Problem 1 Flashcards
What ranking takes the colorectal cancer for most deadly cancer
4th
Risk factors for colorectal cancer
male sex age family history obesity lack of physical exercise smoking excessive alcohol intake red and processed meat intake Diabetes type 2 inflammatory bowel disease previous colorectal cancer or adenomas hereditary colorectal cancer syndromes infection with certain bacteria like Fusobacterium nucleatum and Bacteroides fragilis (picture)
What percentage of total deaths and cancer diagnosis
10%
What rank for women and men for most common
2nd for women
3rd for men
Highest rates in which countries
most developed countries
Why is there a decrease in the incidence
screening programs
There is a worrying increase of colorectal cancer for who
people younger than 50 years specifically rectal cancer and left-sided colon
Based on twin studies, what percentage of heritability is colorectal cancer
12-35%
What are the 2 kinds of hereditary colorectal cancer syndromes
non-polyposis and polyposis
Examples of non-polyposis syndromes
Lynch and familial colorectal
Why is the Lynch diagnosis frequently missed
few adenomas, and if present they can be mistaken for sporadic lesions
What is the solution for not missing the diagnosis of Lynch syndrome
Systemic molecular screening of the tumor for patients under 70
Cause du syndrome de Lynch
dysfunction of the DNA mismatch repair system
SO expansion or contraction of the microsatellite regions so microsatellite instability
+deficiency of mismatch repair proteins
Is microsatellite instability specific for Lynch syndrome
No
Are Lynch patients at risk of other cancers
Yes, endometrial, small bowel, ovaries, hepatobiliary, stomach, ureter, renal pelvis
What is advised for Lynch patients from 20 to 25 years
1-2 yearly colonoscopies
Most cancers arise from…
a polyp
3 steps to cancer formation
aberrant crypt
polyp (neoplastic precursor lesion)
cancer
How long does it take for cancer to form
10-15 years
What is the origin cell for colorectal cancers
stem cell or stem-like cell
Where do the stem cells reside (causing cancer)
base of the crypts
How many major precursor lesion pathways
- traditional adenoma-carcinoma pathway (chromosome instability process) 70-90% of colorectal cancers
- serrated neoplasia pathway 10-20%
What happens in the traditional adenoma-carcinoma pathway
initiated by APC mutation, followed by RAS activation or function loss of TP53
What happens in the serrated neoplasia pathway
RAS and RAF mutations and epigenetic instability characterized by the CpG island methylation phenotype leading to microsatellite stable and instable cancers
also, presence of polymerase-ε or POLE mutations or mismatch repair deficiency [dMMR]) leading to a hypermutated phenotype.
Why is right/left sides important
metastasis settings and responsiveness to anti-EGFR drugs
What are the molecular subtypes of colorectal cancer
CMS 1 MSI immune
CMS 2 canonical
CMS 3 metabolic
CMS 4 mesenchymial
Which subtypes are mostly common for the right side
MSI-immune and metabolic
What are the symptoms
occult or overt blood
change in bowel habits
anemia
abdominal pain
Does bleeding always mean something malignant
no, could be benign
How do we diagnose colorectal cancer
Colonoscopy
What is a complementary method to diagnose
CT scan
What is very important to check in blood test to diagnose
CEA
What does a high concentration of CEA pre-operative and post indicate
pre: bad prognosis
post: residual disease
Why do mismatch repair test
Lynch
adjuvant fluoropyrimidine based therapy
and identifying patients who can respond to immunotherapy
What are RAF and RAS mutations implicated in
proliferation
apoptosis
angiogenesis
Treatment for T1 cancers and techniques
Depending on its size, the endoscopic techniques are:
en-bloc endoscopic mucosal resection
endoscopic submucosal dissection
endoscopic full-thickness resection.
The last 2 should be considered when there is a high suspicion of superficial submucosal invasion.
How has surgery been optimized
by the use of sharp dissection along the embryological planes within the mesofascial interface, according to the so-called complete mesocolic excision principle.
