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How water motion can tell us about cancer treatment effectiveness

Jana CebullaBlogger: Jana CebullaPostDoc
MR Cancer Group, Department of Circulation and Medical Imaging

 

 

 

Just as every human being is a unique individual, every cancer has its own characteristics, and this is increasingly being recognised in cancer treatment. Targeted therapies are being developed that attack cancers on the molecular level and treatment strategies are tailor-made for each patient.

But how do we know that a treatment actually works?

Typically, treatment response is measured as a change in tumour size using anatomical MRI or CT images, or tumour markers found in body fluids. However, these changes usually occur quite late in the course of the treatment. This is especially true of new, targeted therapies that do not directly kill cancer cells, but cause more subtle structural changes in the tumour tissue. These new therapies aim for a better treatment effect with less side-effects, but because the changes are so subtle, it also means it could be more difficult to see if a treatment is effective or not.

We therefore need different methods to assess such structural changes in the tumour.

In the MR Cancer group at NTNU, we are testing magnetic resonance imaging (MRI) modalities that can visualise structural changes in the tumour that occur on the cellular level rather than changes in tumour size.

Brain tumours, blood sample and water diffusion map of tumour.

Figure 1: Left: MRI of brain tumours (Anne-Line Stensjøen). Middle: blood sampling. Right: “water diffusion map” of a tumour (Jana Cebulla).

One of these methods is “diffusion MRI”, where the brightness of the image depends on the random movement of the water molecules in the tissue, which is called diffusion. In previous blogs by Siver Moestue and Jose Teruel, we have already described how we can use diffusion MRI to diagnose cancer: usually water diffusion is more restricted in malignant (bad) tumours than in normal tissue or benign (good) tumours. But how can we use diffusion MRI to monitor treatment response?

When tumours respond to treatment, the tumour cells and their surrounding cells change in their function or structure. For example, if a tumour cell dies, its cell membrane becomes porous and more permeable, and water can diffuse more freely.

Illustration of water diffusion among cancer cells.

Figure 2: Left: densely packed tumour cells where the water diffusion is restricted especially because of cell membranes.
Right: Dying cells with permeable membranes that restrict water diffusion much less. (Cebulla, Doctoral thesis at NTNU; 2015:174)

And we can measure this with diffusion MRI.  Tumours responding to treatment can be distinguished from non-responding tumours by an increase in ADC, which stands for “apparent diffusion coefficient” – the average distance that a water molecule travels within a certain time. This is illustrated in Figure 2 which shows how much further and more freely the water molecules can move among dying cancer cells than within a ‘healthy’ tumour. This method was used in one of our recent studies, where we characterised the effects of a drug targeting a specific pathway in the cells (PI3-Kinase pathway).

Tumours before and after treatment.

Figure 3: The left tumour shows no obvious difference in the anatomical image before or after treatment, while the increase in ADC suggests that the tumour responds to treatment. The right tumour does not show response to treatment (Cebulla et al. Br J Cancer 2014).

Diffusion MRI is already being used for tumour detection. However, monitoring treatment response using these techniques is not yet part of routine. It is difficult to decide how much the ADC has to change in the tumour in order to consider it a real treatment response. Further international standardisation of the method is therefore necessary for the technique to be used routinely.

The MR cancer group at NTNU will continue to explore how we can detect response to cancer treatment at early time points using diffusion MRI and other advanced imaging technologies. The goal of this research is to provide more personalised cancer treatment that is tailored to the individual patient.

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Furry and fit: get moving this Movember!

Debbie Hill og Leslie WoodBloggers: Researcher Debbie Hill og PhD Candidate Leslie Euceda Wood
MR Cancer group, Department for ciruclation and medical imaging

 

 

 

It’s that time of year again! And this year, the Movember Foundation is challenging YOU to move every day this month to tackle physical inactivity. In keeping with the Movember spirit, the MR Cancer group (and friends!) donned their best training gear, and ventured out into the crisp breeze of a lovely November morning. Not only to raise a few smiles, but also to raise awareness for men’s health and prostate cancer.

MR Cancer-gruppen i treningstøy og barter.

According to the Movember Foundation a lack of physical activity is the fourth leading risk factor for global mortality, causing 3.2 million deaths worldwide per year. There is a push to combat physical inactivity by:

  1. Getting people moving (check out the MOVE campaign)
  2. Raising awareness on the dangers of physical inactivity & benefits of activity for both physical and mental health
  3. Finding new ways to encourage physical activity
  4. Investing in projects that increase understanding of what motivates men to move. Continue reading

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Planning the direction for CIUS

CIUS-people

Photo: Kristina Jones/NTNU

45 people from both academia and the industry were present at the first meeting discussing the direction for half the different work packages at NTNUs new centre CIUS, a Centre for Innovative Ultrasound Solutions for health care, maritime, and oil & gas.

