advised.
b) Inclusion of subcutaneous fat in the surgical specimen facilitates adequate thickness and assessment of surgical margins by pathologist.
c) Imiquimod has been used for lentigo maligna in cosmetically sensitive locations.
d) It enhances immune response. It is a Toll-like receptor 7 agonist that activates immune cells, increasing interferon and other cytokines

Question 21

a) What is the importance of SLNB?
b) When should SLNB be done? How does it work?
c) What is the indications for a SLNB? (thickness)
d) What is the false negative rate of SLNB?
e) What is the approx % of patients with SLN involvement according to melanoma thickness?

Answer 21

a) SLNB is a valuable staging tool for the evaluation of regional nodal status. SLNB provides prognostic information and helps identify patients at high risk for relapse who may be candidates for adjuvant therapy.
b) Ideally SLNB should be done at the same time as WLE. Blue dye with radioisotope is injected around the primary site, SLN is identified by inspection at the nodal basin for blue stained node/high uptake radioisotope. Identified node/s then removed for histopathologic analysis.
c) In melanoma, lesions >0.8mm generally undergo SLNB. For melanomas 0.76-0.8mm thick, SLNB may be considered for lesions with high risk features such as ulceration, high mitotic index, or lymphovascular invasion, but WLE alone is the usual definitive therapy.
d) False negative ~4% of the time.
e) <1.0mm =6.0%
1. 01-2.0mm=14.0%
2. 01-4.0mm=27.3%

>4.0mm=39.1%

(www.mskcc.org/normograms/melanoma/sentinel_lymph_node_metastasis)

Question 22

a) What is the current standard of care for patients with a positive SLN?
b) What adjuvant therapies are available for patients with postitive SLN, and clinically localised melanoma (Stage I, II)?
c) Describe the MOA of the combined immunotherapy?

Answer 22

a) Complete lymphadenectomy. NB: Complete lymph node dissection is not necessary for patients with lymph node micrometastasis <1mm.
b) Immunotherapy: Ipilimumab + Nivolumab (median survival >5 years)

Nivolumab; Pembrolizumab (median survival >3 years)

**Many with L-T response ?cure

Targeted Therapy: BRAF + MEK inhibitors. Median survival >2 years. ~1/3 alive at 5 years.

c) Ipilimumab is a recombinant human IgG1 immunoglobulin monoclonal antibody that binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). CTLA-4 is a down-regulator of T-cell activation pathways. Blocking CTLA-4 allows for enhanced T-cell activation and proliferation. In melanoma, ipilimumab may indirectly mediate T-cell immune responses against tumors.

Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from binding. The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore disrupted. This prolongs the life of the T cell and leads to increase immune system response.

Combining ipilimumab (anti-CTLA-4) with nivolumab (anti-PD-1) results in enhanced T-cell function that is greater than that of either antibody alone, resulting in improved antitumor responses in metastatic melanoma and advanced renal cell carcinoma.

Question 23

a) What are the options for skin biopsy, what is the best biopsy technique (why) and what is the recommended biopsy margin?
b) What are the indications for a shave biopsy and what are the shortfalls?
c) In what percentage of patients with a melanoma, have another melanoma found on skin check at the same time?

Answer 23

a) Superficial shave biopsy, Saucerisation shave biopsy (deeper biopsy extending 1-4mm deep to mid-dermis or S/C tissue), punch biopsy, excisional biopsy or incisional biopsy. Recommended biopsy margin is 2mm. NB: Avoid flap closure in biopsy.
b) The indications for a shave biopsy are when the suspicious lesion is very large or on a difficult location e.g. top of the head, face or neck. The drawbacks are that often the shave biopsy will traverse the base of the lesion, leading to inaccurate results about the depth of the lesion. Punch biopsies which do not involve the entire lesion could lead to false negatives.
c) 10-15% of melanoma patients have a second melanoma present.

Question 24

a) Where can melanomas recur, what is the name according to location?
b) What are the treatment options for in-transit disease and distant skin and soft tissue metastases?
c) Patients rendered disease free after surgery may be at high risk of recurrence, what is the role of radiotherapy in regionally metastatic melanoma?
d) What is the indication in regionally metatic melanoma for radiotherapy?

Answer 24

a) At the edge of the scar or graft, as satellite metastases, which are within 2 cm of the scar; as in-transit metastases, which are >2 cm from primary lesion but not beyond regional nodal basin; or, most commonly, as metastasis to a draining lymph node basin
b) Surgical Excision, another option is-Topical immunotherapy such as imiquimod,historically, intralesional bacille Calmette-Guerin (BCG) has been used with high rates of regression-however with unacceptable levels of anaphylactic reaction and death from disseminated BCG.
c) Radiotherapy can reduce the risk of local recurrence after lymphadenectomy, but does not affect overall survival.
d) Patients with large nodes (>3–4 cm), four or more involved lymph nodes, or extranodal spread on microscopic examination

Question 25

a) When is systemic adjuvant therapy primarily indicated? What are some exceptions?

Answer 25

a) Patients with stage III disease, but high-risk, node-negative patients (>4 mm thick or ulcerated lesions), and patients with c_ompletely resected stage IV disease_ also may benefit.

Question 26

a) At diagnosis, what is the percentage of patients with early stage disease and those who will already have mets?
b) What is the probability of recurrence in stage IA to stage IIIC disease at presentation?
c) Prognostically, which location of metastasis is slightly better?
d) What is another prognostic marker in blood testing?

