What is metastatic colorectal cancer?
The third most common type of cancer is colorectal cancer. mCRC is the metastatic type of colorectal cancer being located at the colon or rectal part of the human body. It appears more often in men than in women, but women often suffer from the more aggressive right-sided type of the cancer. The right-sided type of mCRC goes along with a worse prognosis of survival. Generally, one can distinguish between left- and right-sided colorectal cancer, where left-sided mCRC patients have better prognoses concerning the progression-free survival (PFS). The PFS is a factor that measures how long people survive after the cancer treatment without the tumor progressing again. A lot of mCRC cases are related to higher ages, because age is one of the risk factors. Other risk factors are a bad lifestyle (bad diet habits, alcohol consumption, etc) and less frequently also genetic factors.

Classification of mCRC patients is done by the oncologists on basis of anatomical tumor characteristics like grading and staging. Grading indicates how similar a tumor cell is to a normal cell, whereas staging gives information about the size and the spreading of the tumor. Since not all patients have the same present biomarkers (biologically measurable parameters of biological processes, that are known to have prognostic or diagnostic expressive power) and clinical data (measured values like weight, height, blood pressure, vitamin d value etc.), not all treatments will work equally well for all patients. Thus, a more personalized approach is being aspired, where in addition to grading and staging several other molecular biomarkers and individual clinical data of the patient play a more important role in the treatment decision.

What does REVERT mean?
The abbreviation REVERT origins from the long title “taRgeted thErapy for adVanced colorEctal canceR paTients”. REVERT is an international project funded by the EU, that started in 2020 and is planned to end in 2023. Specialists from Italy, Spain, Sweden, Luxembourg, Romania, and Germany were chosen to participate in the project, involving clinicians, pathologists, biologists, software developers, and also artificial intelligence (AI) specialists. BioVariance is part of the work package being responsible for the development of the AI solutions, thus BioVariance will offer some machine learning solutions for the question of the project.

What is the aim of the project?
The project aims at generating the REVERT database of molecular and clinical data collected from several hundred metastatic colorectal cancer patients that had visited one of the participating hospitals located at the different countries within the EU in the past. The database is then used as a basis for machine learning models to aspire a more personalized therapy approach for treating newly diagnosed patients. In the future, the trained AI model will predict a suitable first-line treatment for each new patient, who has not received any cancer medication yet, supporting the clinicians in their treatment decision. In addition to that, a clinical study will be executed with several new patients that decide to participate and want to be treated according to the AI-based results. This prospective clinical study will be performed with already authorized and commonly used chemotherapies and not with new treatments. The expectation concerning the AI-based results is to provide another more objective decision factor for clinicians, that is free from the subjective decision of the attending doctor at the hospital. Finally, the machine learning (ML) solutions will be combined in an app, that can support clinicians in the future.

What is machine learning and how is it used in the context of the project?
Machine learning algorithms use underlying mathematical models to recognize certain patterns in the patient’s data. The primary dataset of the REVERT database contains several processes of cancer treatments, the known survival outcome and about 150 other molecular and clinical features of hundreds of mCRC patients from the last 10 years. According to the underlying mathematical models, it is possible to derive some new rules from this dataset, that make it possible to predict outcomes for each new patient that was not included in the primary data. Therefore, the primary dataset must be used to (i) train and thereby generating ML models and to (ii) test and evaluate these generated models. In addition, the ML models allow to spot important features, that have a strong influence on the outcome prediction. For the primary dataset the actual outcome is already known, allowing us to see for how many patients the model predicted the correct outcome.

In the REVERT project BioVariance’s ML algorithms are used to create models that can classify whether a certain patient is likely to respond to different chemotherapies, that have been approved for years. During the project, several chemotherapies have already been categorized by the clinicians as being equally well for treating mCRC and that are now considered for the project. The related question for the ML algorithms is to predict the first-line treatment (= initial treatment, that is recommended for a disease, here: chemotherapy) having the highest chance of success for a certain patient.

What is the current status of the project and what is still to come?
At the moment, the machine learning models are already trained and tested on the previously collected dataset. BioVariance’s models and the models of three other REVERT members are used to predict the best first-line treatment for real patients participating in a phase two clinical study that started in March this year. The first few patients that were diagnosed with mCRC and enrolled to the study have already been processed with the ML models and were treated according to the model outcomes.

The main focus lays on the continuous improvement of the ML algorithms to get the best predictions possible. In the near future the ML models will be included into the REVERT app interface. This allows clinicians to directly enter patient’s data into the REVERT app and get a prediction for the most suitable first-line treatment on a patient-based level.

This approach is an important step into the direction of personalized medicine, since the huge amount of each patient’s data is intensively analyzed and leads to the best treatment for that patient individually, whereas in the current decision process patients get more or less grouped into stages or grades and are then treated in the same way. Finally, the clinical study will show whether the more personalized approach will be able to improve the survival of the patients.

Der Beitrag BioVariance is a member of the EU-funded REVERT Project erschien zuerst auf BioVariance - data-driven diagnostics.

The facts

„Colorectal carcinoma“ means several malignant tumor types in the colon or rectum. Malignant tumors rarely occur in other intestinal areas like small intestine or caecum. ^[1]

Colorectal cancer (CRC) had a low incidence rate in 1950. However, it became a predominant cancer type and now accounts for about 10% of cancer-related mortality in western countries.^[1,2] CRC is the second most common cancer type in men and women in Germany. It ranks third behind lung and breast cancer worldwide. In Germany, about 26.000 women and 32.300 men developed CRC in 2016, while 11.400 women and 13.400 men died from it. More than half of the patients developing CRC had an age of 70 years and above. Only 10 % of the new cases occur before the age of 55. ^[2] The lifetime risk of developing CRC is about 6 %, with chronic inflammatory bowel diseases and other important factors like unhealthy diet or lack of exercise raising the cancer risk. Inheritable genetic mutations cause 3-5 % of all CRC cases, especially colon cancer. Affected people have a very high risk of developing cancer in the early age of 20-40 years. ^[1]