– At this point, before we can start the work, it is important for us to point out the further direction for the research in some of the work packages at the centre. Work packages 1-4, in ultrasound knowledge and technology, and no 7, in clinical feasibility, are the fundament onto which all the other work packages will build, Asta Håberg, the head of CIUS, says.

CIUS is a Norwegian Research Council appointed centre for research-based innovation (SFI) and is located at Department of Medical Imaging and Circulation at Norwegian University of Science and Technology (NTNU) in Trondheim.

– CIUS will deliver novel ultrasound technology solutions for the benefit of the involved partners, new diagnostic tools for the benefit of patients and the Norwegian healthcare system, important knowledge disseminated in highly recognized scientific journals, and skilled personnel to further exploit the future potential of ultrasound imaging in Norwegian industries, healthcare and academia, Håberg says.

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Shutting off blood supply to an extremity to protect the heart

på operasjonssal

Foto: Geir Mogen

In a study just published in the International Journal of Cardiology, researchers from CERG and the Department of Cardiothoracic Surgery at the St. Olav’s Hospital have shown that shutting off the blood supply to an arm or leg before cardiac surgery protects the heart during the operation.

We wanted to see how the muscle of the left chamber of the heart was affected by a technique, called RIPC (remote ischemic preconditioning), during cardiac surgery. RIPC works by shutting off the blood supply to an arm or a leg before heart surgery. The goal is to reduce risk during cardiac surgery in the future.

Read more at CERG’s blog

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To treat or not to treat? The role of PET/MRI in prostate cancer

Mattijs ElschotBlog by: Mattijs Elschot
Postdoctoral Fellow at MR Cancer Group

Some prostate cancer patients need radical surgery to survive, whereas others can do without any form of treatment. The urologist determines to which group a patient belongs. Researchers at NTNU/St. Olavs Hospital investigate whether a PET/MRI scan can help making the correct decision.

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Early markers of a potentially dangerous type of prostate cancer

Morten Beck RyeBloggers: May-Britt Tessemansattebilde.may-britt.tessem and Morten Beck Rye

As we speak there are no accurate methods to diagnose potentially dangerous prostate cancer in an early stage of cancer.

From a pathologist’s point of view, aggressive cancers look totally similar to harmless subtypes in the beginning of development. As a consequence, the patients will be at high risk of overtreatment in the majority of cases where prostate cancer is detected. We urgently need new tools and markers to sort out the potentially dangerous types of prostate cancer from the non-dangerous in early disease. Most importantly, this will save the patients from reduced quality of life due to unnecessary surgical interventions, and also be economically beneficial for society.

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New method for characterizing brain tumors

Blogger: Morteza EsmaeiliMortezaE
Postdoctoral Fellow at MR Cancer Group, NTNU

 

A new non-invasive method can identify a special mutation in a type of brain tumor called gliomas. This unique test can assist in research towards new treatments that target cancer cells in glioma patients carrying this mutation. The new method is developed by my colleagues and me at MR Cancer Group at NTNU and researchers at the Departments of Radiology and Pathology of Radboud University Medical Center in Nijmegen. We believe it is an important step towards improved tools for the diagnosis and treatment evaluation of brain tumor patients.

Gliomas are common subtypes of primary brain tumors that originate from glial cells in the brain. There are different grades of gliomas, indicating their degree of aggressiveness; however, they are most often classified as “low-grade” or “high-grade” gliomas. Glioblastomas are the most aggressive type of gliomas. Various types of gliomas have been identified, and they have different clinical behavior and response to treatment. This means there is an urgent need for more accurate and precise diagnosis, prognosis, and therapy monitoring tools.

MR-bilde av en hjerne

Gliomas are common subtypes of primary brain tumors that originate from glial cells in the brain. A new non-invasive method can identify a special mutation in gliomas. (Photo: Geir Mogen/NTNU)

Conventional anatomical imaging methods, such as magnetic resonance imaging (MRI) (Figure 1), provide limited information on tumor characterization and prognosis. Advances in personalized patient management and new drug treatments for brain tumors have generated increasing demand for reproducible, non-invasive, quantitative imaging biomarkers.

