![Image](https://www.worldsupporter.org/sites/default/files/styles/medium/public/bundle/wereldbol_summaries_joho_single_boek_1_150x190px_0.png?itok=PgQm9J5z)
Molecular diagnostics is a subspecialty of pathology that utilizes molecular biology techniques to:Detect normal and disease statesMake a prognosisIdentify druggable targetsMolecular biology techniques utilize DNA, RNA and enzymes that interact with nucleic acids to understand biology at a molecular level:KRAS mutationsEGFR deletionEML4-ALK or ROS translocations in NSCLCEt cetera (Proto)oncogenes have several therapeutic targets based on the hallmarks of cancer:Growth factorGrowth factor receptorIntracellular signal transduction pathwayCell cycle regulatorsTranscription factorsAnti-apoptotic factorsAbnormal activation of these targets leads to cancer. This activation can be caused by:Dominant mutations at cellular levelSingle mutations → 1 allele is sufficient In a tumor cell, chromosomes become heavily dysregulated. This can even lead to entire chromosomes changing. When the chromosome number changes, it is called aneuploidy. Activating mutations can be divided into 3 categories:TranslocationPoint mutationsMissense mutationsAn amino-acid is changed into another amino-acidNonsense mutationsA stop codon is introduced instead of an amino acid → truncated proteinSilent mutationsEven though a base pair is changed, it still codes for the same amino acidIndel/frameshift mutationsA base is deleted and the next nucleotide is taken for translationAmplificationA normal gene becomes amplified and has multiple copies Molecular diagnostics are useful to diagnose several things:Tumor phenotypeMalignancyOrigin of the tumorHeredity Therapy can consist of:Personalized medicineTreatment of cancerDrugs targeting specific mutations/pathways The vast majority of...
JoHo can really use your help! Check out the various student jobs here that match your studies, improve your competencies, strengthen your CV and contribute to a more tolerant world
A normal epithelial cell has to go through several stages to be transformed into a metastasizing tumor. There is a progressive development from normal to neoplastic tissue, with many non-malignant intermediate stages.
Cancer development is driven by the accumulation of mutations:
A mutation is a permanent alteration in a parental DNA-sequence → a cell or organism. If it is in a parental organism, it is a hereditary mutation → is transferred to a child. If it occurs in a cell, the mutation is transmitted to the daughter cells.
There are two classes of mutations:
In case of multi-locus deletions, a fairly big part of a chromosome is deleted. This leads to a loss of function of the deleted alleles. Deletion on an autosomal chromosome leads to hemizygosity for multiple genes → only copy of the allele remains. Hemizygosity means that only 1 copy of the gene is left in 1 cell.
If there is a gene that consists of 5 exons, and there is a deletion of exon 2 and another deletion of exon 2 and 3, the mutation is intragenic. This doesn’t necessarily lead to loss of function, but most of the time, it does.
This has mutagenic consequences:
Base pair mutations over a gene can be distinguished in mutations which occur in:
In a splicing consensus of intronic and exonic sequences the following is visible:
If this GT sequence is changed into an AT sequence, the exon isn’t recognized anymore → cannot encode its information into a protein. The same thing happens at the other end
.....read moreThere are 10 hallmarks of cancer which distinguish epithelial cells from carcinomas:
Tumor promoting inflammation and genome instability and mutation are enabling characteristics → enhance the cancer development progress. The other hallmarks are fundamental changes in cell physiology.
When proliferative signaling is sustained, growth is stimulated constantly:
The phenotype is dominant → only 1 allele needs to be mutated. Some tumor cells:
Normal body cells are in equilibrium with growth suppressors and growth promotors. There are several checkpoints for controlling this:
The R-point is the restriction point. Here, the Rb protein plays an important part → phosphorylation of Rb is necessary to release the restriction point. The Rb pathway is mutated in virtually all types of tumors. The Rb pathway can be inhibited by itself or by other means such as:
Both mutations cause Rb to become hypophosphorylated.
DNA-integrity checkpoints monitor 3 things:
A key player in this is p53, which is also called the guardian of the genome. It can be activated by:
Activation of p53 leads to:
In more than 50% of all human tumors, p53 is mutated. p53 protective pathways are affected in more than 90% of all tumors. The following happens:
The Li Fraumeni syndrome is a hereditary mutation. It is a heterozygous mutation of p53 which leads to multiple primary tumors at young age. It is inherited dominantly. During development, in many tissues the second allele is lost → everyone gets cancer. It is recessive on cell level.
In case of Wnt signaling, b-catenin is degraded by antigen presenting cells (APC):
There are multiple risk factors for cancer. The most important ones are:
Risk factors can be split into controllable and non-controllable risk factors. Most are non-controllable, such as age and gender.
Age is the greatest risk factor for cancer development. The peak of incidence of cancer is around 70 years. This isn’t equal for all cancer types → during puberty, the incidence of bone cancer rises due to fast growth.
The more someone ages, the more times cells are divided and the more likely it is that mistakes are accumulated in DNA-strands. Because there are 3 billion base pairs, mistakes occur easily.
Odds are generally against cancer:
Nevertheless, if someone lives long enough, many cell divisions occur and the chance of developing mutations becomes more likely. Because stem cells have to supply a constant amount of new cells throughout life, they divide a lot. This can cause mutations to accumulate at different sites.