In the year 2018, the World Health Organization counted about 1,8 Mio new CRC cases and 880.000 deaths. ^[3,4] More than 50 % of the new cases were registered in Asia (see Fig. 1). The global incidence rate is estimated to increase up to 3 Mio until 2040. ^[3]

As described above, men are stronger affected by CRCs than women. ^[2,3,6] Additionally, cancer cases strongly increased in the developed countries due to the ageing population in the recent years (see Fig. 2). ^[3]

Sex differences

Although women have a lower incidence of CRC than men, right-sided CRCs occur more frequently in women compared to men, whereas left-sided CRCs have an equal frequency between both sexes. Several evidences demonstrate that the rate of right-sided CRC cases is strikingly higher in women than in men (61.7% vs 38.3%), while only slightly more left-sided CRC cases are observed in women than men (52.1% vs 47.8%). The reason for this sex difference is still not proven and of concern for women, due to the association of right-sided CRCs with the poorest clinical outcomes among all CRC patients. ^[5]

Studies revealed that metabolite rates in the glycolysis pathway, pentose phosphate pathway, carnitine shuttle metabolism, asparagine synthesis, methionine metabolism and the polyamine synthesis pathway showed sex-related differences when measured in tumor samples compared to normal samples. Tumors from women and men also used different metabolic intermediates between the sexes for energy production to support cell growth. ^[5] Thus, modern CRC therapy approaches should ideally consider not only common molecular information, but also details of sex-specific mechanisms.

Further studies also indicate that the gut microbiota is partly correlated with the tumor development as well as emerging drug resistance. ^[4,6]

The upgrade of personalized colorectal cancer treatment

Personalizing cancer treatment is still challenging. No expert believes in finding a magic cure against CRC nowadays. However, therapeutic approaches based on patient’s genetic variations provide the most promising chances for patients. Numerous genetic mutations are already associated with risk of CRC. ^[7] But the manual search for gene variants and appropriate drugs in cancer therapy is very labour intensive and time consuming, while the number of new medical insights gained from scientific research continuously increases. Further, economic acting must be brought into accordance with patient welfare.

Therefore, BioVariance has now developed the web-based platform OncoVariant to identify the most suitable medication for patients suffering from colorectal, breast or prostate cancer. State-of-the-art automatization and parallelization techniques are combined for comparing patient’s gene variants with profound knowledge from worldwide databases regarding treatment options. The final report contains information about patient’s variants and appropriate clinical evidence as well as information on the proposed drugs and their interactions. The examination of numerous high-quality databases ensures the high value of the proposed therapy options. Thus, OncoVariant enables personalized cancer therapy while minimizing time and effort on behalf of attending physicians. ^[8] Finding the perfect treatment for each patient is now as easy as never before.

Here you can find more information about the web-based platform OncoVariant.

Contact Person:

Kerstin Hammer

Sources

Der Beitrag Colorectal cancer – The evil within erschien zuerst auf BioVariance - data-driven diagnostics.

World Cancer Day

Many people wonder why there is still no cure for cancer yet. But cancer isn’t just one disease. It is more than 100 diseases, and each of these types is divided into several sub-types. Thus, tumor heterogeneity, which leads to differential treatment responses, remains the leading challenge for effective treatment.

The World Cancer Day is a global initiative established in the year 2000 and led by the Union for International Cancer Control (UICC). Each February 4^th it serves to raise awareness of the global battle against cancer and the urgent need for an improvement of cancer research, prevention and treatment. This year’s slogan “I Am and I Will.” is a reminder that everyone can play an important part in reducing the global burden of cancer and can impact his future. ^[1]

Cancer – Then and now

Fifty years ago, most cancers were treated with extensive surgical resections. For example, the radical mastectomy for breast cancer was initiated by William Stewart Halsted in the late 19th century. Removal of the entire breast, the pectoral muscles and the surrounding lymph nodes was supposed to be essential for curing the cancer and preventing it from spreading. Until the early 1970’s there was no evidence that this procedure really works as expected. The first conducted study regarding extensive resection finally proved that there was no survival benefit from this surgical procedure. ^[2]

Cancer has moved from the third leading cause of death in 1990 to the second leading cause in 2013, behind cardiovascular disease. Between 1990 and 2013, incident cases for every cancer increased worldwide, ranging from 9% for cervical cancer up to 217% for prostate cancer. Since the risk for most cancers increases with a higher life expectancy, aging contributed between 20% and 40% of these incidences. ^[3] Cancer is a leading cause of death worldwide, with 18 Mio new cases and 9,5 Mio deaths globally in 2018 (see Fig. 1+2). Approximately 65% of deaths due to cancer occur in developing countries (see Fig. 3). ^[4,5,6,7,8]

Cancer is estimated to become a major cause of morbidity and mortality in the coming decades in every region of the world. The rise in the ageing population is a primary reason for this negative trend, as already mentioned in the previous blog entry. In the last 15 years, life expectancy has increased by about 5% in Europe, over the past 15 years. So, 11% of women and 7.5% of men were 65 years or older in 2016. ^[9] Other risk factors, which act cancer promoting, are smoking and lack of exercises, for example. About 40 % of all new cancer cases in Europe could be prevented, if people were aware of these risk factors and the factors were greater included in early detection methods. ^[1,5,10]

The situation in developing countries

The rising trend of new cancer cases is a particular threat to developing nations with low and middle income. The deficient health systems cannot offer complex and expensive cancer treatments because of limited resources and lacking diagnosis and treatment possibilities. ^[3,5]

Thus, cancer is often diagnosed in late stages. ^[5,6] Further, poor education of health professionals, missing guidelines, limited facilities and oncologists for cancer treatment, misconception about pain drugs as well as a bad informing of patients by the physicians result in inappropriate cancer management. Many developing countries only invest less than 1% of the national budget into healthcare, in contrast to well developed countries investing about 7%. ^[7]

The global incidence of cancer is expected to rise from 18 Mio in 2018 to 22 Mio until 2030. Approximately half of the new cases are supposed to occur in developing countries, especially in Asia. ^[7,8]