Recent developments have concentrated on the role of physiological and metabolic MRI, such as magnetic resonance spectroscopy (MRS, see an example in Figure 2), and other molecular imaging methods in understanding the metabolic processes associated with tumor growth and progression. These studies have indicated that cancer cell metabolism, contrary to the metabolism in normal cells, is modulated and reprogrammed to facilitate additional/excessive demands for biomass generation and rapid cellular growth and proliferation. This particular characteristic of cancer cells can be targeted as a “weak point” to kill these cells.

This particular characteristic of cancer cells can be targeted as a “weak point” to kill these cells.

Furthermore, the utility of various techniques in distinguishing between aggressive and benign tumors, tumor grading, and treatment response evaluation and monitoring are also of interest.

Conventional MR imaging of glioblastoma

Figure 1: Conventional MR imaging of glioblastoma. Tumor regions can be identified by different MR contrasts; For example, (A) T1-weighted pre-contrast exhibit a low-intensity lesion in the left frontal lobe region (yellow arrow), (B) post-contrast MR image demonstrates a focus of enhancement in that area, (C) and T2-weighted MR image shows increased-intensity at the same region. These MR techniques enable non-invasive imaging and diagnosis of tumor lesions in the brain. Illustration is adapted from Ahmed R. et al. Cancer Manag Res, 2014 (with permission).

During our study, we uncovered a new imaging biomarker to identify glioma subtypes with different prognosis and therefore this biomarker may be used for a better clinical management, avoiding extra cost for patients and communities. More specifically the biomarker concerns metabolite levels associated with a mutated IDH gene found in more than 70% of the brain tumors classified as low-grade gliomas and secondary gliomas. Glioma patients with this mutation actually have a better prognosis.

In particular, with our MRS technique we observe the indirect effect of the mutation in the IDH1 gene on the level of some phospholipid metabolites, which can be considered a molecular “finger print” for this mutation. These metabolites are major components of phospholipid metabolism in the synthesis of cancer cell membranes.

MR spectroscopy provides information additional to conventional MRI

Figure 2: MR spectroscopy provides information additional to conventional MRI. T2-weighted MR images of a mouse brain with glioma tumor (top, A) and a healthy mouse brain (bottom, B), and corresponding MRS data from area of interest (blue circles, C and D). MRS detects signals for different metabolites in normal brain and tumor tissue. In particular phospholipid metabolites are of interest to characterize brain tumors. (from left to right); PE, phosphoethanolamine; PC, phosphocholine; GPE, glycerophosphoethanolamine; GPC, glycerophosphocholine. Adapted from Esmaeili M. et al. Cancer Res. 2014 (with permission).

To be a bit technical: IDH1 acts in an energy-generating pathway known as the citric-acid cycle, and the IDH1 mutations associated with cancer causes a metabolite called 2-hydroxyglutarate to accumulate. IDH1 catalyzes the conversion of isocitrate into α-ketoglutarate, a reaction that takes place in energy-generating metabolic pathways. Most remarkable is that the mutated IDH1 enzyme has acquired the capacity to produce 2-hydroxyglutarate, which can accumulate in high concentrations in gliomas with the mutation. 2-hydroxyglutarate is commonly called an oncometabolite. Our finding shows that the mutation also alters lipogenesis in brain cancer cells. Phospholipid metabolism is a major network supporting cellular lipogenesis and cell membrane turnover.

The discovery of the IDH1 mutation has generated such intense interest that pharmaceutical companies are keen to find drugs that target mutant IDH1 gliomas

The discovery of the IDH1 mutation has generated such intense interest that pharmaceutical companies are keen to find drugs that target mutant IDH1 gliomas, with some companies focusing exclusively on targeting cancer metabolism. The findings of this study and those published recently on IDH related metabolism could be used in the development of drugs for cancers with these mutations. In addition, these findings enable the detection through non-invasive imaging of the direct metabolic consequence of a genetic mutation in a cancer cell. This offers a potential new tool in the management of brain tumor patients.

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Spectacular images of tumor blood vessels

Jana CebullaBlogger: Jana Cebulla
PhD Candidate at MR Cancer group

 

Angiogenesis is the formation of new blood vessels from pre-existing vessels. This process takes place during wound healing, but is also essential during the development of certain diseases, such as cancer.

In order to grow beyond a size of 1-2mm, tumors send out chemical signals telling nearby blood vessels to send new vessels in the direction of the tumor. This way, the cancer cells can get sufficient supplies of oxygen and nutrients. Angiogenesis has also been found to help cancer spread to other parts of the body (i.e. metastasize).