Hereditary means segregating in the family → transmission of cancer material. There is a familial high chance of genetic problems in the family, but the cause is unknown. Prevalence of hereditary cancers depends on the cancer type:
Environmental factors most often directly affect DNA molecules. Geographical and societal differences hint that environmental factors play a part in the development of cancer:
Other examples of environmental factors are:
The chance of getting cancer increases with age:
If someone has a sibling with breast cancer and is 40-50 years old, the chance of developing breast cancer is 2x as high as usual. In case of colon cancer, the cancer is 3x as high. Among monozygotic twins, the risk is higher → genetic factors play an important role in the risk of developing cancer.
There are 14.000 new diagnoses of breast cancer per year in the Netherlands, of which 3.500 die every year. 13% have a first degree relative.
Genetic factors play a role in whether or not someone develops breast cancer:
There are 200 SNPs (single nucleotide polymorphisms) that increase the risk of breast cancer → per SNP, the increase is 0,1%, but multiple SNPs can be present at the same time.
Genetic counseling is useful to:
Many cancer-causing genes have been discovered. Examples are:
1 of the following situations has to be present to test for genetic breast cancer (BRC):
BRCA1 and BRCA2 mutations are associated with inheritable breast cancer. They are DNA-repair genes. Chances of developing cancer if 1 of these mutated genes is present are high:
BRCA mutation carriers undergo different types of surveillance, starting at early age:
For males with a BRCA2 gen, the risk of developing prostate cancer is 2-4x as high.
They undergo a blood test for PSA at the GP, every 2 years starting at the age of 45.
In case of Li Fraumeni syndrome (LFS), there is a mutation of the TP53 gen. LFS is characterized
.....read moreMany cell divisions are required in embryonic development and during human life. Daughter cells inherit identical DNA. Cell division requires accurate DNA duplication and takes approximately 5 hours. 6 x 109base pairs are copied almost flawlessly → there is less than 1 error per division.
If not repaired, DNA lesions can lead to mutations. Mutations can arise during regular DNA replication → DNA replication errors. Base mis-incorporation can occur, for example, a T can be inserted opposite of a G. Originally, there are 60.000 errors per cell division. However, there are several processes to correct such mistakes:
Lynch syndrome is a hereditary colon cancer. In case of Lynch syndrome, there is a mismatch repair deficiency. Several mutations predispose to developing Lynch syndrome, such as mutations in:
Humans are continuously exposed to sources which damage DNA. DNA damaging agents can form threats to genome stability:
In case of sunbathing there is exposure to UV-light. This causes replication blocks → a base is linked to another base → DNA polymerase stops because it cannot recognize a base. The DNA polymerase stops replicating → causes cell death.
A number of polymerases can bypass DNA damages → translesion synthesis polymerases (TLS). Because TLS can replicate damaged DNA, cell death is prevented. Sometimes these polymerases make errors, leading to a next round of replication for mutation.
POLη is the translesion polymerase bypassing mutation due to UV-damage. This is one of the most precise translesion polymerases → has evolved a lot. If another translesion polymerase bypasses the DNA damage, the chance of errors is higher.
A germline homozygous mutation of POLη leads to xeroderma pigmentosum variant-patients. Because other translesion polymerases have to do the work, these patients have sun-damaged skin and can easily develop skin cancer.
Human cells also produce DNA damage every day:
BRCA and Lynch syndrome occur very frequently in the population. Both syndromes are caused by DNA repair genes.
Even though germline mutations are equally distributed through the genome, hereditary cancer cases associate with syndromes caused by mutations in DNA repair genes. On the other hand, cancers related to inherited APC-mutations are also relatively frequent.
There is an association between DNA repair defects and clinical prognosis. Lung cancers have much more mutations than breast cancers. However, if there are more mutations, a tumor doesn’t necessarily have a worse prognosis. There are several reasons for this:
Colorectal cancer can develop in several different ways:
Even though MMR-deficient (mismatch repair deficient) or POLE-mutated (polymerase mutated) tumors have more mutations than MMR-proficient tumors, they have a better prognosis up to stage 3. In stage 4, the prognosis is equally bad for all tumors. This means that more mutations actually result in a better prognosis. This can be explained by:
MMR-deficient and POLE-mutated tumors have a lot of lymphatic infiltrates in their tumors.
In endometrial cancer, MMR-deficient and POLE-mutated tumors are also present. Here, POLE-mutated patients do better than patients who are MSS (microsatellite stable) or MSI (microsatellite instable). MSI-patients are MMR-deficient and MSS-patients are MMR-proficient. POLE-mutated and MSI patients have more lymphocyte infiltrates, which mainly consist of CD8 T-cells, than MSS-patients.
Approximately 10% of all breast cancers carry defects in the BRCA genes, of which half are due to germline mutations. There has been a long debate about whether there is a relation between prognosis in breast cancer and the status of BRCA mutations. Recently, a big study has shown that there is no difference between BRCA-positive and BRCA-negative patients.
Arguments supporting an association between BRCA1 mutations and worse prognosis are:
Arguments against an association between BRCA1 mutations and a worse prognosis are:
A spiculated mass is a mass with spikes going into the surrounding tissue. Benign lesions generally don’t grow in this type of fashion → a biopsy needs to be taken.
FNAC stands for fine needle aspiration cytology:
This isn’t a histology biopsy, because the cells are loose.
Biopsies can be taken to test for breast cancer. Various cells become visible:
In a normal situation, the following is visible:
Signs of cancer cells are:
Several important terms are:
A tumor is malignant when:
A carcinoma can be invasive or in situ. Which of the 2 is the case cannot be seen on a biopsy:
DCIS and invasive ductals cannot be distinguished on a microscopy slide → malignancy cannot be distinguished from carcinoma in situ. A core biopsy is necessary to do this. It also can be useful to palpate the lymph nodes in the axilla. Tumor cells in lymph nodes proof that the disease is malignant. An adenocarcinoma is a carcinoma in glandular tissue. It can metastasize in lymph nodes.