Excision for rectal cancer surgery
Total mesorectal excision is the standard oncological
approach
Laparoscopy for surgery ?
yes for colon cancer
debated for rectal cancer
Can colorectal cancer be an emergency ?
yes if obstruction or perforation
How can colonic obstruction be relieved
by a decompressing colostomy or endoscopic stenting.
Decision for stenting should be multidisciplinary since it can limit the later use of anti-VEGF
drugs due to risk of perforation.
Benefit of preoperative radiotherapy
reduces risk of recurrence
Most used therapy is
Chemoradiotherapy with a dose of 45–50 gray in 25–28 fractions, and with a fluoropyrimidine as radiation sensitiser.
The preffered local ablative therapy for liver
Radiofrequency ablation
For larger lesions and those close to vascular structures, microwave ablation or stereotactic radiotherapy might be good alternatives.
Local treatment of lung metastases
Resection, stereotactic radiotherapy and radiofrequency ablation
Treatment of peritoneal metastases
Cytroreductive surgery and hyperthermic intraperitoneal chemotherapy
What is the main drawback of oxaliplatin use
sensory neuropathy
What component indicates a good prognostic when it is present
dMMR for stage II
What does the systemic therapy for metastatic colorectal cancer include
a chemotherapy backbone (Fluoropyrimidines, oxaliplatin, and irinotecan) paired with a
biologic (anti-VEGF or anti-EGFR antibody).
What is the anti-VEGF monoclonal antibody called
Bevacizumab
What does the anti-VEGF antibody target
angiogenesis
Other anti-VEGF agents are…
aflibercept and ramucirumab
What therapy do right-sided tumors not benefit from
anti-EGFR
What should we test before using anti-EGFR therapy
RAS and RAF mutations
Which first line therapy to use for left-sided RAS and RAF-wild-type metastatic colorectal
anti-EGFR agents (cetuximab or panitumumab) or
anti-VEGF agents (bevacizumab) can be used
Examples of anti-EGFR agents
cetuximab and panitumumab
Which tumors do not respond well to systemic treatment
BRAF-V600E mutations
Treatment for BRAF-V600E mutation tumors
Upfront triplet chemotherapy with bevacizumab is recommended. Combinatorial strategies (BRAF-inhibitors and anti-EGFR antibodies paired with
chemotherapy or MEK inhibitors)
Treatment for patients with refractory metastatic colorectal cancer who have not responded to systemic therapies
Regorafenib (a so-called dirty tyrosine-kinase inhibitor) and TAS-102 (combination of trifluridine and tipiracil, an oral anti-metabolite)
Treatment for the 4–5% of tumours with dMMR or high MSI (MSI-H)
PD-1 blockade with immunotherapies such as nivolumab or pembrolizumab is now approved. Combination immunotherapy (nivolumab and ipilimumab) is also approved.
What is bowel dysfunction after restorative rectal cancer resection called
low anterior resection syndrome
How to manage low anterior syndrome
by dietary changes, medication (eg, loperamide) and anal irrigation
What can the rectal cancer treatment, particularly combined radiation and surgery, affect
bladder and sexual function
Chemotherapy side effects
cumulative neuropathy (paraesthesia, numbness or tingling affecting activities of daily living from platinum chemotherapy), and liver toxicity
What is the guaiac test
Screening for microscopic amounts of blood with the guaiac test (or guaiac-based faecal occult blood tests) reduced colorectal cancer mortality by approximately 16% more than a decade ago.
Prevention for patients with Lynch Syndrome
colonoscopic surveillance should be performed at a 2 yearly interval for all LS patients.
At what age should we start colonoscopies for Lynch
We recommend colonoscopy from age 25 years for
MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers.
