The method, first of its kind worldwide, was developed thanks to the use of adaptive genetic algorithms (AGA) and will allow an early alert through a urine test, capable of warning of possible bladder cancer.

In the research process, the design of this system was the contribution given by the UCR scientists and is the cornerstone of innovation. Its function is clear: reduce the complexity of the data to build a scale of malignancy and thus differentiate tumor cells from normal ones.

But the AGA will not act alone. To increase the accuracy of the results, the algorithms are based on the data obtained through flow cytometry technology. This technique uses a laser light responsible for counting and classifying each cell (individually), in order to discover whether or not they are carcinogenic.

“In recent years, attempts have been made to develop urinary markers to detect bladder cancer. However, none of them was able to reach an acceptable level to become a standard diagnostic procedure. For that reason, from the United States they contacted us to help develop a method that would allow us to consolidate an easy, fast, cheap and high-performance test and, most importantly, without being invasive”, said Dr. Rodrigo Mora Rodríguez, the only Costa Rican microbiologist in the team and collaborator of the Laboratory of Teaching in Surgery and Cancer (DCLab-UCR).

The pair of UCR scientists who developed the innovative method

The test reached 98% sensitivity, in the detection of the disease and 87% specificity: the ability to exclude healthy individuals. The above marks a revolutionary breakthrough in favor of international health. Currently, to know if a person has bladder cancer, an invasive test known as cystoscopy should be performed.

This process consists of introducing a thin instrument, similar to a tube, through the urethra, which has a light and a lens. The main disadvantage of this procedure is that, during the examination, there is a risk that the apparatus introduces bacteria and causes an infection.

This test is currently applied when there are suspicions and on numerous occasions, healthy patients are subjected to an unnecessary invasive procedure, now more unnecessary because the diagnosis will be made by a urine test, subjected to this innovative method.

What was achieved with the creation of this method, explained Dr. Mora, is “that the urine test is more oriented to screening for early detection and to avoid unnecessary cystoscopy; that is, it will only be done when it is really required. For example, if a patient has small amounts of blood in the urine (microhematuria), the urine test we design can be done. If the result is negative, it would prevent the person from undergoing a cystoscopy. On the contrary, if the result is positive, the patient can have a cystoscopy to know the severity of cancer”, he explained.

Healthy bladder

Based on data from the Globocan 2018 report of the World Health Organization (WHO), about 549,393 people have bladder cancer and 199,922 will die worldwide due to this cause. In Costa Rica 210 new cases are counted every year; of them, almost half of the Costa Ricans diagnosed die. Those who survive have a 50% to 80% chance of having the disease again.

Dr. Diana Zamora Bolaños, a specialist in medical oncology at Calderón Guardia Hospital, explained that the most frequent symptom of bladder cancer is hematuria (bloody urine). Sometimes, the patient can see the blood in the urine and, other times, it can only be detected by a test. Special attention must be paid, as the signs and symptoms of cancer can be confused with a bladder infection.

How did it all start?

The method, which still needs to pass some validation stages for its clinical application, was initiated by a group of five American scientists who decided to give a chance to a protein called PD-1 / PD-L1. This element is used by cancer cells to evade the body’s immune response and thus proliferate.

The specialists knew that, if the total content of PD-L1 in the urine is higher than usual, it is because it could be in the presence of a malignant tumor. Also, they knew that the urine could remove cells detached from the bladder known as epithelial and look for aneuploidies in them – alterations capable of causing cancer. As was the case with PD-L1, the greater the number of aneuploidies, the more likely it is to have the disease.

Only one thing was missing: algorithms efficient and robust enough to find combinations, as well as classify and quantify cancer cells with high certainty in the results. It is at that time when Costa Rican researchers appear. Dr. Mora, together with Dr. José Guevara Coto, a bioinformaticist at the DCLab-UCR, who created the AGA and the scale of malignancy necessary to identify the samples of cancer patients.

“We decided to turn to the UCR because we have had a long and fruitful scientific relationship with this university. We were excited to use the tremendous experience of Dr. Mora and Guevara, for their ability to translate science into clinical information through bioinformatics”, said Bruce Patterson, one of the international researchers.

Bioinformatics is a multidisciplinary area that unites computer science, statistics, and biological sciences. By merging these branches it was possible that the researchers, for the first time since the final collection of the data, managed to develop the scale of malignancy.

“The algorithms were used to make a selection of the most relevant characteristics from flow cytometry. That selection reduces background noise, by choosing those that contribute to the prediction of the state (healthy or sick), and eliminating from a subset, those that do not provide information to the prediction”, added Guevara.

In the urine, there are also immune system cells called leukocytes. When the body has a disease or infection, these cells increase their levels. That increase is vital because it provides additional information on the content of PD-L1 in these cells, which could influence the immune system’s response to the tumor.

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The urine test can not only quantify the expression of PD-L1 protein but also obtain additional information about treatment options and see if a patient is a candidate for immunotherapy – a therapeutic option that activates the immune system to help the body fight the illness-.

“If the cells coming from the urine have PD-L1, then you can think that you are an immunotherapy candidate. Why is it important? Because not all patients are suitable for immunotherapies and they are also very expensive. This test would be a valuable contribution to precision medicine and would identify those patients in whom the therapeutic approach will really be effective”, Mora explained.

Now, for the test to finally be implemented at the clinical level, it requires complementary validation studies and Costa Rica is planned to lead that process. According to the expert, there is still no set date for its beginning, as funding and collaboration with urologists are required.

If everything is satisfactory, Costa Rica is able to apply this test in the country. The Faculty of Microbiology of the UCR has the necessary equipment to carry it out and make it available to the Costa Rican population, concluded doctors Mora and Guevara.

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