Macroscopical aspects of malignancies are:
There are many kinds of mesenchymal tumors:
These tumors can be benign of malignant:
Epithelium is the coverage and lining of the body. Tumors can be:
Epithelial tumors can be benign of malignant:
Melanocytes can be benign or malignant:
Tumors in testicular epithelium are always malignant → seminomas.
Totipotent cells can form all kinds of tissues. They are also located in the testis and ovaries. Tumors are called teratomas:
In women, teratomas are often benign. They can contain all types of tissues, even complete teeth.
Salivary glands have many different features. Tumors in salivary glands can vary greatly. They can be benign or malignant:
Grading defines the impact of grade and stage in different malignancies and can explain the differences between these features. A grade can be used as a biomarker, which is:
For all tumor types, there are different grading systems.
There are 4 grades for benign tumors:
Bloom and Richardson made grades which can be used to predict the survival rate, for instance for breast cancer:
The Fuhrman grading system can be used in renal cell carcinomas. These cells have clear cytoplasms. The bigger the nucleoli (dots in the nuclei), the higher the grade. There are 4 grades in total.
The Gleason scoring system can be used in case of prostate cancer. It is based on the amount of nicely formed ducts:
Metastasis is Greek word, which in medical use describes the shift of disease from one part of the body to another. It is mainly used in context of cancer.
In the 19th century, Jean Claude Recamier recognized that cancer can spread from a primary tumor.
Stephan Paget came up with the seed-and-soil theory. He stated that the growth of a tumor is not a matter of chance, but that there must be an affinity between the tumor cells and the site where they are metastasizing.
Sister Mary Joseph noticed that a tumor in the umbilicus usually is a metastasis of a tumor elsewhere → a sister Mary Joseph node is a secondary lesion in 1-3% of abdominal cancers. Its metastatic route is unclear.
In 1929, James Ewing states that metastatic dissemination occurs by purely mechanical factors.
The mechanistic theory states that mechanical forces and circulatory patterns between the primary tumor and the secondary site account for organ specificity. This forms a contradiction to the seed-and-soil theory. In the end, both theories proved to be correct → depends on the cancer type.
In 1965, Bernard Fisher described breast cancer as a systemic disease. He stated that early-stage breast cancer can be more effectively treated by lumpectomy, in combination with radiation therapy, chemotherapy and/or hormonal therapy than by radical mastectomy. Mastectomy is an extremely invasive procedure where the breasts, muscles and lymph nodes are removed. If metastasis has already occurred, such treatment isn’t useful.
In 1975, Isiah Fidler stated that metastasis is the result from the survival of only a few tumor cells. The process of metastasis and invasion is comprised of several stages:
This is a complex process which consists of different steps. A tumor clone needs to acquire all these features, which is quite difficult. One of the ways they can do this is through genomic instability. Once a tumor cell has acquired the 10 hallmarks of cancer, it can metastasize.
In 2002, Robert Weinberg and Jean Paul Thiery introduced the concept of EMT (epithelial to mesenchymal transition). This concept is specifically applied to epithelial tumors:
EMT most often refers to functional characteristics gained during malignant progression rather than
.....read moreMolecular diagnostics is a subspecialty of pathology that utilizes molecular biology techniques to:
Molecular biology techniques utilize DNA, RNA and enzymes that interact with nucleic acids to understand biology at a molecular level:
(Proto)oncogenes have several therapeutic targets based on the hallmarks of cancer:
Abnormal activation of these targets leads to cancer. This activation can be caused by:
In a tumor cell, chromosomes become heavily dysregulated. This can even lead to entire chromosomes changing. When the chromosome number changes, it is called aneuploidy.
Activating mutations can be divided into 3 categories:
Molecular diagnostics are useful to diagnose several things:
Therapy can consist of:
The vast majority of tissue is frozen and put into paraffine slides. This can be used for histological images → the location of tumor cells can be identified.
A tumor consists of:
Lots of lymphocytes are visible around tumor cells.
A tumor is a mix of neoplastic cells and supporting “normal” cells. The tumor cell percentage is the estimated % of tumor cells. Tumor cells are genetically instable and have a large variety. They can be distinguished as follows:
There are 87 FDA approved drugs. For each drug, there is a molecular target which needs to be tested in the lab for 45 different disease indications. Every drug acts upon 1 hallmark of cancer.
A BRAF melanoma is caused by a BRAF mutation of the BRAF inhibitor. The following is found:
Cancer is the emperor of all maladies, the king of all terrors. The attention to and visibility of cancer is growing:
Cancer has become a more and more visible disease over the last two centuries. It has developed into the disease of modern times. The disease became a major object of medical, social, economic and political concern.
In the 17th century, breast cancer was seen as a female disease because only in women it was visible on the outside. Breast amputation was preformed, which had to be done very fast. Of course, men also had breast cancer, but they attributed the signs to something else than a tumor in the body. Breast cancer was connected with lust in sexuality because no breast cancer was found in nuns.
In the 19th century, a first turning point in cancer history occurred. It was stated that diseases weren’t located throughout the entire body, but could emerge from certain tissues and other parts. There was a localist approach focused on cells, tissues and organs. Doctors opened up a body and found tumors inside. Rudolf Virchow made an important statement: “all cells arise from other cells and malignant cells grow too fast”.
