Cancer immunology

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cancer_immunology 

 

Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models

Cancer immunology is an interdisciplinary branch of biology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

Definition

Cancer immunology is an interdisciplinary branch of biology concerned with the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, where the immune system is used to treat cancer. Cancer immunosurveillance is a theory formulated in 1957 by Burnet and Thomas, who proposed that lymphocytes act as sentinels in recognizing and eliminating continuously arising, nascent transformed cells. Cancer immunosurveillance appears to be an important host protection process that decreases cancer rates through inhibition of carcinogenesis and maintaining of regular cellular homeostasis. It has also been suggested that immunosurveillance primarily functions as a component of a more general process of cancer immunoediting.

Tumor antigens

Main article: Tumor antigen

Tumors may express tumor antigens that are recognized by the immune system and may induce an immune response. These tumor antigens are either TSA (Tumor-specific antigen) or TAA (Tumor-associated antigen).

Tumor-specific

Tumor-specific antigens (TSA) are antigens that only occur in tumor cells. TSAs can be products of oncoviruses like E6 and E7 proteins of human papillomavirus, occurring in cervical carcinoma, or EBNA-1 protein of EBV, occurring in Burkitt's lymphoma cells. Another example of TSAs are abnormal products of mutated oncogenes (e.g. Ras protein) and anti-oncogenes (e.g. p53).

Tumor-associated antigens

Tumor-associated antigens (TAA) are present in healthy cells, but for some reason they also occur in tumor cells. However, they differ in quantity, place or time period of expression. Oncofetal antigens are tumor-associated antigens expressed by embryonic cells and by tumors. Examples of oncofetal antigens are AFP (α-fetoprotein), produced by hepatocellular carcinoma, or CEA (carcinoembryonic antigen), occurring in ovarian and colon cancer. More tumor-associated antigens are HER2/neu, EGFR or MAGE-1.

Immunoediting

Cancer immunoediting is a process in which immune system interacts with tumor cells. It consists of three phases: elimination, equilibrium and escape. These phases are often referred to as "the three Es" of cancer immunoediting. Both adaptive and innate immune system participate in immunoediting.

In the elimination phase, the immune response leads to destruction of tumor cells and therefore to tumor suppression. However, some tumor cells may gain more mutations, change their characteristics and evade the immune system. These cells might enter the equilibrium phase, in which the immune system does not recognise all tumor cells, but at the same time the tumor does not grow. This condition may lead to the phase of escape, in which the tumor gains dominance over immune system, starts growing and establishes immunosuppressive environment.

As a consequence of immunoediting, tumor cell clones less responsive to the immune system gain dominance in the tumor through time, as the recognized cells are eliminated. This process may be considered akin to Darwinian evolution, where cells containing pro-oncogenic or immunosuppressive mutations survive to pass on their mutations to daughter cells, which may themselves mutate and undergo further selective pressure. This results in the tumor consisting of cells with decreased immunogenicity and can hardly be eliminated. This phenomenon was proven to happen as a result of immunotherapies of cancer patients.

Tumor evasion mechanisms

Multiple factors determine whether tumor cells will be eliminated by the immune system or will escape detection. During the elimination phase immune effector cells such as CTL's and NK cells with the help of dendritic and CD4+ T-cells are able to recognize and eliminate tumor cells.

• CD8+ cytotoxic T cells are a fundamental element of anti-tumor immunity. Their TCR receptors recognise antigens presented by MHC class I and when bound, the Tc cell triggers its cytotoxic activity. MHC I are present on the surface of all nucleated cells. However, some cancer cells lower their MHC I expression and avoid being detected by the cytotoxic T cells. This can be done by mutation of MHC I gene or by lowering the sensitivity to IFN-γ (which influences the surface expression of MHC I). Tumor cells also have defects in antigen presentation pathway, what leads into down-regulation of tumor antigen presentations. Defects are for example in transporter associated with antigen processing (TAP) or tapasin. On the other hand, a complete loss of MHC I is a trigger for NK cells. Tumor cells therefore maintain a low expression of MHC I.
• Another way to escape cytotoxic T cells is to stop expressing molecules essential for co-stimulation of cytotoxic T cells, such as CD80 or CD86.
• Tumor cells express molecules to induce apoptosis or to inhibit T lymphocytes:
  • Expression of FasL on its surface, tumor cells may induce apoptosis of T lymphocytes by FasL-Fas interaction.
  • Expression of PD-L1 on the surface of tumor cells leads to suppression of T lymphocytes by PD1-PD-L1 interaction.
• Tumor cells have gained resistance to effector mechanisms of NK and cytotoxic CD8+ T cell:
  • by loss of gene expression or inhibition of apoptotic signal pathway molecules: APAF1, Caspase 8, Bcl-2-associated X protein (bax) and Bcl-2 homologous antagonist killer (bak).
  • by induction of expression or overexpression of antiapoptotic molecules: Bcl-2, IAP or XIAP.

Tumor microenvironment

Immune checkpoints of immunosuppressive actions associated with breast cancer

• Production of TGF-β by tumor cells and other cells (such as myeloid-derived suppressor cell) leads to conversion of CD4+ T cell into suppressive regulatory T cell (Treg) by a contact dependent or independent stimulation. In a healthy tissue, functioning Tregs are essential to maintain self-tolerance. In a tumor, however, Tregs form an immunosuppressive microenvironment.
• Tumor cells produce special cytokines (such as colony-stimulating factor) to produce myeloid-derived suppressor cell. These cells are heterogenous collection of cell types including precursors of dendritic cell, monocyte and neutrophil. MDSC have suppressive effects on T-lymphocytes, dendritic cells and macrophages. They produce immunosuppressive TGF-β and IL-10.
• Another producer of suppressive TGF-β and IL-10 are tumor-associated macrophages, these macrophages have mostly phenotype of alternatively activated M2 macrophages. Their activation is promoted by TH type 2 cytokines (such as IL-4 and IL-13). Their main effects are immunosuppression, promotion of tumor growth and angiogenesis.
• Tumor cells have non-classical MHC class I on their surface, for example HLA-G. HLA-G is inducer of Treg, MDSC, polarise macrophages into alternatively activated M2 and has other immunosuppressive effects on immune cells.

