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- Gliomas are the most common type of brain cancer. Despite being rare compared to other cancers, they nevertheless cause significant morbidity and mortality.
- In research spanning more than a decade, a team at NIMHANS looked for evidence that the body actually mounts an inflammatory response in patients with gliomas.
- One important finding was that patients who had the most aggressive form of brain cancer also had the most severe derangements in their blood parameters.
- The team also analysed data from hundreds of patients and found for the first time that the unique molecular signature of glioblastoma correlated with the inflammatory response.
Inflammation (from Latin ‘inflammare’, to set on fire) is the first reaction of living tissues to all forms of insult and injury. It is characterised by calor (heat), dolor (pain), rubor (redness) and tumor (swelling).
These effects are the result of complex interactions between the injured tissue, the circulatory system and the immune system, which ultimately cause an increase in blood flow to the site of injury. Increased blood flow brings with it vital chemicals and cells that help in the defense against pathogens, in healing, and in repair.
A healthy inflammatory response is crucial for wound healing and fighting infections. Without this vital housekeeping function, even a minor injury or infection could develop into a full-blown life threatening crisis.
However, inflammation is a double edged sword. Inflammation out of proportion to the insult underlies a vast array of illnesses, both acute and chronic. Conditions such as lupus, rheumatoid arthritis, Crohn’s disease, multiple sclerosis, etc. are all debilitating illnesses that occur due to an inflammatory reaction that is out of control.
Inflammation can also trigger new diseases and complicate existing ones. For instance, persistent inflammation is associated with the development of cancers of the colon, pancreas and breasts. In addition to causing cancers, inflammation can also drive cancer growth through processes not very different from the ones involved in healing.
Not surprisingly, the presence of an inflammatory response in patients with these cancers connotes a shorter survival.
Behind enemy lines
The blood-brain barrier is a highly complex, microscopic barrier that exists between blood vessels and the cells of the brain. Like a country’s border security, it regulates the movement of chemicals and cells into and out of the brain.
Owing to the presence of this barrier, brain cancers behave quite differently from cancers that occur elsewhere in the body. For one, they almost never spread outside the central nervous system, since the cancer cells can’t access the blood vessels.
But if cancer cells can’t get out of the brain, inflammatory cells shouldn’t be able to get in. Does that mean that inflammation is not really an issue with brain cancers?
This was indeed thought to be the case for several decades.
Dr Venkatesh Madhugiri, a professor of neurosurgery at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, was among the first people in the world to question the conventional wisdom that brain cancers are not associated with an inflammatory response.
“There is now enough data that shows that the body mounts a significant inflammatory response to brain cancers,” Dr Madhugiri said. “And as is the case with cancers elsewhere in the body, the inflammatory response is also associated with worse outcomes.”
His work focuses on brain cancers, and he has published extensively on the role of inflammation and how it affects patient survival.
The many faces of glioma
Gliomas are the most common type of brain cancer. Despite being rare compared to other cancers, they nevertheless cause significant morbidity and mortality. Inflammation associated with gliomas makes the disease process a whole lot worse.
“This inflammation is not just local, i.e. confined to the brain, but a global response; it’s like the entire body is on fire,” said Dr Akshat Dutt, of the department of general surgery at the All India Institute of Medical Science (AIIMS), Jodhpur.
In research that has spanned more than a decade, Dr Madhugiri and his team began by looking for any evidence that the body actually mounts an inflammatory response in patients with gliomas. They first examined the blood cell counts of these patients and compared them with the values from a large group of healthy, young volunteers. Sure enough, they found significant differences between the healthy control group and the glioma group.
Glioma patients had the kind of blood picture that was expected in a chronic inflammatory condition: consistently lower haemoglobin levels and a higher percentage of neutrophils (a kind of white blood cell).
One important finding that their study generated was that patients who had the most aggressive form of brain cancer, called glioblastoma multiforme, also had the most severe derangements in their blood parameters. This meant not all brain cancers are equal from the point of view of inflammation.
“Glioblastoma is vastly heterogeneous, with its myriad genetic aberrations and behaviours and it has been extensively studied. What wasn’t well established was how this variability related to the inflammatory profile of this cancer and how that ultimately influenced patient survival,” Dr Subeikshanan Venkatesan, a member of Dr Madhugiri’s research team, said.
To answer these questions, the team analysed data from hundreds of patients with glioblastomas. The results were nothing short of dramatic. The team was able to demonstrate for the first time ever that each unique molecular signature of glioblastoma correlated with the inflammatory response to the tumours.
A new hope
Glioblastoma is usually a death sentence: patients who receive this diagnosis usually survive just 15 months after their diagnosis, despite aggressive treatment. But in their large cohort of glioblastoma patients, Dr Madhugiri and his team unexpectedly identified a small group of patients who survived longer than three years.
Their curiosity piqued, the team began to analyse how these long-term survivors differed from those that didn’t make the cut. “Of course, certain factors that are associated with longer survival, such as a younger age and a specific molecular signature, were already known. Our research confirmed the significance of these factors,” Dr Madhugiri said.
“But these factors cannot be modified. The crucial new finding was that the long term survivors seem to have a much more muted inflammatory response.”
A triple whammy of unfavourable clinical factors, molecular profile and inflammation status leads to a more aggressive disease course and hence worse survival.
Does that mean if we improve one of these factors, we can alter the outcome? “That is a very exciting prospect, since inflammation is something we can modify,” according to Dr Madhugiri.
There are innumerable drugs to suppress inflammation today, ranging from steroids to non-steroidal anti-inflammatory drugs, even the newer immune modulators.
Many of these drugs are ubiquitous in clinical practice and are used to treat a wide variety of conditions, from simple allergies and sprained ankles to lupus and rheumatoid arthritis. Does this mean they can immediately be repurposed to treat glioblastoma?
Unfortunately, initial clinical trials with steroids and some anti-inflammatory drugs have not yielded promising results. “But this is certainly not the end of the line,” Dr Madhugiri said. “There are several receptor-specific anti-inflammatory agents available today. Another very promising treatment option is the use of immunotherapy, which has demonstrated benefits in other types of cancers. Clinical trials of these agents in glioblastoma are only beginning.”
The hope is that one day in the near future, these clues may offer a way to stop the ravages of this deadly disease.
Dr Vikram Singh is a consultant neurosurgeon, Orchid Medical Centre, Ranchi.