Artificial Intelligence – A milestone in cancer therapy

Over the past decades, a continuous evolution in cancer research has been performed. Various modern diagnosis methods, like genome screening in early stage, allow the early identification of cancer diseases before they cause symptoms (see Fig. 4). With new state-of-the-art technologies using Artificial Intelligence, large amounts of cancer data have been collected. ^[11,12] Specialized computer-based methods improve the efficiency and quality of clinical work and reduce the number of medical errors. Cognitive solutions combine technical and industry-specific content with highly modern methods of machine learning to promote research. The idea of using Artificial Intelligence first developed in the early 1950’s. Alan Turing described basic approaches of using machine learning, genetic algorithms and deep learning in his article “Computing Machinery and Intelligence”. In 1956, Artificial Intelligence was officially named at Dartmouth College. ^[11,13]

AI technology has been widely introduced into various fields of diagnostics. The amount of data generated in clinical studies and other application areas doubles every three years. ^[13] Especially „omics“ data (e.g. genomics, metabolomics, proteomics) would be of no use without comprehensive analysis and the appropriate context. Newest bioinformatics approaches are based on the individual genetic signature of the patient’s tumor for receiving recommendations on the optimal therapy. So far, more than 50,000 cancer genomes are sequenced and millions of genetic variants are identified, which might impact the growth of cancer cells and might also influence the response to treatment. The comparison of patient’s data with high-quality literature from various databases supports the physician in choosing the best possible therapy individually. This modern system includes relevant information regarding health, costs and potential responses to certain therapies, thus improving the individual healthcare for patients while reducing costs, avoiding inappropriate therapies and faster receiving the right diagnosis. ^{[12,13,14,15]}

Future chances

Well developed countries are currently entering a new era of oncology. High-quality and comprising knowledge will ensure the appropriate use of the existing and huge amount of data and the state-of-the-art technical solutions which will be presented prospectively. The future of cancer prevention and therapy provides many new chances and challenges. Thus, promising techniques for early detection of cancer in combination with personalized therapy options allow not only the reduction of the expenditure of time, money and resources, but also the improvement of the physical and mental health of patients suffering from cancer.

Contact Person:

Kerstin Hammer

Sources

Der Beitrag The Global Burden of Cancer erschien zuerst auf BioVariance - data-driven diagnostics.

The current situation

Due to great progress regarding early cancer diagnosis, diagnostics, therapy and care in the last decades, the survival rate and quality of life of patients suffering from breast cancer increased significantly in Germany. Despite that, breast cancer remains a big challenge in medicine: In 2012, breast cancer was the second most common cancer in the world with an amount of 12 % of all cancer cases. ^[1]

Breast cancer represents more than 30 % of all cancer cases in women, followed by colon cancer (12 %) and lung cancer (9 %). By contrast, the incidence of breast cancer in men is nearly 1 %. More than 70.000 women and 600 men develop breast cancer every year in Germany, causing every eighth woman to receive a cancer diagnosis in her lifetime. ^[2,3,4] But with modern diagnostics and therapeutic approaches the current chance for recovery is up to 80 %.

However, which are the factors influencing the risk of developing cancer? The exact reasons still remain unclear, whereas the age, hormonal balance, lifestyle (e.g. diet, sports, smoking,…) and genetic predisposition of the patient act as influencing factors for cancer development. ^[1,2,5,6]

Breast cancer counts as a geriatric disease like the most cancer types, developing at a mean age of 63 years, (see Fig. 1). When receiving the diagnosis, 25 % of the patients are younger than 55 years and 10 % are younger than 45 years. ^[2,3,4,6]

Genetic risks

Cancer is not a hereditary disease in general, but some types of cancer are based on a inherited genetic mutation. Genes showing a higher cancer risk and being present in every human are BRCA1 and BRCA2. A mutation in one of these genes increases the risk of cancer development up to 80 %. Anyway, just 5-10 % of the breast cancer patients are affected by a BRCA mutation. ^[2,3,5,7,8]

In addition to these genes, about 60 other genes can also increase the risk of breast cancer development. These mutations are extremely rare and just have a low effect on the cancer risk, except several mutations accumulate in the patient’s genome. ^[7]

Preventive and therapeutic options

Possible treatment options of breast cancer are surgery, antihormone (endocrine) therapy, chemotherapy, radiotherapy und novel treatments with targeted drugs. The individual choice of the therapy depends on breast cancer type, stage of disease, health status and possible comorbidities. Additional cancer influencing factors like sensivity to hormones or aggressiveness are considered when choosing the most promising treatment. ^[2,3]

Nowadays, targeted drugs are used for breast cancer treatment increasingly. Artificial antibodies don’t harm the whole body, but just interact with certain cell attributes promoting cancer growth. Thus, cancer therapy becomes more bearable for patients while becoming more effective against cancer cells. Targeted treatment also works in advanced and metastatic breast cancer. But patients lacking the required cell attributes won’t derive any benefit of this treatment option. ^[2,3,4]

For example, 15-30 % of all breast cancer patients show an increased appearance of HER2 receptors on cancer cells, causing excessive proliferation and tumor growth and making this form of cancer more aggressive. In this case, the high-performance drug Trastuzumab can be applied for therapy, being a potent antibody against HER2. ^[4,9,10] The chance for complete recovery is low in severe cancer cases, but this drug allows a long life as possible and good quality of life after all.

With many different and complex types of breast cancer, special genetic analyses came to the market for the purpose of prevention and early detection. The molecular analysis of certain gene combinations showing potential mutations are intended to support the choice of promising therapy options. For example, the OncotypeDX test analyzes a panel of 21 genes being associated with breast cancer development, resulting in a prediction whether a patient with certain types of breast cancer will benefit from chemotherapy. ^[1,7,10] However, gene analyses are not yet completely recognized as an additional value in healthcare.