Immunomodulation methods

Immune system is the key player in fighting cancer. As described above in mechanisms of tumor evasion, the tumor cells are modulating the immune response in their profit. It is possible to improve the immune response in order to boost the immunity against tumor cells.

• monoclonal anti-CTLA4 and anti-PD-1 antibodies are called immune checkpoint inhibitors:
  • CTLA-4 is a receptor upregulated on the membrane of activated T lymphocytes, CTLA-4 CD80/86 interaction leads to switch off of T lymphocytes. By blocking this interaction with monoclonal anti CTLA-4 antibody we can increase the immune response. An example of approved drug is ipilimumab.
  • PD-1 is also an upregulated receptor on the surface of T lymphocytes after activation. Interaction PD-1 with PD-L1 leads to switching off or apoptosis. PD-L1 are molecules which can be produced by tumor cells. The monoclonal anti-PD-1 antibody is blocking this interaction thus leading to improvement of immune response in CD8+ T lymphocytes. An example of approved cancer drug is nivolumab.
  • Chimeric Antigen Receptor T cell
    • This CAR receptors are genetically engineered receptors with extracellular tumor specific binding sites and intracellular signalling domain that enables the T lymphocyte activation.
  • Cancer vaccine
    • Vaccine can be composed of killed tumor cells, recombinant tumor antigens, or dendritic cells incubated with tumor antigens (dendritic cell-based cancer vaccine) 

Relationship to chemotherapy

Main article: cancer immunotherapy

Obeid et al. investigated how inducing immunogenic cancer cell death ought to become a priority of cancer chemotherapy. He reasoned, the immune system would be able to play a factor via a 'bystander effect' in eradicating chemotherapy-resistant cancer cells. However, extensive research is still needed on how the immune response is triggered against dying tumour cells.

Professionals in the field have hypothesized that 'apoptotic cell death is poorly immunogenic whereas necrotic cell death is truly immunogenic'. This is perhaps because cancer cells being eradicated via a necrotic cell death pathway induce an immune response by triggering dendritic cells to mature, due to inflammatory response stimulation. On the other hand, apoptosis is connected to slight alterations within the plasma membrane causing the dying cells to be attractive to phagocytic cells. However, numerous animal studies have shown the superiority of vaccination with apoptotic cells, compared to necrotic cells, in eliciting anti-tumor immune responses.

Thus Obeid et al. propose that the way in which cancer cells die during chemotherapy is vital. Anthracyclins produce a beneficial immunogenic environment. The researchers report that when killing cancer cells with this agent uptake and presentation by antigen presenting dendritic cells is encouraged, thus allowing a T-cell response which can shrink tumours. Therefore, activating tumour-killing T-cells is crucial for immunotherapy success.

However, advanced cancer patients with immunosuppression have left researchers in a dilemma as to how to activate their T-cells. The way the host dendritic cells react and uptake tumour antigens to present to CD4⁺ and CD8⁺ T-cells is the key to success of the treatment.

Childhood cancer

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Childhood_cancer 

 

Childhood cancer
Other names	Pediatric cancer
A girl trying out hats to wear after chemotherapy against a Wilms' tumor
Specialty	Pediatrics, oncology

Childhood cancer is cancer in a child. About 80% of childhood cancer cases can be successfully treated. thanks to the modern medical treatments and optimal patient care. However, only about 10% of children diagnosed with cancer reside in high-income countries where the necessary treatments and care is available. Childhood cancer represents only about 1% of all types of cancers diagnosed in children and adults. For this reason, childhood cancer is often ignored in control planning, contributing to the burden of missed opportunities for its diagnoses and management in countries that are low- and mid-income.

In the United States, an arbitrarily adopted standard of the ages used are 0–14 years inclusive, that is, up to 14 years 11.9 months of age. However, the definition of childhood cancer sometimes includes adolescents between 15 and 19 years old. Pediatric oncology is the branch of medicine concerned with the diagnosis and treatment of cancer in children.

Signs and symptoms

Leukemia

See also: Leukemia

This is the most common type of cancer during childhood, and acute lymphoblastic leukemia (ALL) is most common in children. ALL usually develops in children between the ages of 1 and 10 (it could occur at any age). This type of cancer is more prevalent in males and in whites.

Signs & Symptoms:

Frequent delayed diagnosis (early symptoms are nonspecific)

• Generalized malaise
• Loss of appetite
• Low-grade fever
• Pallor
• Petechiae  
• Ecchymoses
• Bone pain
• Significant, unintended, and sudden weight loss

Physical examination:

• Significant lymphadenopathy
• Hepatosplenomegaly should raise suspicion for leukemia.

Important: It is recommended that a complete blood count is obtained (CBC) if any suspicious finding arise.

Central nervous system tumors

This is the second most common malignancy diagnosed during childhood.

Signs and Symptoms

• Ataxia
• Other gait disturbances (hydrocephalus due to aqueduct compression)
• Cranial nerve abnormalities as a result of brainstem compression

Hodgkin's disease

The likelihood of developing Hodgkin's disease increases during childhood and it peaks in adolescence.  