What are tumeurs desmoides
tumeurs mésenchymateuses bénignes à agressivité locale sans potentiel métastatique. Les tumeurs desmoïdes proviennent d’une prolifération tumorale au dépend des fibroblastes et myofibroblastes du tissu conjonctif.
appartiennent au groupe des tumeurs conjonctives parmi lesquelles on distingue des tumeurs malignes (cancers type sarcomes ou tumeurs stromales gastro-intestinales. . .) et des tumeurs bénignes (lipomes, fibromes. . .).
Physiopathologie d’une mutation APC
La mutation germinale du gène APC aboutit à une perte de la fonction de la protéine APC, ce qui conduit à l’instabilité et la dégradation du complexe Wnt/APC/b-caténine conduisant la libération de la b-caténine (facteur de transcription), dont l’accumulation au niveau nucléaire stimule la division cellulaire
What is FAP
maladie à transmission autosomique dominante liée à une mutation germinale du gène APC
What is the syndrome de Gardner
L’association d’une polypose colorectale et de tumeurs
desmoïdes
La particularité des tumeurs desmoïdes associées à la PAF
localisation majoritairement intra-abdominale et risque de complication
TD
Les tumeurs desmoïdes « TD » ou fibromatose agressive
ne présentent pas de risque de dissémination à distance
mais une agressivité locale qui peut entraîner des complications
graves
FR des tumeurs desmoides
histoire familiale
chirurgie pendant l’ enfance (colo-protectomie)
mutation
grossesse
Mutations associees au syndrome de Lynch
anomalie constitutionnelle touchant les gènes de réparation de l’ADN du système MMR à pénétrance incomplète.
soit MLH1, MSH2, MSH6 ou PMS2 ou du
gène EPCAM (situé en amont du promoteur du gène MSH2 et qui conduisant à l’inactivation
épigénétique du gène MSH2). Une inactivation somatique de l’autre copie du gène (par
mutation, perte d’hétérozygotie..) aboutit alors à l’inactivation du gène MMR, et à la perte de
fonction de la proteine.
diagnostic syndrome de Lynch
-Critères d’Amsterdam II mais manque de sensibilité
-Critères d’Amsterdam élargis et des critères
de Bethesda II. Ils sont plus sensibles mais moins spécifiques
-Il existe 2 techniques pour identifier un phénotype MSI : la biologie moléculaire par PCR pour mise en evidence d’une MSI et l’immunohistochimie (IHC) qui permet de mettre en évidence la perte d’expression de protéines du système MMR (tumeurs MMR déficientes)
les 2 formes du syndrome de Lynch
Il existe deux formes phénotypiques variantes du syndrome de Lynch :
-le syndrome de Muir Torre, dont le spectre est élargi aux tumeurs cutanées sébacées et aux kérato acanthomes
-le syndrome de Turcot, dont le spectre inclut le cancer du côlon et des tumeurs du système nerveux central
(glioblastome, médulloblastome, épendydome).
What is Lynch-like syndrome
En cas d’absence d’identification de mutation constitutionnelle d’un gène MMR chez un patient porteur d’une tumeur MSI (en cohérence avec les résultats d’immunohistochimie), et d’absence de méthylation somatique du promoteur du gène MLH1, le syndrome de Lynch ne peut être exclu, portant le diagnostic de syndrome « Lynch Like »
Physiopathologie du syndrome de Lynch (3 Hypothesis)
- l’altération tardive du système MMR au sein du polype colique évolué aboutissant à l’accumulation des mutations nécessaires au cancer
- perte bi-allélique précoce.
- l’absence de passage par le stade d’adénome colique.
When do we use immunotherapy and examples of meds
MSI sont de mauvais pronostic
Efficacité de l’immunothérapie chez les patients avec un CCR MSI ayant résisté aux chimiothérapies cytotoxiques classiques.
Anticorps monoclonal anti PD-1, le pembrolizumab, Nivolumab.
Un traitement par nivolumab associé à un Ac anti-CTLA4, l’ipilimumab
Effet de l’aspirine sur polypes
le taux de développement de polypes n’était pas diminué