Initiatives for fighting cancer

In 2008, the Federal Ministry of Health initiated the „National Cancer Plan“ in collaboration with the German Cancer Society, the German Cancer Aid and the Association of German Tumor Centers. This project comprises several multidisciplinary members und focuses on current problems in early detection and prevention of cancer. Coordinated by the Federal Ministry of Health, it is supported by VDI/VDE Innovation + Technique. Involved health insurances, pension insurances, providers as well as research and patients’ organizations collaborate closely and cross-sectoral, working on the following focal points: ^[11]

• Advancement of the early cancer detection: Compliance with existing quality regulations, improvement of information services and participation rates of patients
• Advancement of the healthcare infrastructure regarding oncology and quality assurance: Ensured access to oncological care, distribution and application of existing guidelines, qualitative reporting to providers and payers
• Efficient and individual oncological treatment: ensured and fast access to effective and innovative cancer therapies
• Stronger orientation to patients: Consulting and supportive services, involvement of patients into medical decisions

Additionally to the „National Cancer Plan“, the Federal Ministry of Health, the German Cancer Society and the German Cancer Aid just initiated another cancer initiative called  “National Decade against Cancer”. Aim of this project is to improve the early detection and prevention of cancer and to provide new oncological insights in a faster and more efficient way to patients within the next 10 years. Further, the initiative intends to build a National Center for Cancer Prevention as well as 8 National Centers for Tumor Diseases. Main objects are the research on the influence of chronic inflammation on cancer progression, the development of molecular testing methods for early cancer detection and the production of vaccines against cancer. The Federal Ministry invested 60 Mio. € in this project. ^[12]

Future perspective

New insights in the fields of breast cancer and the increasing focus on Personalized Medicine require a stronger structuring and a closer cross-linking between research and care. A more efficient and faster transfer of knowledge from basic research to clinics and back to research is a big challenge, but can be coped with the introduction of appropriate statutory conditions and consistent cancer registries. An additional expansion of the services in the ambulant cancer care and a stronger orientation towards patients will enable a high-quality, innovative and cross-sectoral cancer care and will promote the fight against breast cancer.

Contact person:

Kerstin Hammer

Sources

Der Beitrag The eternal fight against Breast Cancer erschien zuerst auf BioVariance - data-driven diagnostics.

Because of the World-Kidney-Day on March 14, there is a new post about another rare disease in Germany. The renal cell carcinoma is the most common form of kidney cancer and appears mainly among elderly people. This blog discribes the location, structure and function of this organ, kidney cancer in general, as well as causes and treatment of this disease.

The kidney

Location

Every person has two bean-shaped kidneys, each weighing just under 120 grams.¹ They are located on the back side of the body at the eleventh and twelfth vertebra below the diaphragm.² Thereby the right kidney lies a little bit deeper than the left one, because the liver is located above it.²

Anatomy

The kidney is divided into renal tissue and renal pelvis due to the structure.³ The fomer contains about one million small filter units, called nephrons consisting of glomeruli (renal corpuscle) and tubuli (renal tubes).⁴ The renal tissue contains the cortex, the renal medulla and the calyces.¹ The renal medulla consists of 10 to 12 conical structures, called the renal pyramids.⁵ The hilum of kidney encompasses the kidney artery and vein and acts like a passage for the lymphatic vessels, nerves and the ureter.⁴ The kidney is enclosed by the renal capsule, also called connective tissue capsule, performing a protective task.⁴

Function

The purification of the blood and the formation of urine are the main tasks of the kidney.³ The nephrons detoxify the body by filtering harmful substances from the blood and secreting it as urine into the urinary tract.^1,3 The purified blood is then trace back to the body via the kidney vein.⁴ The urine produced in this way is collected in the renal pelvis and is transported via the ureter into the bladder to be excreted through the urethra.³

Kidney cancer

According to the German Cancer Registry, all malignant diseases of the kidney, renal pelvis and ureter are reffered as kidney cancer.⁶ In case of the most common form of kidney cancer, the renal cell carcinoma (hypernephron), the cells of the renal tubes begin to degenerate.^1,6 This form accounts for approximately 90-96% of all kidney tumors.⁷

Because the kidney is heavily supplied with blood and connects to large blood vessels, tumor cells can rapidly spread throughout the body and form metastases.⁶ These occur mainly in the lungs, liver, brain and bones.⁶

Epidemiology

Malignant tumors in the kidney are generally rare in Germany and account for around 2% of all tumors.⁶ Over here, every year about 6,000 women and 10,000 men develop kidney cancer,¹ thereby men are twice as common affected.⁸

Statistics show that the incidence among men increased since the 1990s, whereas it decreased among women since 2009.⁸ Age-standardized mortality rates are decreased in both sexes.⁸ The average age at diagnosis is 72 years for women and 67 years for men.⁸ Young peole are very rarely affected by this cancer type.³

Cause

An exact cause leading to the formation of renal cell carcinomas isn’t known.⁶ Often, it can’t be determined even afterwards.³ However, carcinogenesis is favored by several risk factors:

• Smoking^6,7
• Alcohol abuse^6,7
• Hypertension^6,7
• High-fat diet⁶
• Low fluid intake⁶
• Chronic kidney weakness⁶
• Contact with kidney damaging substances⁷
• Increasing age⁶
• Hereditary factors⁶

Therapy

The most important procedure after getting a diagnosis is an operation.⁹ The affected kidney is partially or completely removed.⁹ In 96.5% of all cases, only one kidney is affected by cancer.¹ The efficiency of the healthy kidney can fully compensate the loss of the removed kidney.⁹ Once the tumor has spread, radiation is used (additionally).⁹ Chemotherapy isn’t effective in the treatment of kidney cancer.⁹

Targeted therapy

Targeted therapy is part of personalized medicine.¹⁰ The focus is based on the biological properties of the tumor.¹⁰ By testing for specific biomarkers, the differences between a healthy and a cancer cell can be determined.¹⁰ On this basis, drugs are used, for example, to suppress certain metabolic processees and thus prevent the growth of cancer cells.⁹ There’re already several targeted drugs for the treatment of kidney cancer approved (for example bevacizumab, sorafenib)⁹ another 26 are under developement.¹¹

Contact person:
Kristina Schraml (kristina.schraml@biovariance.com)

Sources

Der Beitrag Renal cell carcinoma – a rare disease in Germany erschien zuerst auf BioVariance - data-driven diagnostics.