Signs and Symptoms

• Painless mass in the neck
• Persistent cough secondary to a mediastinal mass
• Less commonly: splenomegaly or enlarged axillary or inguinal lymph nodes
• Intermittent fever
• Drenching night sweats
• Loss of greater than 10 percent of total body weight.
• Anorexia
• Fatigue
• Pruritus
• Persistent painless mass

Non-Hodgkin's lymphoma

This type of cancer is more common in older children, and it is less prevalent than Hodgkin's disease.

Signs and Symptoms

If abdomen is affected

• Abdominal pain
• Vomiting or diarrhea
• Palpable mass and intussusception

If mediastinum is affected

• Severe dyspnea
• Superior vena cava syndrome

If head and neck masses are affected

• Palpable mass
• Cranial nerve palsies
• Nasal obstruction

Neuroblastoma

This cancer is an extracranial solid tumor commonly diagnosed in childhood.  

Signs and Symptoms

• Dysfunction of the location of the primary tumor
• Anorexia
• Abdominal pain
• Distention.

Wilms' tumor

See also: Wilms' tumor

This malignancy presents as an abdominal mass in a child.

Signs and Symptoms

• Abdominal pain
• Gross hematuria
• Hypertension
• Fever.

Malignancies of the musculoskeletal system

A tumor that arises in the musculoskeletal system often presents as a mass, a painful extremity or, occasionally, a pathologic fracture.

Signs and Symptoms

• Pain awakens a child at night
• Significant extremity dysfunction (when trauma is not involved)

Genetic syndromes associated with cancer

The cause of cancer is not yet well understood. Several chromosomal disorders and constitutional syndromes are associated with it.

Learning problems

Main article: Learning problems in childhood cancer

Children with cancer are at risk for developing various cognitive or learning problems. These difficulties may be related to brain injury stemming from the cancer itself, such as a brain tumor or central nervous system metastasis or from side effects of cancer treatments such as chemotherapy and radiation therapy. Studies have shown that chemo and radiation therapies may damage brain white matter and disrupt brain activity.

This cognitive problem is known as post-chemotherapy cognitive impairment (PCCI) or "chemo brain." This term is commonly use by cancer survivors who describe having thinking and memory problems after cancer treatment. Researchers are unsure what exactly causes chemo brain, however, they say it is likely to be linked to either the cancer itself, the cancer treatment, or be an emotional reaction to both.

This cognitive impairment is commonly noticed a few years after a child endures cancer treatment. When a childhood cancer survivor goes back to school, they might experience lower test scores, problems with memory, attention, and behavior, as well as poor hand-eye coordination and slowed development over time. Children with cancer should be monitored and assessed for these neuropsychological deficits during and after treatment. Patients with brain tumors can have cognitive impairments before treatment  and radiation therapy is associated with increased risk of cognitive impairment. Parents can apply their children for special educational services at school if their cognitive learning disability affects their educational success.

Risk factors

Risk factors are any genetic or environmental exposure that increase the chances of developing a pathological condition. Some examples are age, family history, environmental factors, genetics, and economic status among others.

Demographic risk factors

• Childhood cancer varies by age, sex, ethnicity, and race. Its incidence peaks in infancy with about 240 cases/million/year.
• This rate decreases to 128 cases per million from 5–9 years of age, and it rises again to 220 cases/million.
• Slight male dominance for most childhood cancers.

Environmental factors

• High dose ionizing radiation and prior chemotherapy are accepted causes of childhood cancer, each raising risk several fold (4-7).

Genetic factors

Identified Cancer Predisposition Syndromes

• Li-Fraumeni syndrome (TP53)
• Hereditary breast or ovarian cancer (BRCA 1⁄2)
• Colorectal cancer/polyposis syndromes
• Familial retinoblastoma (RB1)
• Familial and genetic factors are identified in 5-15% of childhood cancer cases. In <5-10% of cases, there are known environmental exposures and exogenous factors, such as prenatal exposure to tobacco, X-rays, or certain medications. For the remaining 75-90% of cases, however, the individual causes remain unknown. In most cases, as in carcinogenesis in general, the cancers are assumed to involve multiple risk factors and variables.

Aspects that make the risk factors of childhood cancer different from those seen in adult cancers include:

• Different, and sometimes unique, exposures to environmental hazards. Children must often rely on adults to protect them from toxic environmental agents.
• Immature physiological systems to clear or metabolize environmental substances
• The growth and development of children in phases known as "developmental windows" result in certain "critical windows of vulnerability".

Also, a longer life expectancy in children avails for a longer time to manifest cancer processes with long latency periods, increasing the risk of developing some cancer types later in life.

Advanced parental age has been associated with increased risk of childhood cancer in the offspring. There are preventable causes of childhood malignancy, such as delivery overuse and misuse of ionizing radiation through computed tomography scans when the test is not indicated or when adult protocols are used.

Diagnosis

Types

Two girls with acute lymphocytic leukemia demonstrating intravenous access for chemotherapy.

The most common cancers in children are (childhood) leukemia (32%), brain tumors (18%), and lymphomas (11%). In 2005, 4.1 of every 100,000 young people under 20 years of age in the U.S. were diagnosed with leukemia, and 0.8 per 100,000 died from it. The number of new cases was highest among the 1–4 age group, but the number of deaths was highest among the 10–14 age group.

In 2005, 2.9 of every 100,000 people 0–19 years of age were found to have cancer of the brain or central nervous system, and 0.7 per 100,000 died from it. These cancers were found most often in children between 1 and 4 years of age, but the most deaths occurred among those aged 5–9. The main subtypes of brain and central nervous system tumors in children are: astrocytoma, brain stem glioma, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, high-grade glioma, medulloblastoma and atypical teratoid rhabdoid tumor.