In 1900, the words cancer genetics and oncologist did not exist. Chemotherapy wasn’t present, but a cancer hospital was. Radiation therapy could already be preformed. In 1913, the Netherlands Cancer Institute (NKI) was established.
In the early 20th century, cancer increasingly became a public health problem. This formed a second turning point. It statistically came more to the surface because the life expectancy started to rise. People started thinking more about prevention and control and saw it as “an enemy we have to fight”. Several patterns became visible, such as apprentice chimney sweepers getting scrotal cancer. Between the 1930s and 1960s, surgery underwent huge developments.
After World War II, the complexity, risk and genetics of cancer became more and more visible. The erosion of cancer as a social taboo started.
Between the 1960s and 1980s, the relation between environment, behavior and cancer became increasingly visible. This formed a third turning point. For instance, smoking used to be very normal but caused many cases of cancers. Open minded doctors where needed, because the industry would put profit before health. They would create doubt about the relationship between smoking and lung cancer → “more doctors smoke Camels than any other cigarette”. Cancer was described as a single monolithic entity, which isn’t true.
In cancer, there are 3 types of heterogeneity:
Examples are:
Heterogeneity forms a major issue for the treatment of cancer.
There are 2 origins of intra-tumor heterogeneity:
The fact that a new clone evolves, doesn’t mean it will survive:
Inter-tumor heterogeneity is a morphological heterogeneity between tumors → one tumor is well/moderately differentiated while the other is poorly differentiated.
Heterogeneity becomes clear when the protein expression is observed. For instance, 1 tumor can have high levels of PD-L1 expression while the other doesn’t. Tumor cells which are negative for PD-L1 respond negative to the treatment.
Not only the tumor cells present in tumors can differ, but also other cells, for instance immune cells.
Heterogenic tumors arise as follows:
Of all the clones, 1 clone can remain resistant to therapy.
Clonal cooperation refers to characteristics of cancer provided by distinct cancer cell clones. Different clones, which all are present in the same tumor, have different functions:
Aside clonal cooperation, there is competition between cancer cells. Cells compete for nutrients, space and oxygen. Many clones that are generated during tumor progression do not survive. This competition is driven by selective pressure, which is driven by either external factors or intrinsic features of cancer cells:
Different genes are mutated in different cancers. Only TP53 mutations occur in nearly every type of cancer. The large majority of mutated genes differs considerably from one tumor to the other tumor type. They play different roles in healthy tissues. This inter-patient heterogeneity has consequences for the treatment.
An example is HER2, which is mainly expressed in breast and urothelial cancer. These cancer types can be treated with trastuzumab.
Inter-patient heterogeneity can
.....read moreThe incidence peak of cancer is around the 6th decade of life. Therefore, it isn’t important in the evolution or in shaping the immune system → mainly occurs after reproductive age.
In the beginning of the 20th century, a number of scientists proposed a theory of immune surveillance, which later was further confirmed:
This shows that the immune system plays an important role in tumor growth.
The presence of certain immune cells correlates with both improved and worse tumor behavior and prognosis.
T-cells are associated with both a good and bad prognosis, depending on the type:
Macrophages are often associated with immunosuppressive activity. They can produce cytokines like IL-10 or TGF-β, which counteract immune activity. There are 2 types of macrophages:
The majority of macrophages in tumors are M2 → make a bad prognosis.
When a cell is targeted by carcinogens such as UV-radiation or cytotoxic drugs, the following happens:
However, a lot of these pathways are shut down in tumors. This causes the immune system to not be able to recognize tumor cells through these mechanisms anymore.
HLA-II molecules present proteins which are cut into peptides to cells. Although the main function of B-cells is antibody production, they can also produce HLA-I and HLA-II. Antigen presenting cells are:
These cells have HLA molecules:
Both dendritic cells and macrophages have phagocytic capacity. Dendritic cells are the most effective APCs → provide the right co-stimulatory signal.
However, not all peptides/proteins are presented to T-cells. This depends on the HLA alleles present in the immune system, which differs per person. Furthermore, even if a peptide is presented, not all peptides can be recognized by T-cells → an individual must have a compatible T-cell receptor that can recognize a specific HLA/peptide complex.
Antigens presented to immune cells by tumor cells are:
A tumor grade reflects intrinsic biological behavior of tumors. In general, a low grade is less aggressive. It is necessary to grade a tumor for treatment and prognosis:
Tumors are graded based on the microscopic appearance of cancer cells. Dependent on the tumor, there are 2-4 degrees of severity. An example is:
The amount of grades differs per tumor type. In case of breast cancer, there are only 3 grades. These grades can be linked to the expected 5 year survival rates:
Tumor staging is used to determine the extent of disease spread in patients:
Cancer staging is useful for:
There is no unique staging system. However, most staging systems do consist of several common elements:
In general, the higher the stage, the worse the prognosis.
