HC3: Cancer biology

Hallmarks

There are 10 hallmarks of cancer which distinguish epithelial cells from carcinomas:

1. Deregulating cellular energetics
2. Sustaining proliferative signaling
3. Evading growth suppressors
4. Avoiding immune destruction
5. Enabling replicative immortality
6. Activating invasion and metastasis
7. Inducing angiogenesis
8. Resisting cell death
9. Genome instability and mutation
10. Tumor promoting inflammation

Tumor promoting inflammation and genome instability and mutation are enabling

HC5: Hereditary aspects of cancer

Risk of developing cancer

The chance of getting cancer increases with age:

• 8% by the age of 65
• 25% by the age of 80
• 32% by the age of 100

If someone has a sibling with breast cancer and is 40-50 years old, the chance of developing breast cancer is 2x as

HC7: Clinical relevance of genetic repair mechanisms

Introduction

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

HC9: Nomenclature and grading of cancer

Nomenclature

Mesenchymal tumors:

There are many kinds of mesenchymal tumors:

• Fat: lipo-
• Bone: osteo-
• Fibrous: fibr-
• Cartilage: chondro-
• Blood vessels: hemangio-
• Muscle: leiomyo-/rhabdomyo-

These tumors can be benign of malignant:

• Benign: -oma
  • Cells are nicely organized
• Malignant: -sarcoma
  • Sarcoma means flesh → malignant tumors are fleshy

HC11: General principles: molecular diagnostics

Molecular diagnostics

Molecular diagnostics is a subspecialty of pathology that utilizes molecular biology techniques to:

• Detect normal and disease states
• Make a prognosis
• Identify druggable targets

Molecular biology techniques utilize DNA, RNA and enzymes that interact with nucleic acids to understand biology at a molecular level:

• KRAS mutations
• EGFR deletion
• EML4-ALK

HC13: Heterogeneity in cancer

Types of heterogeneity

In cancer, there are 3 types of heterogeneity:

• Inter-patient: between patients
• Inter-tumor: between tumors
• Intra-tumor: within the tumor

Examples are:

• Well/moderately differentiated versus poorly differentiated
• Tumors with a strong T-cell infiltration versus with a poor T-cell infiltration
• Cancer cells are different when they are at the core than when

HC15: Framework oncology and staging

Tumor grading

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:

• Lower grade → better prognosis
• Higher grade → worse prognosis

Tumors are graded based on the microscopic appearance of cancer cells. Dependent

HC18: Biomarkers for early detection of cancer

Biomarkers

Cancer can be diagnosed based on:

• Physical examination
• Blood tests
• CT-scans
• Biopsies to obtain tumor tissue

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:

• Small parts

HC20: Radiation oncology

Radiation oncology

Radiation 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:

• Radiation oncology uses as much radiation as possible, radiology uses as little radiation as possible
• Nuclear medicine is done with the use of soluble radionuclides, radiation oncology

HC22: Chemoradiation

Enhancement of sensitivity

The therapeutic window can be increased by:

• Fractionation of the total dose
• Decreasing the toxicity → lower the dose to normal tissue
• Increasing the tumor control → enhancing the sensitivity

The sensitivity can be enhanced via:

• Chemoradiotherapy
  • Radiotherapy + chemotherapy
• Biological agents
  • Cetuximab in head and neck

HC24: Diagnostics in hematology

Case

A 40-year-old man visits the GP with complaints of fatigue and pallor. The GP thinks the most likely clinical problem is anemia.

Automatic hematology analyzer

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

HC26: Malignant lymphomas

Principles of lymphoid differentiation

There are 2 types of malignant lymphomas:

• T-cell lymphoma/NK-cell lymphoma
• B-cell lymphoma

Pluripotent hematopoietic stem cells (HSC) differentiate into:

• Common lymphoid precursor cells (CLP) → differentiate into:
  • T-precursor cells → naïve T-cells → T-memory cells
  • B-precursor cells → B-memory cells or plasma cells
  • NK-cells
• Common myeloid

HC29: HLA & minor histocompatibility antigens

Allogeneic SCT

There are 2 ways of doing an allogeneic SCT:

• Allogeneic SCT with T-cells present in the cell graft: transplantation of an immune system of a healthy donor with the aim to induce a strong T-cell response against the cancer cells of the patient
  • Mature donor T-cells in the stem

HC31: Targeted therapy and hematological malignancies

Monoclonal antibodies

Tumor specific monoclonal antibodies:

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.

Rituximab:

Chemotherapy combined with CHOP monoclonal antibodies leads to a significant increase of survival

HC34+35: Secondary hemostasis I&II

Secondary hemostasis

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:

• Rapid formation of a clot upon injury
• Limited to the site of injury

HC37: Cancer, coagulation and thrombosis

The link between cancer and thrombosis

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.

HC39: Thrombosis

Cause

Thrombosis is caused by a decrease in anticoagulant factors. Deep vein thrombosis (DVT) has the following symptoms:

• Red skin
• Warm
• Painful calf
• Swelling
• Shining skin
• Pain while walking

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