Other, less common childhood cancer types are:

• Neuroblastoma (6%, nervous system)
• Wilms tumor (5%, kidney)
• Non-Hodgkin lymphoma (4%, blood)
• Childhood rhabdomyosarcoma (3%, many sites)
• Retinoblastoma (3%, eye)
• Osteosarcoma (3%, bone cancer)
• Ewing sarcoma (1%, many sites)
• Germ cell tumors (5%, many sites)
• Pleuropulmonary blastoma (lung or pleural cavity)
• Hepatoblastoma and hepatocellular carcinoma (liver cancer)
• Juvenile myelomonocytic leukemia

Medical specialties

Overall, treating childhood cancer requires a multidisciplinary team of doctors, nurses, social workers, therapists, and other members of the community. Here is a brief list of doctors that can treat childhood cancer:

• Pediatric oncologist: These doctors specialize in treating childhood cancers.
• Pediatric hematology-oncologist: These doctors specialize in treating blood diseases in children.
• Pediatric surgeon: These doctors specialize in performing surgery on children.
• Adolescent and young adult oncology (AYA): AYA is a branch of medicine that deals with the prevention, diagnosis, and treatment of cancer in adolescents and young adults, often defined as those aged 13–30. Studies have continuously shown that while pediatric cancer survival rates have gone up, the survival rate for adolescents and young adults has remained stagnant. Additionally, AYA helps patients with college concerns, fertility, and sense of aloneness. Studies have often shown that treating young adults with the same protocols used in pediatrics is more effective than adult-oriented treatments.

Other specialties that can assist in the treatment process include radiology, neurosurgery, orthopedic surgery, psychiatry, and endocrinology.

Treatment

Childhood cancer treatment is individualized and varies based on the severity & type of cancer. In general, treatment can include surgical resection, chemotherapy, radiation therapy, or immunotherapy.

Recent medical advances have improved our understanding of the genetic basis of childhood cancers. Treatment options are expanding, and precision medicine for childhood cancers is a rapidly growing area of research.

The side effects of chemotherapy can result in immediate and long-term treatment-related comorbidities. For children undergoing treatment for high-risk cancer, more than 80% experience life-threatening or fatal toxicity as a result of their treatment.

Psychosocial care of children with cancer is also important during the cancer journey, but the implementation of evidence-based interventions need to be further spread across pediatric cancer centers. In general, psychosocial care can include therapy with a psychologist or psychiatrist, referral to a social worker, or referral to a pastoral counselor. Family-centered psychosocial care is one approach that can be used to not only support the patient's psychosocial well-being but also support the parents and any caregivers of the patient.

Prognosis

Main article: Cancer survivor

With the advancement of new treatments for childhood cancer, 85% of individuals who had childhood cancer now survive 5 years or more. This is an increase from the mid-1970s where only 58% of children with childhood cancer survived 5 years or more. However, this survival rate is dependent on many factors such as the type of cancer, age of onset, location of the cancer, cancer stage, and if there is any genetic component to the cancer. Survival rate is also impacted by socioeconomic status and access to resources during treatment.

Since adult survivors of childhood cancer are living longer, these individuals may experience long-term complications that are associated with their cancer treatment. This can include problems with organ function, growth and development, neurocognitive function and academic achievement, and risk for additional cancers.

Premature heart disease is one example of a major long-term consequence seen in adult survivors of childhood cancer. These individuals are eight times more likely to die of heart disease than other people, and more than half of the children treated for cancer develop some type of cardiac abnormality, although this may be asymptomatic or too mild to qualify for a clinical diagnosis of heart disease.

Childhood cancer survivors are also at risk of sustaining adverse effects on the kidneys and the liver. Specific cancer treatments such as cisplatin, carboplatin, and radiotherapy are known to cause kidney damage. The risk of liver damage is increased in those who have had radiotherapy to the liver and in those with other risk factors, such as a higher body mass index or chronic viral hepatitis. Certain treatments and liver surgery may also increase the risk of adverse liver effects in childhood cancer survivors.

To help monitor for these long-term consequences, a set of guidelines have been created to facilitate long term follow up for childhood, adolescent, and young adult cancer survivors. This provides guidance for healthcare professionals on how to provide high quality follow-up care and appropriate monitoring. These guidelines also help healthcare providers collaborate with oncology specialists, in order to create recommendations specific to an individual patient.

Epidemiology

Epidemiology is the study of the distribution and determinants of disease frequency in the human population and the study of how to control health problems. Internationally, the greatest variation in childhood cancer incidence occurs when comparing high-income countries to low-income ones. This may result from differences in being able to diagnose cancer, differences in risk among different ethnic or racial population subgroups, as well as differences in risk factors. An example of differing risk factors is in cases of pediatric Burkitt lymphoma, a form of non-Hodgkin lymphoma that sickens 6 to 7 children out of every 100,000 annually in parts of sub-Saharan Africa, where it is associated with a history of infection by both Epstein-Barr virus and malaria. In industrialized countries, Burkitt lymphoma is not associated with these infectious diseases. Non-Hispanic white children often have a better chance of survival compared to other racial and ethnic groups. Where an individual lives is one of the biggest determinants of health in the world, as illness and healthcare options can vary by an individual's postal code.