The TNM staging principles is the most used staging system for solid tumors:
The rules per tumor differ → prefix modifiers can be useful:
For instance, a PA report states the following:
To determine what therapy is effective, it is necessary to make a therapeutic plan. This can be done according to the WHO 6STEPS method:
To make a therapeutic plan for a specific patient, it is necessary to understand:
Cancer is a heterogenous disease → it has different causes and requires different treatments. There are 3 main forms of cancer treatment:
To make a patient-specific therapeutic plan, the following needs to be determined:
Sometimes, curation isn’t possible anymore and treatment is palliative. Palliative treatment consists of:
There are 4 groups of pharmacological therapy which can be used as cancer treatment:
The core medication list consists of the most used drugs for cancer. It is necessary to know the:
The core medication list is built up as follows:
In normal cells, cell division is regulated by growth stimulating factors and growth inhibiting factors:
In cancer cells, growth is out of control. This is caused by:
The cell cycle consists of 5 stages:
Cancer can be diagnosed based on:
A biomarker refers to a measurable indicator of some biological state or condition. Humans shed particles into the bloodstream or environment as evidence of their presence in a particular location:
Biomarkers are measured and evaluated to examine:
An ideal tumor marker for diagnosis:
Samples for biomarker detection are:
Tumor cells and products circulate in blood and are easily detectable. However, tissue forms the issue. There is a limited access to tissue:
Because tissue access is limited, there is an increased interest in circulating tumor cells (CTCs). CTCs shed by primary and metastatic tumors can be used as “liquid biopsies”, providing real-time information about the patient’s current disease state. Molecular profiling in CTCs can be used for patient selection to stratify for targeted therapy or serve as well-defined treatment targets.
Potential clinical applications of CTCs are:
CTCs are not whole tumor cells → they are circulating biomarkers. CTCs are very rare in the blood of cancer patients, ranging from 1 to over 1000 in 10 ml blood samples, which usually contain 50-100 billion red and white blood cells.
Microparticles from a tumor are released into the bloodstream. Microparticles are:
Clinical uses of biomarkers are:
A biomarker for screening must be:
A biomarker for monitoring treatment efficacy must:
The ideal tumormarker
.....read moreIn 2012, there where 14 million new cancer cases, 8 million cancer deaths and 33 million people living with cancer. These numbers will only increase. Even though surgeons aren’t the only doctors involved in cancer therapy, 80% of all solid cancers need surgery.
Surgical oncology has several challenges which need to be taken into account:
There is an evolution in surgery from more invasive to less invasive.
There are several types of surgical oncology:
Curative surgery is an intervention with the aim of curing the disease. Several things happen:
There are 3 situations in cancer where acute surgery is necessary:
What kills first, has to be treated first. An example of this is the removal of a tumor which obstructs the colon → the tumor is removed to restore the normal function. Chances of cure in case of acute surgery are much lower than in normal, elective surgery.
Palliative surgery is an intervention with the aim of easing the complaints of the patient. The chance of curation is 0%.
Palliative surgery may be useful to:
Complications of palliative surgery may be:
Palliative surgery usually isn’t preformed on old and frail patients.
Prophylactic surgery is preformed in the tissues where the main tumor often metastasizes in order to prevent further spread of the disease.
Debulking is the act of decreasing the number of tumor cells, and thereby removing the major part of the tumor load. This is applied in case of ovarian cancer and is usually followed by chemotherapy.
Resectability describes what kind of resection needs to be done:
In surgery, less is always more → less invasion leads to less morbidity.
This principle can
.....read moreRadiation oncology is a separate discipline in oncology where ionizing radiation is used to treat cancer. It is not the same as radiology or nuclear medicine:
50% of cancer patients are irradiated. Radiotherapy can be a form of curative or palliative treatment. Together with other treatments, it increases the numbers of long survivors.
There are several types of ionizing radiation:
External beam radiotherapy uses the photons of γ-rays. A linear accelerator can be turned on or off. This is a form of local treatment → there only is radioactivity when the linear accelerator is on. Afterwards, patients won’t be radioactive anymore.
Radiation oncology has the following mechanism of action:
The aim is to kill the tumor. The side effects of the therapy are determined by the slow down of cell division in surrounding healthy tissues. This causes both acute and late cell side effects.
A higher dose does not always give more tumor control → the likelihood of tumor control isn’t a linear line but is S-shaped. The higher the dose, the higher the toxicity to both tumor and normal cells. The aim of radiotherapy is to kill the tumor without normal cell damage.
The therapeutic window or safety window refers to a range of doses which optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity. It is the space between the tumor control curve and toxicity curve.
There are ways to increase the therapeutic window:
Increasing the therapeutic window enhances the sensitivity.
Radiation therapy has early,
.....read moreAn oncologist is a doctor who treats cancer and provides medical care for a person diagnosed with cancer. The field of oncology has 3 major areas:
A medical oncologist treats cancer using hormonal therapy, chemotherapy or other medications such as targeted therapy or immunotherapy.
Drug treatments can attack all the cancer cells throughout the body. Most breast cancer cells metastasize to the lymph nodes.
Goals of breast cancer treatment are:
There are 4 types of therapy for breast cancer:
Factors deciding a certain therapy in metastatic breast cancer are:
Hormonal therapy is directed towards tumors which are hormonal dependent for their growth:
Estrogen is a steroid which binds to the estrogen receptor on ER+ breast cancer cells → stimulates tumor cell growth. Approximately 60-70% of breast cancers express estrogen and/or a progesterone receptors. The goal of hormonal treatment is to block the stimulating of cancer growth by steroids.
There are 2 types of hormonal treatment of ER+ breast cancer:
Side effects of hormonal treatment are very hard to see. Doctors may perceive that the treatment is going well and that
.....read moreThe therapeutic window can be increased by:
The sensitivity can be enhanced via:
Chemoradiation is a combination between radiotherapy and chemotherapy. This can be:
If chemoradiation is used, DNA damage to tumor cells is more often fatal than with irradiation alone. Normal cells have a greater variety of escape mechanisms and repair the damage, which causes them to be more able to repair DNA than tumor cells → have a higher tolerance to the therapy. There are different modes of action for radiation and chemotherapy. Chemotherapy is used as a radiosensitizer which enhances the effect of radiotherapy.