Answer 26

a) 84% will have early stage disease and 4% will present with metastasis.
b) <5% with stage IA to >90% with stage IIIC

NB: Patients with a history of melanoma who develop symptoms suggesting recurrence of disease should undergo restaging.

c) The prognosis is better for patients with skin and subcutaneous metastases (M1a) than for lung (M1b) and worst for those with metastases to liver, bone, and brain (M1d).
d) Elevated serum LDH is a poor prognostic factor and places the patient in stage M1a(1) regardless of the site of the mets

Question 27

a) Adjuvant treatment for stage IV melanoma has changed dramatically since 2011. What 3 T-cell checkpoint inhibitors are now FDA approved?
b) What 4 oral agents that target the MAP kinase pathway?
c) Is surgery an option for metaststic disease?

Answer 27

a) Ipilimumab, Nivolumab, and Pembrolizumab.
b) the BRAF inhibitors-Vemurafenib & dabrafenib

the MEK inhibitors-Trametinib and Cobimetinib

(& the oncolytic virus talimogene laherparepvec)

c) Surgery should be considered for patients with oligometastatic disease because they may experience long-term disease-free survival after metastasectomy. Patients with solitary metastases are the best candidates, but surgery can also be used for metastases at more than one site if a complete resection can be achieved. Patients rendered free of disease can be considered for adjuvant therapy or a clinical trial because their risk of developing additional metastases is very high.

Question 28

a) What Immunotherapy is available for stage IV patients?
b) What is the MOA and what is the infusion regimen?

Answer 28

a) Interleukin 2 or Aldesleukin is used to treat stage IV patients who have good performance status.

b) Aldesleukin is an interleukin-2 which promotes proliferation, differentiation, and recruitment of T and B cells, natural killer (NK) cells, and thymocytes. This can _stimulate lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) cells._Treatment requires hospitalisation in a HDU setting. If tolerated 4-6 cycles can be given over 4-6 months to allow for recovery from toxicity b/t cycles. L-T disease-free survival (probable cure) is observed in 5% of treated patients.

Question 29

a) What are the most common checkpoint blockade adjuvant therapies used for the management of metastatic melanoma?
b) What is the main benefit and side effects of checkpoint blockade adjuvant therapies?
c) In the event of toxicity, what is the best managment plan?

Answer 29

a) Ipilimumab, Nivolumab and Pembrolizumab have been approved to treat metastatic melanoma. Combination T-cell checkpoint therapy, blocking both inhibitory pathways (CTLA-4 & PD-1) with ipilimumab and nivolumab, leads to superior antitumor activity compared to treatment with either agent alone.
b) Main benefit from immune-based therapy is the durability of the responses achieved. The most common immune-related adverse events were skin rash and diarrhea (sometimes severe, life-threatening colitis), but toxicity can involve any organ (e.g., hypophysitis, hepatitis, nephritis, pneumonitis, myocarditis, neuritis).
c) Vigilance, interruption of therapy and early intervention with steroids (or other immunosuppressive agents, such as anti-tumor necrosis factor antibodies or mycophenolate mofetil) can mitigate toxicity and prevent permanent organ damage.

Question 30

a) What targeted therapy is currently available for metastatic melanoma?
b) How do these targeted therapies work?
c) What is the biggest limitation with targeted therapies at present?

Answer 30

a) Two BRAF inhibitors, vemurafenib and dabrafenib, have been approved for patients whose stage IV melanomas harbor a mutation at position 600 in BRAF.
b) RAF and MEK inhibitors of the MAP kinase pathway can induce regression of melanomas that harbor a BRAF mutation. Combined BRAF and MEK inhibition to address the rapid adaptation of the majority of melanomas that use MAP kinase pathway reactivation to facilitate growth when BRAF is inhibited.
c) Major limitation of both monotherapy and combined therapy appears to be the acquisition of resistance; the vast majority of patients relapse and eventually die.

NB: Patients who develop resistance to BRAF and MEK inhibition are candidates for immunotherapy or clinical trials.

Question 31

a) What is a specific side effect of BRAF targeted therapy?
b) What is another rare mutation commony seen in acral and mucosal melanomas?
c) Is there a role for chemotherapy in metastatic melanoma

Answer 31

a) Development of numerous skin lesions, some are well-differentiated squamous cell skin cancers (SCC) (seen in up to 25% of patients). This process is blocked by the MEK inhibitor, which explains why these lesions occur less frequently during combined therapy. Patients should be co-managed with a dermatologist as these skin cancers will need excision.
b) c-kit receptor tyrosine kinase. Melanomas with activating c-kit mutations can have clinically meaningful responses to imatinib. MEK inhibitors are being investigated in clinical trials.
c) No chemotherapy regimen has ever been shown to improve survival of patients with metastatic melanoma. The advances in immunotherapy and targeted therapy have relegated chemotherapy to the palliation of symptoms.

Question 32

a) What is the initial approach to a patient with metastatic disease
b) What are the basics of follow-up for patients with melanoma
c) Describe ECOG performance status levels

Answer 32

a) Biopsy of the lesion should be tested for a druggable mutation (e.g. BRAF and c-kit)
- > If BRAF-wildtype tumour then immunotherapy is recommended.
- >If BRAF only mutation, initial therapy with combination BRAF and MEK inhibitors OR immunotherapy is acceptable.
- >Consideration for enrollment in clinical trial
- >Timely integration of palliative care/hospice for patients whom are poor candidates for above therapy.
b) Skin examination and surveillance 6 monthly. For stage IIA disease 6-12 monthly PET scans (note from webinar). Diagnostic imaging surveillance is recommended for higher stage disease.
c) 1-Asymptomatic

2-Symptomatic but completely ambulatory

3-Symptomatic, <50% in bed during the day

4-Symptomatic, >50% in bed, nut not bedbound

5-Bedbound

6-Death