United States

In the United States, cancer is the second most common cause of death among children between the ages of 1 and 14 years, exceeded only by unintentional injuries such as injuries sustained in a car wreck. More than 16 out of every 100,000 children and teens in the U.S. were diagnosed with cancer, and nearly 3 of every 100,000 died from the disease. In the United States in 2012, it was estimated that there was an incidence of 12,000 new cases, and 1,300 deaths, from cancer among children 0 to 14 years of age. Cancer is the second leading cause of death in males and fourth in women under the age of 20 in the United States. The survival rate of children with cancer has improved since the late 1960s which is due to improved treatment and public health measures. The estimated proportion surviving 5 years from diagnosis increased from 77.8 percent to 82.7 percent to 85.4 percent for those diagnosed in the 1990s, 2000s, and 2010–2016.

Statistics from the 2014 American Cancer Society report:

Ages birth to 14

Sex	Incidence	Mortality	Observed Survival %
Boys	178.0	23.3	81.3
Girls	160.1	21.1	82.0

Ages 15 to 19

Sex	Incidence	Mortality	Observed Survival %
Boys	237.7	34.5	80.0
Girls	235.5	24.7	85.4

Note: Incidence and mortality rates are per 1,000,000 and age-adjusted to the 2000 US standard population. Observed survival percentage is based on data from 2003-2009.

Sub-Saharan Africa

A large number of children in Africa live in low- and middle-income countries where there is limited access to prevention or treatment of cancer. The under-five mortality rate (U5MR), a robust indicator of child health, is at 109 per 1,000 live births. The proportion of childhood cancer is higher in Africa than in developed countries, at 4.8%. Kids with cancer are disadvantaged compared to kids in developed countries; therefore their statistic for childhood cancer is higher. In sub-Saharan Africa, 10% of children die before their 5th birthday, yet it is not due to cancer; communicable diseases such as malaria, cholera, and other infections are the leading cause of death. Children with cancer are often exposed to these preventable infections and diseases. Tumor registries only cover 11% of the African population, and there is a significant absence in death registration, making the mortality database unreliable. Overall, there is a lack of reliable data, as there is limited funding and many diseases are largely unknown to this population.

United Kingdom

Cancer in children is rare in the UK, with an average of 1,800 diagnoses every year but contributing to less than 1% of all cancer-related deaths. Age is not a confounding factor in mortality from the disease in the UK. From 2014 to 2016, approximately 230 children died from cancer, with brain/CNS cancers being the most commonly fatal type.

Foundations and fundraising

Part of the proceeds from the sale of yellow silage wrappings goes to childhood cancer research, Brastad, Sweden

Currently, there are various organizations whose main focus is fighting childhood cancer. Organizations focused on childhood cancer through cancer research and/or support programs include: Childhood Cancer Canada, Young Lives vs Cancer and the Children's Cancer and Leukaemia Group (in United Kingdom), Child Cancer Foundation (in New Zealand), Children's Cancer Recovery Foundation (in United States), American Childhood Cancer Organization (in United States), Childhood Cancer Support (Australia) and the Hayim Association (in Israel). Alex's Lemonade Stand Foundation allows people across the US to raise money for pediatric cancer research by organizing lemonade stands. The National Pediatric Cancer Foundation focuses on finding less toxic and more effective treatments for pediatric cancers. This foundation works with 24 different hospitals across the US in search of treatments effective in practice. Childhood Cancer International is the largest global pediatric cancer foundation. It focuses on early access to care for childhood cancers, focusing on patient support and patient advocacy.

According to estimates by experts in the field of pediatric cancer, by 2020, cancer will cost $158 million annually for both research and treatment which marks a 27% increase since 2010. Ways in which the foundations are helped by people include writing checks, collecting spare coins, bake/lemonade sales, donating portions of purchases from stores or restaurants, or Paid Time Off donations as well as auctions, bike rides, dance-a-thons. Additionally, many of the major foundations have donation buttons on their respective websites.

In addition to advancing research focusing on cancer, the foundations also offer support to families whose children are affected by the disease. The estimated total cost for one child with cancer (medical costs and lost parental wages) is $833,000. Organizations such as the National Children's Cancer Society and the Leukemia and Lymphoma Society can provide financial assistance for the costs associated with childhood cancer like medical care, home care, child care, and transportation.

Importance of family support

The emotional challenges that a parent may encounter can disrupt their child's treatment, parenting and support for the child who is ill and their siblings, and impact overall family stability. Therefore, having a support network during this time is important. Different foundations fund support groups within hospitals and online for parents and families to aid in the coping process. Targeted support for siblings of children with cancer is also warranted. Resources that account for family context, age, and gender can help siblings process cancer-related emotional reactions. These targeted resources help promote family activities and normal family functioning, while enhancing family adjustment over time.

The foundations for pediatric cancer all fall under the 501(c)3 designation which means that they are non-profit organizations that are tax-exempt. The "International Childhood Cancer Day" occurs annually on February 15.

Epidemiology of cancer

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Epidemiology_of_cancer 

 

The age-adjusted death rate from cancer per 100,000 inhabitants in 2004.

  no data

  less than 55

  55–80

  80–105

  105–130

  130–155

  155–180

  180–205

  205–230

  230–255

  255–280

  280–305

  more than 305

Age adjusted, new cases of cancer in 2017

The epidemiology of cancer is the study of the factors affecting cancer, as a way to infer possible trends and causes. The study of cancer epidemiology uses epidemiological methods to find the cause of cancer and to identify and develop improved treatments.

This area of study must contend with problems of lead time bias and length time bias. Lead time bias is the concept that early diagnosis may artificially inflate the survival statistics of a cancer, without really improving the natural history of the disease. Length bias is the concept that slower growing, more indolent tumors are more likely to be diagnosed by screening tests, but improvements in diagnosing more cases of indolent cancer may not translate into better patient outcomes after the implementation of screening programs. A related concern is overdiagnosis, the tendency of screening tests to diagnose diseases that may not actually impact the patient's longevity. This problem especially applies to prostate cancer and PSA screening.