Chemo- and radiotherapy can be used to create synergy:
Chemotherapy inhibits nucleotide metabolism, while radiation is effective in a different phase of the cell. Chemotherapy treats hypoxic cells, which are less radiosensitive for radiotherapy. Chemoradiation is seen as local treatment to increase local control and thereby cure.
Chemoradiation is only used in curative treatment:
As primary treatment, chemoradiation can be used as an organ saving treatment. This can be useful when curative resection causes a large loss of function and therefore isn’t possible or when the patient isn’t operative anymore. Examples are:
Chemoradiation as adjuvant treatment increases the local control after resection, for example in case of stomach cancer. It can prevent recurrence.
Chemoradiation as neoadjuvant treatment:
Examples are operable esophageal cancer and advanced stage rectal cancer.
Chemoradiation has much more acute side effects in contrast to surgery:
Blood forms 8% of the total body weight, the other 92% consists of fluids and tissues. Blood is made up for 55% of blood plasma and for 45% of formed elements. Plasma is mostly made up of water, formed elements of red blood cells, white blood cells and platelets.
Blood has many functions:
Erythrocytes form the largest fraction of blood cells → there are 5 x 1012erythrocytes per liter blood. They are red cells → cause the red color of blood. Erythrocytes can spend up to 120 days in the circulation. They have no nucleus and are fully differentiated → no proliferation takes place. Their function is oxygen transport.
Erythrocytes contain hemoglobin:
The normal leukocyte count in blood is 4-10 x 109 per liter. Leukocytes can differentiate into:
Thrombocytes are present in the blood in a concentration of 150-400 x 109/L. They cause coagulation in case of vessel damage:
Thrombocytes have a lifespan of 8-10 days.
Elements are in constant turnover and have different lifespans:
Production must react to rapid changes in the environment to ensure homeostasis. Only mature elements gain access to the circulation. In case of infection or bleeding, production can increase 3-8 folds.
Stem cells are capable of self-renewal, the ability to go through numerous cycles of cell division while maintaining an
.....read moreA 40-year-old man visits the GP with complaints of fatigue and pallor. The GP thinks the most likely clinical problem is anemia.
The GP requests a complete blood count (CBC) → a differential count of Hb, leukocytes, and thrombocytes. Blood goes through an automatic hematology analyzer, a laser which gets scattered when it encounters a blood cell:
The machine is able to identify the cells based on size and complexity. The results are shown in a diagram, which makes it possible to determine how many and what kind of cells there are.
Results of the CBC show:
Acute leukemia is suspected. In leukemia, there are too many leukocytes compared to other cells. The diversity also is less.
Microscopic leukocyte differentiation consists of a blood smear stained with May Grunwald Giemsa. In case of acute leukemia, differentiation of leukocytes is lost → many strange looking leukocytes which all look the same are present.
There are several levels of diagnostics which make it possible to examine different structures:
The bone marrow is the principle site of hematopoiesis. Examination of the bone marrow provides additional information for diagnostic clues seen in the peripheral blood:
Several diagnostic tests on the bone marrow tissue can be done:
Bone marrow aspirates are liquid components of bone marrow. On bone marrow aspirates, tests can be done as well:
Myeloid malignancies are divided into 3 categories:
Chronic myeloid leukemia is a disorder of proliferation → it is a stem cell disease.=
A 48-year-old male patient suffers from fatigue, but has no other complaints. Physical examination shows pallor and an enlarged spleen.
A laboratory test shows:
Leukocyte differentiation shows:
There shouldn’t be any promyelocytes, myelocytes and metamyelocytes present in the blood. The only cells that should be present are mature blood cells.
The diagnosis is Philadelphia chromosome positive chronic myeloid leukemia (CML). The driver mutation of CML is BCR/ABL, caused by a translocation of chromosome 9 and 22. This mutation causes cells to have a proliferative advantage. There is no mutation in differentiation genes → differentiation in mature stages is normal. Therefore, neutrophils are segmented as usual.
Chromosome 9 contains the ABL gene, chromosome 22 contains the BCR gene. The mutation takes place as follows:
It is unknown why the translocation of chromosome 9 and 22 occurs. There is no relation with exposition to chemicals.
Chronic myeloid leukemia has a slowly progressive course and is a member of the myeloproliferative diseases:
Symptoms of chronic myeloid leukemia are:
Due to the known mutated shape of BCR/ABL tyrosine kinase, there is a specific inhibitor which binds to the ADP spot of tyrosine kinase → cannot bind to ATP. This causes the signaling pathway to halt. Normally, ATP activates a signaling cascade causing absent regulation.
Chronic myeloid leukemia has 3 phases:
Over time, the normal cells in the bone marrow are outcompeted by the mutated cells. In the later stages of the disease, the mutated
.....read moreThere are 2 types of malignant lymphomas:
Pluripotent hematopoietic stem cells (HSC) differentiate into:
By morphology alone, CLPs cannot be distinguished from CMPs → additional tests are necessary. A plasma cell is recognizable thanks to its big Golgi system. This is the only type of cell which can be distinguished by cell morphology alone. The difference between T-cells and B-cells can be made by looking at cell type specific antigens which are present on the cell:
The primary purpose of lymphocytes is to recognize an antigen receptor. Precursor cells, like blast cells, do not have antigen receptor (AgR) expression yet → they are AgR negative. Both AgR positive and negative cells can cause neoplasia:
If mature cell receptors are destroyed, the cell goes into programmed apoptosis. This doesn’t happen in case of plasma cells, because they don’t have a receptor.