Tumors of the central nervous system

In Germany every year about 1,750 children youger than 15 years getting the diagnosis cancer, another 360 children between the age of 15 and 17.¹ Tumors of the central nervous system (CNS) are the second leading types of cancer after leukemia among children with a incidence of 430 kids per year.^1,2 In contrast to the peripheral nervous system, the central nervous system includes the nerve tracts of the brain and spinal cord.³ It serves as a central organ regarding integration, coordination and regulation and processes both external sensory impressions and interior stimuli.³ A major problem in the treatment of brain tumors is the blood-brain barrier, which separates the brain and spinal cord from the bloodstream.^4,5 This barrier ensures that the blood vessels in the brain are protected from harmful substances, which are possibly present in the bloodstream.^4,5 Thus, not all cytotoxic drugs are able to overcome this barrier.^4,5

High-grade Glioma

Gliomas are defined as solid tumors of the central nervous system caused by degeneration of glial cells, the supporting tissue of nerve cells.^2,6 They are classified into low-grade and high-grade gliomas.⁶ Among children and young people high-grade gliomas rarely occur with a proportion of 10-15% of all tumors of the central nervous system.⁶ About 60-80 kids and adolescents under the age of 15 get the diagnosis of a high-grade glioma in Germany every year.⁶ This corresponds to a proportion of 5-10 patients per 1,000,000 children.⁶ High-grade tumors grow rapidly and aggressively, destroy healthy tissue and can contribute to the formation of new tumors through migration.⁶ Depending on the location, origin and malignancy of gliomas, different forms can be distinguished.⁶ The variant with the worst prognosis is the Diffuse Intrinsic Pontine Glioma.⁶

Diffuse Intrinsic Pontine Glioma (DIPG)

Diffuse Intrinsic Pontine Glioma describes a tumor which is located in the brain stem and is responsible for one-third of all high-grade gliomas among children.⁶ The brain stem includes the midbrain, pons and the Medulla oblongata. It controls vital bodily fuctions such as breathing, the blood pressure and reflexes. This area is the central junction of all nerves running between the brain and the rest of the body.⁶ DIPG is also called Diffuse Midline Glioma with Histone H3K27M Mutation,⁶ because in 78% of all cases histone H3 is non-functional by changing a lysine (K) with a methionine (M) at position 27 through a point mutation.⁷ Histones are important for both DNA packaging and gene expression. If these proteins are mutated, changes in the expression of certain genes override essential control mechanisms, which in turn promotes tumor development.⁷ Due to the localization of the pontine glioma and the diffuse infiltrating grwoth, this malignant tumor is inoperable and there’s no chance of healing.⁸

Epidemiology

DIPG is a rare disease  with a total of 300 new cases in Europe and North America each year.⁸ Nevertheless, DIPG is the most common fatal brain tumor among children (between the age of 4 and 9 years). The 5-year survival rate is less than 1%.⁸ After getting the diagnosis, the median survival rate is 9 months.⁸

Therapy

The current standard therapy is radiation, there’s no effective chemotherapy.⁹

Foundation for innovative medicine

The foundation for innovative medicine, which was founded in 2014 and consists of a volunteer team, has focused on the research and prevention of cancer, especially on childhood brain tumors.¹⁰ The perform for example projects helping to define effective therapies for incurable cancer types.¹⁰ A private initiative called DIPG Fighter was originated after the death of Lina (7 years). Their aim is supporting the foundation financially regarding DIPG research. Currently, a new technology is developed, which will allow predictions about the chances of drugs crossing the blood-brain barrier. This should speed up finding a appropriate treatment for DIPG. There’re many activities started by the DIPG Fighter to raise funds for this enormously important research. One of them is the participation at the Balkan Express. This will be presented by us separately in the near future.       Contact Person: Kristina Schraml (kristina.schraml@biovariance.com) Sources

Der Beitrag DIPG – Fight for a cure! erschien zuerst auf BioVariance - data-driven diagnostics.

On February 4th was World Cancer Day. That’s why the current blog post answers the question of what cancer actually is and how it develops.

History

Cancer was already described by the ancient Egyptians in the so-called „Edmin Smith Papyrus“.¹ It pictured the removal of tumors from the breast of women using a tool called „fire drill“.¹ it was also noted that there’s no treatment for this type of disease.¹

In fact, a 3,000-year-old Egyptian mummy who has died of breastcancer was found.² Nearby, archaeologists discovered a 2,800-year-old male mummy with the so far oldest case of multiple myeloma.² However, the oldest known case in general is a skeleton of an Egyptian who died 3,200 years ago of a soft tissue tumor that had already metastasized to the bones.³ Resulting lesions are still visible today.³

Definition

The Latin term tumor is translated to growth or lump and descibes an abnormal enlargement of a tissue.⁴ Because certain types of tumors looked like the feet of crabs due to the surrounding dilated blood vessels, it was used to define the name of disease.¹

Types of tumors

A tumor can be differentiated by the tissue from which it originally came:

• Carcinomas: Arise in the epithelium and account for approximately 80% of all malignant tumors⁵
• Sarcomas: Arise in the connective and supporting tissue (fatty tissue, muscles, tendons) or muscle tissue and represent only about 1% of the malignant disease⁶
• Blastomas: embryonic tumors arising during tissue and organ development⁴

These types of tumors are summarized as solid tumors because they initially have a distinct limitation and a tight tissue association.⁴

In contrast, there are systemic cancers (systemic = affecting the whole body) spreading throughout the body from the oneset of the disease.⁴ This category includes malignant diseases of the hematopoietic and lymphatic systems (leukemia and lymphoma).⁴

Classification

• Benign tumors displace surrounding tissue but don’t cross the border to adjacent tissue.⁴
• Semimaligne tumors are „limited malignant“.^4,7 They invade surrounding tissue but fail to form metastases.^4,7

• A malignant tumor is called cancer.^4,7 It grows uncontrolled and disordered and invades and destroys surrounding tissue.^4,7 Tumor cells can spread through blood vessels or lymphatics and form metastases.⁴
• Precancerous lesions tissue changes that are highly likely to develop into malignant tumors.⁷
• Carcinoma in situ (translated: cancer at the site of origin) describes a malignant tumor in its early stage which hasn’t broken through the basal membrane of the origin yet and hasn’t invaded other tissues.⁷