Some cancer researchers have argued that negative cancer clinical trials lack sufficient statistical power to discover a benefit to treatment. This may be due to fewer patients enrolled in the study than originally planned.

Organizations

State and regional cancer registries are organizations that abstract clinical data about cancer from patient medical records. These institutions provide information to state and national public health groups to help track trends in cancer diagnosis and treatment. One of the largest and most important cancer registries is Surveillance Epidemiology and End Results (SEER), administered by the US Federal government.

Health information privacy concerns have led to the restricted use of cancer registry data in the United States Department of Veterans Affairs and other institutions. The American Cancer Society predicts that approximately 1,690,000 new cancer cases will be diagnosed and 577,000 Americans will ultimately die of cancer in 2012.

Studies

Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological studies and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.

Risk factors

The approximate relative levels of the preventable causes of cancer in the United States, taken from the article Cancer prevention.

The most significant risk factor is age. According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer." Essentially all of the increase in cancer rates between prehistoric times and people who died in England between 1901 and 1905 is due to increased lifespans.

Although the age-related increase in cancer risk is well-documented, the age-related patterns of cancer are complex. Some types of cancer, like testicular cancer, have early-life incidence peaks, for reasons unknown. Besides, the rate of age-related increase in cancer incidence varies between cancer types with, for instance, prostate cancer incidence accelerating much faster than brain cancer. It has been proposed that the age distribution of cancer incidence can be viewed as the distribution of probability to accumulate the required number of driver events by the given age.

Over a third of cancer deaths worldwide (and about 75-80% of cancers in the United States) are due to potentially modifiable risk factors. The leading modifiable risk factors worldwide are:

• tobacco smoking, which is strongly associated with lung cancer, mouth, and throat cancer;
• drinking alcohol, which is associated with a small increase in oral, esophageal, breast, liver and other cancers;
• a diet low in fruit and vegetables,
• physical inactivity, which is associated with increased risk of colon, breast, and possibly other cancers
• obesity, which is associated with colon, breast, endometrial, and possibly other cancers
• sexual transmission of human papillomavirus, which causes cervical cancer and some forms of anal cancer, vaginal cancer, vulvar cancer, penile cancer, rectal cancer, and oropharyngeal cancer.

Men with cancer are twice as likely as women to have a modifiable risk factor for their disease.

Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include the use of exogenous hormones (e.g., hormone replacement therapy causes breast cancer), exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures. A Western diet is associated with increased exposure of the gastrointestinal tract to bile acids that are produced by the body to digest fatty foods. Bile acids are likely endogenous etiologic agents in gastrointestinal cancer.

Every year, at least 200,000 people die worldwide from cancer related to their workplace. Millions of workers run the risk of developing cancers such as pleural and peritoneal mesothelioma from inhaling asbestos fibers, or leukemia from exposure to benzene at their workplaces. Currently, most cancer deaths caused by occupational risk factors occur in the developed world. It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.

Rates and mortality

New cancer diagnosis in the England in 2012

In the U.S. cancer is second only to cardiovascular disease as the leading cause of death; in the UK it is the leading cause of death. In many developing countries cancer incidence (insofar as this can be measured) appears much lower, most likely because of the higher death rates due to infectious disease or injury. With the increased control over malaria and tuberculosis in some Third World countries, incidence of cancer is expected to rise; in the Eastern Mediterranean region, for example, cancer incidence is expected to increase by 100% to 180% in the next 15 years due to increases in life expectancy, an increasing proportion of elderly people, and the successful control of childhood disease. This is termed the epidemiologic transition in epidemiological terminology.

Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighbouring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various Third World countries, lung cancer incidence has increased in a parallel fashion.

India

According to the National Cancer Registry Programme of the India Council of Medical Research (ICMR), more than 1300 Indians die every day due to cancer. Between 2012 and 2014, the mortality rate due to cancer increased by approximately 6%. In 2012, there were 478,180 deaths out of 2,934,314 cases reported. In 2013 there were 465,169 deaths out of 3,016,628 cases. In 2014, 491,598 people died in out of 2,820,179 cases. According to the Population Cancer Registry of Indian Council of Medical Research, the incidence and mortality of cancer is highest in the north-eastern region of the country. Breast cancer is the most common, and stomach cancer is the leading cause of death by cancer for the population as a whole. Breast cancer and lung cancer kill the most women and men respectively.

Canada

In Canada, as of 2007, cancer is the number one cause of death, contributing to 29.6% of all deaths in the country. The second highest cause of death is cardiovascular diseases resulting in 21.5% of deaths. As of 2011, prostate cancer was the most common form of cancer among males (about 28% of all new cases) and breast cancer the most common in females (also about 28% of all new cases).

The leading cause of death in both males and females is lung cancer, which contributes to 26.8% of all cancer deaths. Statistics indicate that between the ages of 20 and 50 years, the incidence rate of cancer is higher amongst women whereas after 50 years of age, the incidence rate increases in men. Predictions by the Canadian Cancer Society indicate that with time, there will be an increase in the rates of incidence of cancer for both males and females. Cancer will thus continue to be a persistent issue in years to come.

United States

In the United States, cancer is responsible for 25% of all deaths with 30% of these from lung cancer. The most commonly occurring cancer in men is prostate cancer (about 25% of new cases) and in women is breast cancer (also about 25%). Cancer can occur in children and adolescents, but it is uncommon (about 150 cases per million in the U.S.), with leukemia the most common. In the first year of life the incidence is about 230 cases per million in the U.S., with the most common being neuroblastoma. Data from 2004 to 2008 in the United States indicates that the overall age-adjusted incidence of cancer was approximately 460 per 100,000 men and women per year.