There aren’t enough genes to code for the different type of receptors present in the adaptive immune system. This is solved by VDJ (IgH) and VJ (IgL) recombination:
Lymphomas are frequently caused by activation of proto-oncogenes in the course of antigen receptor formation:
This results in resistance to apoptosis and activation of signaling cascades.
B-cell maturation is a dangerous process because it contains double strand DNA breaks → risk of getting mutations. For instance, this can happen when VDJ-recombination activates a proto-oncogene:
Hematopoietic stem cell transplantation (SCT) is performed because:
Disorders treated with autologous SCT are lymphoma and multiple myelomas. SCT is a form of cellular immunotherapy.
A stem cell graft is harvested as follows:
Autologous SCT is performed as follows:
The actual treatment is the chemotherapy → stem cell transplantation only is a rescue procedure.
The difference between allogeneic and autologous SCT is that in allogeneic SCT the graft of bone marrow cells is taken out of a healthy donor instead of the patient.
Allogeneic SCT is performed as follows:
Allogeneic SCT is used to treat:
Allogeneic hematopoietic SCT is a very complex procedure because it messes with 2 different immune systems:
There are 2 ways to prevent graft rejection:
There are 2 ways of doing an allogeneic SCT:
HLA molecules are located on chromosome 6. Per chromosome, there are 6 genes which play a role in HLA. Because humans have 2 chromosomes, there are 12 genes in total which play a role. There are 2 types of HLA molecules:
The HLA groups are located in the peptide binding groove. Only dendritic cells, macrophages and B-cells are capable of HLA-II expression. HLA is highly polymorphic → there are many variants and every different allele has its own name.
Due to negative selection in the thymus of T-cells which have high affinity for HLA self-complexes, there are no T-cells for processing peptides derived from cellular proteins, otherwise autoimmune reactions would be induced.
Donor T-cells recognize foreign peptide-HLA complexes (allo-antigens). When selecting a matching donor, not all 12 but only 10 genes are taken into account → HLA-DP is usually not taken into account:
Therefore, after an unrelated allogeneic SCT, there can be T-cells present in the donor graft which are directed against peptides in mismatched HLA-DP → immune reaction. HLA molecules are major histocompatibility antigens. In case of shared HLA molecules, immune responses against minor histocompatibility antigens can occur.
A minor histocompatibility antigen (MiHA) can be:
While patients experience cancer treatment as a unique life-changing series of events, to medical professionals it constitutes routine work practice.
Joanna Baines wrote an article containing 3 stories of 3 generations of breast cancer:
A timeline of emerging cancer therapies has been created:
CD20 is an IgG isotype expressed antigen on normal and malignant B-cells. It is used for treatment of many B-cell lymphomas → by targeting CD20 antigens, both malignant and normal B-cells are depleted.
Chemotherapy combined with CHOP monoclonal antibodies leads to a significant increase of survival rates. Rituximab, a monoclonal antibody against CD20, leads to:
Monoclonal antibodies can have different mechanisms of action:
Bispecific antibodies are a combination of 2 different antibodies to target B-cells with CD8 T-cells. A bispecific T-cell engager (BiTE) causes proliferation of T-cells via the following mechanism:
A T-cell has a T-cell receptor, which can recognize a peptide presented in an HLA molecule. To activate a T-cell receptor, additional costimulatory signals such as CD28 are necessary as well. If a T-cell receptor is activated, the T-cell proliferates and kills the target cell. A Chimeric antigen receptor (CAR) T-cell uses the intracellular part of a TCR and the extracellular part of a monoclonal antibody:
Thrombophlebtis is thrombosis due to infected vessels. Thrombotic events are the second leading cause of death in cancer patients, after death from cancer itself. The Trousseau syndrome describes the presence of thrombosis in relationship to cancer. Fibrin clots may be induced by cancerous processes:
Patients with cancer have an increased risk for developing venous thrombosis:
The Khorana risk score predicts the risk of cancer associated thrombosis. This risk differs per cancer type and patient:
These scores can be added to predict the risk:
Patients with thrombosis also have a risk of developing cancer:
Cancer and thrombosis are a very bad combination. Extensive screening can identify occult tumors, but this does not improve the survival and can lead to false positive cases. Therefore, currently just a general screening is done.
In cancer patients, anticoagulation with low molecular weight heparin (LMWH) is more effective than vitamin K antagonists in prevention of recurrent venous thrombosis.
Older thrombosis studies also show a potential benefit of anticoagulant treatment. LMWH shows an improved 1-year survival only in patients with localized cancer. This is only a small advantage which isn’t proven. Even though there is a clear correlation, the conclusion is that there is no benefit of LMWH on cancer.
There are many factors which interfere with the coagulation system. As soon as the endothelium layer is broken or compromised, the coagulation begins:
Blood flows as a fluid through the blood vessels to all the organ systems. Upon injury, blood vessel loss has to be prevented. This is done via blood coagulation. Under normal conditions, blood coagulation is a tightly regulated process:
Secondary hemostasis is the conversion of soluble fibrinogen to insoluble fibrin by thrombin (IIa):
Thrombin plays a key role in the conversion of fibrinogen to fibrin. It sometimes also is called coagulation factor IIa.
Fibrinogen is also known as factor I and is very abundant in the plasma → normal levels are 1,5-3 gram/L. It consists of 2 symmetrical half-molecules, each consisting of 3 different polypeptide chains:
Fibrinogen is formed into fibrin as follows:
Thrombin is generated via the coagulation cascade. The coagulation cascade is a sequence of proteolytic reactions, which take place in parts of the surface of activated proteins. In each step, a pro-enzyme is converted to an enzyme, which activates the next pro-enzyme. These are slow reactions which can be sped up by co-factors → a kind of catalysts.