Formation

A tumor is developed when healthy cells in the body change.⁴ Such a change was first described in the gene RAS in 1982.⁸ With this observation researchers could prove that healty human cells are transformed into tumor cells by mutations.⁸

Mutations

A mutation describes a permanent change within the genome. This occurs spontaneouly without external cause or is produced artificially by so-called mutagens (see trigger). The following types of mutations are distinguished:

• Deletion: a part of the DNA is excised
• Insertion: an additional piece of DNA is inserted
• Substitution: a single base is exchanged

Silent mutations usually remain undetected as they have no effect in the organism; in contrast to the loss-of-function mutations, due to which the corresponding  gene product loses its function. These’re

particularly dangerous in genes controlling the cell cycle and repairing DNA damage.⁹

The hallmarks of cancer¹⁰

Douglas Hanahan and Robert A. Weinberg have described the characteristics of cancer cells in their publication „The hallmarks of cancer“.

Trigger

Cancer is a very complex disease with many potential causes. Mutations can occur with or without external influence or are genetically conditioned.⁴ Not all damages result in a mutation.⁹

External influence

• Lifestyle: smoking, obesity, lack of exercise and malnutrition.⁴ Experts estimte that half of all cancers could be avoided by changing the lifestyle.⁴
• Environmental factors: carcinogenic substances, such as chemicals, environmental toxins or radiation^.4 It is estimated that about 4 to 20 out of 100 people suffer from an cancer which develops due to the environment.⁴
• Pathogens: Especially viruses, but also bacteria and parasites. Cervical cancer, for example, is caused by HPV (human papillomavirus) or gastric cancer is caused by the bacterium Helicobacter pylori. Experts estimate that worldwide about every sixth cancer is triggered by an infection, in Germany about 4 out of 100.⁴

Lifestyle and the influence oft he environment are among the main causes.⁹

Cell division⁴

Cell divisions can cause damgage passing from the mother cell to the daughter cell.

A sign of aging

With higher age the risk of cancer rises. The likelihood of permanent damage due to mutations increases, because the cells can’t repair the damage anymore.¹¹

Inheritance

In addition to mutations arising spontaneously, the genetic equipment plays an important role, too. Some people have an increased risk of develop cancer because the corresponding mutated genes can be inherited.⁴ Experts estimate that about 5 to 10 out of 100 cancer cases are genetically determined.⁴ However, this doesn’t mean that every person with these particular genes inevitably suffers from cancer.⁴ Here, the external influences play an additional central role, too.⁴

Relevant genes

These genes include proto-oncogenes and tumor suppressor genes.⁸ Proto-oncogenes occur in every cell and affect the growth, division, and differentiation of a cell. Mutations result in an oncogene that, through its altered gene function, can drive cell growth excessively resulting in cancer formation. Tumor suppressor genes control the cell cycle and can reduce the likelihood of developing a tumor by their ability to induce apoptosis in damaged cells. These include, for example, the protein p53, which is also called „guardian of the genome“. In almost half of all cancer cases there’s a mutation in the gene coding for this protein.⁸

Gene mutations can drive cancer development in two ways: either by activating oncogenes or by deactivating tumor suppressor genes.⁸

 Meanwhile there are over 570 genes associated with cancer.⁸ It’s estimated that at least five different genes must be mutated to override the control mechanisms and thus cause cancer.⁹ The mutations may have different causes.⁹ On average, about 100-1,000 different mutations contribute to the formation of a tumor.⁸

Contact person:

Kristina Schraml (kristina.schraml@biovariance.com)

Sources

Der Beitrag World Cancer Day: What is cancer actually? erschien zuerst auf BioVariance - data-driven diagnostics.

Because the month January is „Cervical cancer awareness month“, this blog post is about this type of cancer. Every woman should think about it because it’s a cancer with good chances of healing when it’s detected in an early stage. So use the cancer screening!

The uterus

The uterus is used for reproduction: the fertilized egg cell nests and the embryo grows up; during birth the baby is driven outwards by the muscular contractions of the uterus.¹

The uterus consists of three parts: the cervix, the isthmus and the uterine body.^2,3 Inside the cervix there’s a mucous membrane (epithelium), whose glands form a viscous fluid (cervical mucus) and thus is responsible for pathogens can’t enter the uterus.⁴ The cervix is a strong muscle tube ending in the uterine orifice.⁴ This area is particularly vulnerable for cell changes⁵(cervical or epithelial dysplasia).¹

Cervical cancer – preliminary stages

Such cell changes are classified into three degrees of severity, depending how much they are progressed.¹ This grouping is called CIN (cervical intraepithelial neoplasia).^1,6

• CIN 1 stands for a mild dysplasia, the changes only effect the upper epithelial layer.^1,6
• CIN 2 stands for a moderate dysplasia, the changes are already in multiple layers.^1,6
• Severe dysplasia is classified as CIN 3, in which the changes affect the entire epithelium.^1,6

A diagnosis of such preliminary stages, also known as precancerosis, doesn’t necessarily mean that it develops into cancer, but the probability increases with the degree of severity.¹

Cervical cancer

Extremely rare – in one out of 100 women – cell changes don’t regress and it end up with cancer.^5,8 On average, this process takes around 15 years.^7,9,10

Causes

The prerequisite for the development of cervical cancer is an infection with the human papillomavirus (HPV).⁵

HPV

There are about 100 different HP viruses responsible for various diseases.^1,10 Human papillomaviruses predominantly affect skin and mucous membrane cells.⁴

For example, HPV 6 and HPV 11 cause benign lesions of:

• the skin (warts)^1,8
• the mucous membranes of genital and anal bodies (warts)^1,8
• the mouth⁹
• the respiratory⁸

HPV 16 and HPV 18 are in the development of

• cancer precursors⁵
• cervical cancer⁵ involved.