Cancer is responsible for about 25% of all deaths in the U.S., and is a major public health problem in many parts of the world. The statistics below are estimates for the U.S. in 2008, and may vary substantially in other countries. They exclude basal and squamous cell skin cancers, and carcinoma in situ in locations other than the urinary bladder. As seen, breast/prostate cancer, lung cancer and colorectal cancer are responsible for approximately half of cancer incidence. The same applies for cancer mortality, but with lung cancer replacing breast/prostate cancer as the main cause.

In 2016, an estimated 1,685,210 new cases of cancer will be diagnosed in the United States and 595,690 people will die from the disease.

• 

  Most common cancers in US males, by occurrence

• 

  in US males, by mortality

• 

  in US females, by occurrence

• 

  in US females, by mortality

Male			Female
most common (by occurrence)	most common (by mortality)		most common (by occurrence)	most common (by mortality)
prostate cancer (25%)	lung cancer (31%)		breast cancer (26%)	lung cancer (26%)
lung cancer (15%)	prostate cancer (10%)		lung cancer (14%)	breast cancer (15%)
colorectal cancer (10%)	colorectal cancer (8%)		colorectal cancer (10%)	colorectal cancer (9%)
bladder cancer (7%)	pancreatic cancer (6%)		endometrial cancer (7%)	pancreatic cancer (6%)
non-Hodgkin lymphoma (5%)	liver & intrahepatic bile duct (4%)		non-Hodgkin lymphoma (4%)	ovarian cancer (6%)
skin melanoma (5%)	leukemia (4%)		thyroid cancer (4%)	non-Hodgkin lymphoma (3%)
kidney cancer (4%)	esophageal cancer (4%)		Skin melanoma (4%)	leukemia (3%)
oral and pharyngeal cancer (3%)	bladder cancer (3%)		ovarian cancer (3%)	uterine cancer (3%)
leukemia (3%)	non-Hodgkin lymphoma (3%)		kidney cancer (3%)	liver & intrahepatic bile duct (2%)
pancreatic cancer (3%)	kidney cancer (3%)		leukemia (3%)	brain and other nervous system (2%)
other (20%)	other (24%)		other (22%)	other (25%)

Incidence of a second cancer in survivors

In the developed world, one in three people will develop cancer during their lifetimes. If all cancer patients survived and cancer occurred randomly, the normal lifetime odds of developing a second primary cancer (not the first cancer spreading to a new site) would be one in nine. However, cancer survivors have an increased risk of developing a second primary cancer, and the odds are about two in nine. About half of these second primaries can be attributed to the normal one-in-nine risk associated with random chance.

The increased risk is believed to be primarily due to the same risk factors that produced the first cancer, such as the person's genetic profile, alcohol and tobacco use, obesity, and environmental exposures, and partly due, in some cases, to the treatment for the first cancer, which might have included mutagenic chemotherapeutic drugs or radiation. Cancer survivors may also be more likely to comply with recommended screening, and thus may be more likely than average to detect cancers.

Children

Childhood cancer and cancer in adolescents is rare (about 150 cases per million yearly in the US). Leukemia (usually acute lymphoblastic leukemia) is the most common cancer in children aged 1–14 in the U.S., followed by the central nervous system cancers, neuroblastoma, Wilms' tumor, and non-Hodgkin's lymphoma. Statistics from the SEER program of the US NCI demonstrate that childhood cancers increased 19% between 1975 and 1990, mainly due to an increased incidence in acute leukemia. Since 1990, incidence rates have decreased.

Infants

The age of peak incidence of cancer in children occurs during the first year of life, in infants. The average annual incidence in the United States, 1975–1995, was 233 per million infants. Several estimates of incidence exist. According to SEER, in the United States:

• Neuroblastoma comprised 28% of infant cancer cases and was the most common malignancy among these young children (65 per million infants).
• The leukemias as a group (41 per million infants) represented the next most common type of cancer, comprising 17% of all cases.
• Central nervous system malignancies comprised 13% of infant cancer, with an average annual incidence rate of nearly 30 per million infants.
• The average annual incidence rates for malignant germ cell and malignant soft tissue tumors were essentially the same at 15 per million infants. Each comprised about 6% of infant cancer.

Teratoma (a germ cell tumor) often is cited as the most common tumor in this age group, but most teratomas are surgically removed while still benign, hence not necessarily cancer. Prior to the widespread routine use of prenatal ultrasound examinations, the incidence of sacrococcygeal teratomas diagnosed at birth was 25 to 29 per million births.

Female and male infants have essentially the same overall cancer incidence rates, a notable difference compared to older children.

White infants have higher cancer rates than black infants. Leukemias accounted for a substantial proportion of this difference: the average annual rate for white infants (48.7 per million) was 66% higher than for black infants (29.4 per million).

Relative survival for infants is very good for neuroblastoma, Wilms' tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.

Cancer cell

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cancer_cell

Cancer cells are cells that divide continually, forming solid tumors or flooding the blood or lymph with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these daughter cells are used to build new tissue or to replace cells that have died because of aging or damage. Healthy cells stop dividing when there is no longer a need for more daughter cells, but cancer cells continue to produce copies. They are also able to spread from one part of the body to another in a process known as metastasis.

Breast cancer cells

Classification

There are different categories of cancer cell, defined according to the cell type from which they originate.

• Carcinoma, the majority of cancer cells are epithelial in origin, beginning in a tissue that lines the inner or outer surfaces of the body.
• Leukaemia, originate in the tissues responsible for producing new blood cells, most commonly in the bone marrow.
• Lymphoma and myeloma, derived from cells of the immune system.
• Sarcoma, originating in connective tissue, including fat, muscle and bone.
• Central nervous system, derived from cells of the brain and spinal cord.
• Mesothelioma, originating in the mesothelium; the lining of body cavities.