The coagulation cascade consists of 2 pathways:
The common pathway consists of the coagulation factors which play a part in both intrinsic and extrinsic pathways:
There are several very important factors in the extrinsic pathway:
Tissue factor (TF) is a transmembrane glycoprotein and a non-enzymatic co-factor of FVIIa. TF is produced by fibroblasts and smooth muscle cells → is expressed on a "hemostatic envelope” around blood vessels. TF normally isn’t present in the blood compartment, but during pathological conditions it can be expressed:
At some point, the platelet plug needs to be removed to return the normal blood flow.
Fibrinolysis is part of the normal hemostasis. It enables repair of the injured vessel wall and is important in resolving an unwanted clot such as a thrombus.
Fibrinolysis consists of the conversion of earlier formed fibrin, which is insoluble, into soluble fibrin degradation products. This process is important because it prevents venous thrombosis and atherothrombosis by removing unwanted clots. It is part of normal hemostasis.
Plasmin is a molecule which degrades fibrin → after degradation, only D-dimers of fibrin are left:
A D-dimer is also a biomarker for the fact that thrombosis is present elsewhere.
Plasmin generation consists of a sequence of proteolytic reactions on the surface of fibrin. There are 2 pathways, dependent of the activator:
Plasmin generation is regulated by:
There is a correlation between thrombosis and fibrinolysis:
Cancer leads to coagulation, which leads to thrombosis. Coagulation itself also leads to cancer, and thrombosis may as well. The link between cancer and thrombosis was established almost 200 years ago by Jean-Baptiste Bouillaud and Armand Trousseau. Trousseau diagnosed himself with thrombosis and predicted he suffered of cancer. Months later, he indeed died of pancreatic cancer.
Cancer and thrombosis are a dual clinical problem. Out of 7 million cancer-associated deaths, 1 million are attributed to thrombotic complications. Patients with cancer and thrombosis have an extremely bad prognosis. The second main cause of death in cancer patients is deep venous thrombosis/pulmonary embolism (VTE):
The risk of developing VTE in case of cancer can be divided into 2 groups:
Not all cancer types confer the same risk for VTE. Patients with pancreas, lung and/or brain cancer have the highest incidence rate of VTE. The more aggressive the tumor, the higher the risk. The risk of VTE reflects the stage of the disease → in remote cancers, the risk of VTE is highest.
Certain cancer treatments can increase the risk of VTE as well:
Treatment of venous thrombosis in cancer patients usually consists of low molecular weight heparin (LMWH), which is more effective than vitamin K agonists. LMWH can be prescribed for 6 months. If VTE still is present after this, it is necessary to switch to vitamin K antagonists.
It is unknown which biological factors cause cancer-associated VTE. Possible causes are:
Microparticles (MPs) are vesicles of 50 nM-1 μM shed from various cells. They are meant for intercellular communication and contain proteins and microRNA. TF+ microparticles (MP-TF) can be shed from:
MP-TF predicts the chance of VTE → if more MP-TF+ is present, the cumulative incidence of VTE is higher:
A hypothesis is that once MP-TF is in the blood, it fuses with platelets, endothelial cells or the ECM. MPs can be measured with:
A bleeding disorder can roughly have 3 different causes:
Bleeding disorders can be congenital or acquired:
Bleeding disorders are analyzed based on:
In case of von Willebrands disease (VWD), there is an abnormality in both primary and secondary hemostasis. The frequency of VWD is <1-1%. It inherits autosomal → men and women are equally affected. There are 3 types of VWD:
VWD is characterized by the following symptoms:
In general, the bleeding tendency is much less severe than in case of hemophilia.
Treatment of VWD can consist of:
Thrombosis is caused by a decrease in anticoagulant factors. Deep vein thrombosis (DVT) has the following symptoms:
In 40% of cases with suspected DVT, the clinical diagnosis is correct. Ultrasounds of the vessels in the leg are primarily used to diagnose DVT. In normal situations, the vein compresses and becomes hard to see. In case of thrombosis, the vein doesn’t become compressed as much. DVT differs from arterial thrombosis because it occurs at sites of stasis.
Post thrombotic syndrome (PTS) is a persistent swollen and painful leg as a result of DVT. Symptoms are:
In post thrombotic syndrome, accumulation of thrombotic platelets causes a leaky valve. Current treatment to prevent the development of post-thrombotic syndrome consists of compression stockings → the venous pressure is increased.
A pulmonary embolism (PE) is an embolization of a venous thrombus into the pulmonary artery. Symptoms are:
A very deadly form of pulmonary embolism is a saddle embolism → almost always results in death.
Diagnosis of pulmonary embolism requires objective imaging:
Diagnostic strategies for pulmonary embolism may consist of an algorithm, such as the clinical decision rule:
In case there are less than 4 points, a D-dimer test is done:
In case there are more than 4 points or D-dimers are >500 ng/ml, a CT or perfusion scan is made:
Currently, a more simple way is used → the YEARS algorithm. If 3 YEARS items are present, a D-dimer test needs to be ordered:
This prevents a lot of unnecessary CT-scans.
The primary aim
.....read more
There are several ways to navigate the large amount of summaries, study notes en practice exams on JoHo WorldSupporter.
Do you want to share your summaries with JoHo WorldSupporter and its visitors?
Field of study
Add new contribution