Viruses are microscopically small particles and consist mainly of genetic material and a protective protein coat.⁷ They’re characterized by the fact that they don’t have their own metabolism and are therefore dependent on a living organism (host) for reproduction.⁷

HPV 16 and HPV 18 are mainly transmitted during sexual intercourse^4,5 or by skin contact in the genital area.⁴ The viruses settle down in cells of the endometrium.⁵ Certain genes of the pathogens are incorporated into the genetic material of the affected cells.⁵ The permanent activity of the foreign genes leads to changes in the host cells.⁵ If these changes aren’t detected timely cancer can develop.⁵ Approximately 70% of all cervical cancers cases are due to infections with these two HPV types.^5,10

Cofactors

In addition to an infection, the following factors are important:

• Smoking^4,7 and passive smoking¹: in the mucous membrane of the uterus, carcinogenic degradation products of tobacco smoke can be detected,¹ thus pathogens can more easily enter the cells. An infection remains longer in women, who smoke; for former smokers the risk remains elevated for about 20 years after quit smoking⁷
• Adipositas¹¹
• Many pregnancies/birhts⁷
• Hormonal contraceptives¹
• Addional genital infections¹
• Lack of hygiene¹
• Unprotected sex¹
• AIDS⁴
• Medications weakening the immune system^1,4

Genetic factors seem to have no influence on the development of an infection and on the development of cancer.¹

However, it has been shown that women with so-called hormonal coils (IUP = intrauterine pessors) are infected only half as often as women who use other contraceptives.⁷ However, this isn’t yet fully understood.⁷ It is believed that the foreign material stimulates the immune response.⁷

Diagnosis

The Pap test, developed by the greek physician George Nicholas Papanicolaou, has been used for early detection since the mid-1940s.⁵ This involves taking a smear from the cervix and cervical canal and thus detecting the asymptomatic precancerous lesions.⁵ They are divided into five stages (Pap I to Pap V).⁵ From stage three further medical tests are necessary.⁵ An example is colposcopy where the cervix is examined for cell changes by a magnifying glass.^5,9

Epidemiology

50% of all women become infected with the virus at least once during their lifetime.⁵ Also re-infection with the same virus is not excluded.⁵ In most cases, however, an infection pass unnoticed,⁴ as the immune system successfully fights against it.^10,11 If there’s a transient tissue change, it often declines by itself.^4,10,11

Cervical cancer is more common among younger women.⁵ Half of the affected are younger than 53 years when they get the diagnosis.^1,5 Women between 40 and 59 are the most affected age bracket^.5

Cervix cancer is the third most common cancer in the world,¹³ in Germany, it occupies the twelfth place (as of 2012).¹ Also, a decline in the number of deaths can be seen since the 1980s. Nonetheless, this cancer is the fourth leading cause of cancer in Germany among women under the age of 44.¹²

In Germany, an average of approximately 4,600 women get the diagnosis every year,^3,4 but the cancer is detected so early in two-thirds that the chances of recovery are very good.³

The 5-year prevalence indicates that cervix cancer is on the fouth place.¹⁴

Symptomes

At the beginning there are no obvious symptoms and appear only as the diasease progresses:⁵

• Fatigue¹
• Irregular menstrual bleeding (after sex,⁵ outside the period,⁵ after strain¹)
• Unusually long menstrual bleeding¹
• Pain during sex⁴
• Lower abdominal pain¹
• Pain during urination/defecation^1,9
• Back pain^1,9
• Weight loss⁵
• Noticeably swollen legs^1,9

Treatment

There are currently three options available for the treatment of cervical cancer, depending on the size and progress of the tumor:³

• Conization: excision of a part oft he cervix (for very small and early detected tumors)³
• Tracherectomy: partial removal of the cervix (only for small tumors and if the lymph nodes aren’t affected yet)³
• Hysterectomy: removal oft he whole uterus³

In advanced cancer, chemotherapy and radiation are also used.³

Prevention

According to the directive of the early detection of cancer, every woman aged 20 or older has the claim to a free examination once a year.⁵ Thereby Pap tests are used to analyse cell changes.⁵

From the age of 35, there is additonal a HPV test detecting the DNA of these viruses.¹⁵

Since 2006 there is a vaccine against human papillomaviruses available.¹³ This is recommended from the age of nine years.¹³ However, it doesn’t work in people who have already come into contact with the pathogens.¹³

These cancer screenings are immensely important as the chances of recovery are very high if the tumor is detected and treated in an early stage.⁵

Australia as a role model

Australia is the world leader in the prevention of cervical cancer and has set the goal of eliminating this type of cancer by 2028.¹² In this case eliminating means creating a incidence rate of less than four per 100,000 women per year.¹² Experts even expect only six new cases in 100,000 female inhabitants in the next two years.¹² Thus, this type of cancer would fall into the category of rare diseases.¹² For comparison: In Germany, the incidence rate is twelve per 100,000.¹² The number of new cases has fallen extremely in Australia due to a good prevention program.¹² For example they switched from the Pap to the HPV test.¹² The rate of vaccinations is also very high with a number of 80-90%.¹² Compared to Germany: here the rate is 31-43%.¹²

Future

Both the Pap and the HPV test are in enormous criticism. It is said that the former fails in 20-50% of all cases.^12,15 The test for viral DNA is therefor more accurate, but there is no statement about the susceptibility to cancer possible.¹⁶

Artificial intelligence

A team of scientists from the National Cancer Institute (NCI) and Global Good has developed an algorithm analyzing digital uterine images to detect the different levels of cancer.¹⁷ Artificial intelligence can provide a greater sensitivity than the ordinary Pap test.¹⁸

Thus, an even more accurate early detection of precancerous lesions is possible.¹⁸

Genetic test

Researchers from the United Kingdom have developed a test that can detect cervical cancer with a rate of 100%.^15,16 This was done on 15,744 women aged between 25 and 65 over five years in Canada.^15,16 The epigenetic-based test doesn’t search for HPV DNA or cell mutations, but analyzes chemical markers on the genome.^16,17 Epigenetics describes all processes altering the activity of a gene in the course of life. Various processes block individual sections of the DNA and is recognized by the novel test.¹⁵ So, it is searched for cancer markers within the genome.¹⁵

It is expected that the genetic test will be established in England in the next five yeas.¹⁵ Compared to the Pap test, this genetic test has a higher accuracy, fewer inspection dates are required and it’s also more cost-effective.¹⁵