Blood vessels that are recruited by a tumor

Blood vessels (orange) that are recruited by a tumor (white) which was grown on the leg of a mouse (surrounding “healthy” tissue in blue). Photo: Jana Cebulla

Hopefully, in the future the worldwide research on angiogenesis can help put together all the pieces in the puzzle and describe how angiogenesis in cancer is regulated and how we can influence it with drugs in order to treat cancer patients more effectively.

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Copenhagen next!

We’re off to Copenhagen! You can meet us at the Science in The City festival from tomorrow until Thursday 26. July.

This is what we are doing there: http://scienceinthecity.dk/en/event/6-can-u-hear-u-sound

On Saturday at 17:00 our researcher Garrett Newton Andersen will demonstrate a hand-held ultrasound machine (Vscan) on stage: http://scienceinthecity.dk/en/event/103-scan-your-heart-stage-can-u-hear-u-sound

ScienceintheCity

 

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Applied Human Physiology in Extreme Environments

Blogger: Andreas Møllerløkken Andreas Møllerløkken

 

 

 

The NTNU Barophysiology Group aims to promote safety and minimize the acute and long-term harmful effects of diving and other extreme environmental exposures. Our work covers the topics of both basic and applied research. Through a translational approach, we study animal models to provide novel and comprehensive knowledge of pathophysiological mechanisms. We also use human field and laboratory studies to obtain physiologically relevant data.

This week we arrange a course, “Enjoy the Cold – Health, Protection and Survival in the Cold – Adaptation and risk assessment of human activities in cold environments” in Ny-Ålesund, Svalbard. This course aims at giving people who are working and participating in activities related to cold environments proper training and insights on different equipment that exists which can be used to manage the different challenges one faces in the cold environment. Through a combination of lectures, discussions, practical work and use of equipment, the participants will gain an intimate knowledge on how to handle work situations as well as accidents.

Measuring oxygen consumption during field work

Measuring oxygen consumption during field work

The Arctic areas have become regions of global importance because of their enormous natural resources and their strategic position. These northern areas are cold, harsh and hostile to man. Working in them is difficult, expensive and demands high levels of technical, scientific, and physiological expertise. Cold weather exposure can cause immediate health problems. For people with ailments, cold exposure can lead to new symptoms, or aggravate those existing. Cold exposure may also cause pain and disease in healthy subjects.

A number of climatic factors are known to increase challenges related to work in the northern areas, such as temperature, wind, icing, the polar low, uncertain weather forecasts and polar night. In addition to climatic factors, regulation of body temperature is affected by activity, technical protective actions/systems and clothing. The climatic problems connected with activity in the arctic areas are not only limited to equipment and equipment function. Cold is one of the most dangerous environmental risk factors for man. Not only does the cold challenge day to day function in those prepared for such an environment, but if conditions become more extreme, then it may also challenge survival. Although the human body has a physiological control mechanism, homeostasis, to maintain a stable and optimal internal environment independent of a changing external environment, this mechanism is not protection enough in the sub-arctic areas. Man is totally dependent on personal protective equipment, established working procedures and training to perform the work within specified safety and efficiency limits.

 Man is totally dependent on personal protective equipment, established working procedures and training

Increasing development and human activity in the Arctic environment calls for increased research focus on the appropriate applied human physiology in order to increase our knowledge on how the organism adapts to extreme environments.

It is well recognized that cold environments have negative health effects on the human body, but an important question is are there any increased health risks due to the physiological stress and decreased performance associated with survival requirements, for example having to wear heavy protective clothing constantly?

The course participants gets to experience field testing of immersion suits

The course participants gets to experience field testing of immersion suits

As diving is likely to be an important activity in these regions, the long-term health effects for divers who undertake the majority of their work in cold water should also be considered. More knowledge is needed to understand which processes come into play when the body’s ability to adaptation is exceeded, why one human reacts differently to another when exposed to the same environments and stressors, and how we can prepare ourselves to be protected against adverse health effects of exposures to extreme environments both in the short and long term.

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In 1990 the course “Health, Protection and Survival in the Cold” was arranged at Svea, and this was the first course in a series of courses that have been held throughout the years since then. All in all, some 250 persons have participated the course since its beginning in 1990, to get a better understanding of the different elements one meets in extreme environments and how they influence our own physiology.

With the increasing activity in the arctic regions, research within the human physiology and its response in the cold environment is necessary and give bases for our course.

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