• 

  Carcinoma

• 

  Leukaemia

• 

  Lymphoma

• 

  Myeloma

• 

  Sarcoma

• 

  Mesothelioma

Histology

Histological features of normal cells and cancer cells

Cancer cells have distinguishing histological features visible under the microscope. The nucleus is often large and irregular, and the cytoplasm may also display abnormalities.

Nucleus

The shape, size, protein composition, and texture of the nucleus are often altered in malignant cells. The nucleus may acquire grooves, folds or indentations, chromatin may aggregate or disperse, and the nucleolus can become enlarged. In normal cells, the nucleus is often round or solid in shape, but in cancer cells the outline is often irregular. Different combinations of abnormalities are characteristic of different cancer types, to the extent that nuclear appearance can be used as a marker in cancer diagnostics and staging.

Causes

• 

  Life cycle of a cancer cell

Main article: Carcinogenesis

Cancer cells are created when the genes responsible for regulating cell division are damaged. Carcinogenesis is caused by mutation and epimutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death. This results in uncontrolled cell division in the body. The uncontrolled and often rapid proliferation of cells can lead to benign or malignant tumours (cancer). Benign tumors do not spread to other parts of the body or invade other tissues. Malignant tumors can invade other organs, spread to distant locations (metastasis) and become life-threatening.

More than one mutation is necessary for carcinogenesis. In fact, a series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell.

Damage to DNA can be caused by exposure to radiation, chemicals, and other environmental sources, but mutations also accumulate naturally over time through uncorrected errors in DNA transcription, making age another risk factor. Oncoviruses can cause certain types of cancer, and genetics are also known to play a role.

Stem cell research suggests that excess SP2 protein may turn stem cells into cancer cells. However, a lack of particular co-stimulated molecules that aid in the way antigens react with lymphocytes can impair the natural killer cells' function, ultimately leading to cancer.

DNA repair and mutation

When a cell is deficient in the capacity to repair DNA damages, such damages tend to be retained within the cell at an increased level. These damages, upon replication of the cell’s DNA, may cause replication errors, including mutations that lead to cancer. Numerous inherited DNA repair disorders have been described that increase cancer risk (see Wikipedia article DNA repair-deficiency disorder). In addition, particular DNA repair enzymes have been found to be deficient in multiple cancers. For example, deficient expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase is observed in several different kinds of cancer (see Wikipedia article O-6-methylguanine-DNA methyltransferase). Although a DNA repair deficiency can predispose a cell lineage to develop cancer, increased (rather than decreased) expression of a repair capability may also emerge in the progression of cancer cell lineages, and this capability may be clinically important as reviewed by Lingg et al. For instance, the DNA repair gene DMC1 encodes a protein that is normally expressed only in cells undergoing meiosis where it helps maintain an undamaged germ-line. However, DMC1 is also expressed in various cancer cell lines including cervical, breast, and lymphoma cancer cell lines. Expression of meiotic DNA repair genes such as DMC1 may promote tumor cell growth by dealing with endogenous DNA damage within the tumor, and may also diminish the effectiveness of anticancer therapy, such as radiation therapy.

Pathology

Cells playing roles in the immune system, such as T-cells, are thought to use a dual receptor system when they determine whether or not to kill sick or damaged human cells. If a cell is under stress, turning into tumors, or infected, molecules including MIC-A and MIC-B are produced so that they can attach to the surface of the cell. These work to help macrophages detect and kill cancer cells.

Discovery

Early evidence of human cancer can be interpreted from Egyptian papers (1538 BCE) and mummified remains. In 2016, a 1.7 million year old osteosarcoma was reported by Edward John Odes (a doctoral student in Anatomical Sciences from Witwatersrand Medical School, South Africa) and colleagues, representing the oldest documented malignant hominin cancer.

The understanding of cancer was significantly advanced during the Renaissance period and in to the Age of Discovery. Sir Rudolf Virchow, a German biologist and politician, studied microscopic pathology, and linked his observations to illness. He is described as "the founder of cellular pathology". In 1845, Virchow and John Hughes Bennett independently observed abnormal increase in white blood cells in patients. Virchow correctly identified the condition as blood disease, and named it leukämie in 1847 (later anglicised to leukemia). In 1857, he was the first to describe a type of tumour called chordoma that originated from the clivus (at the base of the skull).

Telomerase

Cancer cells have unique features that make them "immortal" according to some researchers. The enzyme telomerase is used to extend the cancer cell's life span. While the telomeres of most cells shorten after each division, eventually causing the cell to die, telomerase extends the cell's telomeres. This is a major reason that cancer cells can accumulate over time, creating tumors.

Cancer stem cells and drug resistance

A diagram illustrating the distinction between cancer stem cell targeted and conventional cancer therapies

Scientists have discovered a molecule on the surface of tumors that appears to promote drug resistance—by converting the tumor cells back into a stem cell-like state.

When the tumor cells began to exhibit drug resistance, the cells were simultaneously transforming into a stem cell-like state, which made them impervious to the drugs. It appeared that the treatment itself was driving this transformation by activating a specific molecular pathway. Luckily, several existing drugs, such as Bortezomib for example, can attack this pathway and reverse the cellular transformation, thus 're-sensitizing' the tumor to treatment.

Treatment

In February 2019, medical scientists announced that iridium attached to albumin, creating a photosensitized molecule, can penetrate cancer cells and, after being irradiated with light (a process called photodynamic therapy), destroy the cancer cells.