Therapeutic vaccination

Another goal is to develop a drug for people who already suffer from cervical cancer.¹⁹ A first therapeutic vaccine successfully fight against cancer in the mouse model: in half of them, the tumors regressed.¹⁹ This treatment option stimulates the immune system so it can kills degenerated cells.¹⁹

• Vaccination: the body forms antibodies protecting it from future infections¹⁹
• Therapeutic vaccination: activates cytotoxic T cells¹⁹

The special feature of this type of vaccine is that the epitopes (potein structures) are an important part of the vaccination itself.¹³ They are transported into the lymph nodes and can trigger an immune response.¹³ The cytotoxic T cells come into contact with these proteins and seek out the rest of the body afterwards.¹³ This kills infected cells/ cancer cells.¹³

At the moment, this vaccine is in the preclinical development phase.¹⁹

Contact Person:

Kristina Schraml (kristina.schraml@biovariance.com)

Sources

Der Beitrag Cervical cancer – use the cancer screening erschien zuerst auf BioVariance - data-driven diagnostics.

There is a new blog post because of the german day of the stomach last week. This time, it’s about gastric cancer and a first partial success in the personalized treatment.  

The stomach

The stomach is a flexible, elastic muscular sac connecting to the esophagus and the duodenum, the first section of the small intestine. 

It consists of the gastric cardia, the fundus and the body of the stomach and the pylorus. The main purpose is the buffering of the ingested food. In addition, the stomach takes part in digestion: the food is mixed with the gastric juice and the chyme is passed on the small intestine, where the main part of the digestion takes place. From here, the nutrients can enter the body via the intestinal wall.

The thickness of the stomach wall is only a few millimeters and it consists of serveral layers; inside there is a thin mucous membrane consisting of about 35 million glands producing 2 ½ liters of gastric Juice per day.¹

Stomach carcinoma – Formation

Stomach carcinoma arise from the cells of these glands and are thus a malignant growth of the gastric mucosa. This is the most common form of gastric cancer.¹ The exact mechanisms by which such carcinomas arise, aren’t fully understood. However, previous diseases, nutrition and lifestyle (alcohol and tobacco) play a key role. ²

Gastric bacterium

A pre-existing disease is for example a constant inflammation of the gastric mucosa. Such a inflammation is triggered by the gastric bacterium Helicobacter pylori.²

This microorganism nests in the gastric mucosa and therby damages it. Experts see these infections as one of the most important risk factors for the formation of gastric carcinoma: infected people carry a two to three time higher risk of diagnosed with cancer. ²

Genetic factors

Inheritance plays a minor role in developing the disease. About ten out of a hundred cases are caused by a familial risk.² Such genetic factors may be for example the Hereditary Diffuse Gastric Cancer (HDGC) or the Hereditary nonpolyposis colorectal cancer (HNPCC). Both forms of colon cancer are inherited autosomal dominant and represent an increased risk of developing gastric cancer.³ The former is caused by a mutation in the gene CDH1, which encodes the protein E-Cadherin.³ Cadherins are transmembrane proteins playing a role in the stabilization of cell-cell contacts. When such a gene is inactivated, the cells lose their cohesion and gain the ability to migrate.³ HNPCC is based on a mutation in one of the DNA repair genes of whom six are known yet playing a role in the disease.⁴

Epidemiology

However, the genetic material can also change randomly in the course of life, usually in higher age, which can lead to the development of cancer.²

Thus, in 45% of all cases, the average age of a woman diagnosed with gastric cancer is 75 years, of a man 72 years.⁵

Gastric cancer is a relatively rare disease and affects 19-25 per 100,000 inhabitants in Germany.³

Worldwide approximately one million new cases of stomach cancer are added per year,⁶ in Germany around 16,000 (compared to 65,000 for colorectal cancer per year).⁷ There has been a decline both in the number of new cases and the mortality rate in the last years.⁸

The current five-year survival rate is 33% for women and 30% for men.⁸ This is relatively poor compared to other types of cancer,⁸ making stomach cancer the second most common cause of cancer death after lung cancer.⁶

Treatment of stomach cancer

Probably the most important treatment option is surgery to remove parts or the entire stomach.⁹ Chemotherapy is (additionally) used in an advanced tumor to destroy cells detaching from the tumor.⁹ In a classic Chemotherapy platinum and fluorouracil are used, prolonging median survival by 9-11 months.⁶ However, it rarely heals the disease.

Targeted therapy

Targeted drugs direct towards a point of attack inside the tumor and block processes allowing cancer cells to grow and divide quickly.

The goal is that such points are particularly frequent or distinct in the cancer tissue.

The cytostatic drug Trastuzumab is very effective in the treatment of HER-2 positive breast cancer.⁶ HER-2 stands for human epidermal growth factor 2 and is located on the cell surface. Via these receptors, signals are transmitted from the surface to the interior of the cell. Normal, healthy cells possess only few of such proteins. Through amplification, the coding DNA sections are increased, which is associated with an overexpression of the receptors. If there are too many HER-2 receptors on the surface, the cells divide more frequently and the tumor grows faster und more uncontrollably. Thus, overexpression of this receptor is a point of attack for a targeted drug. Trastuzumab was also admitting in 2010 for metastasizing gastric cancer in combination with chemotherapy (Cisplatin and Capectiabine or 5-Fluorouracil) when a pre-therapy mandatory test shows the overexpression.¹⁰ The proportion is 20% – similiar to that of HER-2 positive breast cancer patients.⁶

A study also demonstrated the beneficial effect of Trastuzumab in gastric cancer:¹¹ Patients survived longer and the mortality risk was reduced by 26%. In 3,807 patients with locally advanced metastasizing gastric carcinoma, 22% showed overexpression of HER-2. Of these, 594 patients were either undergoing standard chemotherapy or get additinally Trastuzumab. The latter showed significantly prolonged progression free survival.

Contact Person:

Kristina Schraml (kristina.schraml@biovariance.com)

Sources

Der Beitrag Stomach carcinoma – a relatively rare cancer erschien zuerst auf BioVariance - data-driven diagnostics.