In imaging exams that track the body’s energy consumption, the brain is usually the main protagonist, glowing intensely on the screen. However, researchers from CEPID CancerThera noticed an intriguing phenomenon: in patients with severe cases of multiple myeloma – a type of bone marrow cancer – the brain’s brightness appears reduced in these images. Based on this observation, they developed a simple, low-cost mathematical method capable of predicting the aggressiveness of the disease and the chances of patient survival.
The study, recently published in the journal European Journal of Nuclear Medicine and Molecular Imaging, uses images from the PET/CT exam, produced by combining a Positron Emission Tomography (PET) scanner and a Computed Tomography (CT) scanner. To generate the analyzed images, the radiopharmaceutical 18F-FDG (Fluorodeoxyglucose), a type of “radioactive glucose,” was used to map where energy consumption is higher – thus revealing the metabolic activity of tumors.
“This study arose quite organically, from the observation that, in some exams, the brains of certain patients with multiple myeloma showed much lower radiotracer uptake than others,” says Dr. Maria Emilia Seren Takahashi, a medical physicist at the Gleb Wataghin Institute of Physics at the University of Campinas (IFGW/Unicamp) and an associated researcher at CancerThera. The study was published under the title “Diagnostic brain-to-liver [18F]FDG uptake ratio predicts survival in multiple myeloma: A retrospective study.”
Dr. Celso Dario Ramos, a nuclear medicine physician, professor at the School of Medical Sciences at Unicamp and principal investigator at CancerThera, led the clinical aspects of the research and explains the dynamics of the reduced uptake. Upon noticing that, in patients with more severe multiple myeloma, the uptake of the 18F-FDG radiotracer was lower in the brain – meaning less glucose was reaching the brain than expected – two hypotheses were raised: “the first would be direct competition between the brain and the tumor for the energy provided by glucose; and the other would be that the tumor produces some substance that inhibits glucose uptake by the brain,” he says, adding that these mechanisms will be further investigated.
The Brain-to-Liver Ratio (BLR)
To turn this visual observation into a practical medical tool, the team proposed an index called the Brain-to-Liver Ratio (BLR). The logic consists of dividing the brain’s brightness (glucose uptake) by the liver’s brightness.
But why the liver? Maria Emilia Takahashi explains: “The comparison between brain and liver was chosen to obtain a metric that would allow an evaluation within the same patient.” Since liver glucose uptake tends to be very stable across individuals, the organ serves as a reliable reference for comparison.
The study results, which retrospectively analyzed exams from 72 patients, showed that individuals with a BLR above 2.7 had an overall survival rate of 52% at five years. In contrast, those with a value below 2.7 had only 10% survival over the same period. The index was also inversely proportional to known tumor burden markers in oncology.
“It is important to highlight that we were not the first to use the relationship between brain and liver uptake. This idea had already been described in the literature,” Takahashi notes. The main novelty of the CancerThera study was how this relationship was quantified and demonstrated to be associated with survival in multiple myeloma patients.
For medical practice, anticipating cancer severity at diagnosis is crucial. “The more data we have about tumor aggressiveness, the more accurate this assessment becomes. Especially when considering a change in treatment, it is necessary to be confident in decision-making,” emphasizes Celso Dario Ramos.
The figures above show how researchers measure and use the Brain-to-Liver Ratio (BLR) in PET/CT exams:
In Figure 1, they highlight two regions:
- Brain (blue regions) → to measure how much glucose it is consuming
- Liver (blue sphere) → used as a stable reference
The idea is to compare the two values to generate a number (BLR).
In Figure 2, we see the clinical impact of this number:
- Low BLR (1.1) → brain takes up little glucose → worse outcome (short survival)
- High BLR (4.9) → brain takes up more glucose → much better outcome (long survival)
In summary: the lower the brain activity relative to the liver, the more aggressive the disease tends to be and the worse the prognosis.
Cutting-edge science applicable to the SUS
One of the main advantages of the BLR metric is its accessibility. The index does not require new equipment or additional exams.
“The calculation of BLR does not require complex data processing or sophisticated mathematical formulas, which makes its application feasible in any Nuclear Medicine service that already performs PET/CT exams,” explains Takahashi. She argues that, because it is simple and uses software already available on hospital workstations, the approach could be easily adopted in Brazil’s Unified Health System (SUS) without major investments.
“Since the measurement of this index is not directly related to the tumor itself, but rather to systemic metabolic changes and inflammatory processes, there is no technical limitation preventing its investigation in other types of cancer, or even in other diseases,” says the medical physicist. CancerThera researchers are already investigating whether this same behavior occurs in tumors other than multiple myeloma to confirm whether this measure also has prognostic value in different clinical situations.
For Ramos, the discovery proposes a paradigm shift in how physicians interpret oncological exams. “The main message of this study is that the body reacts as a whole to cancer, including the brain,” he reflects. “When analyzing a PET/CT exam, physicians should also evaluate brain radiotracer uptake, not only that of the tumor,” he states.
LEARN MORE | The “energy theft” and the brain’s alternative diet
Have you heard of the Warburg Effect? Discovered in the 1920s by physician Otto Heinrich Warburg, this effect describes how cancer cells are extremely “greedy.” Unlike healthy cells, tumors consume massive amounts of glucose inefficiently to multiply rapidly, producing a substance called lactic acid (or lactate) as metabolic waste.
In patients with aggressive multiple myeloma, where the brain appears less bright on PET/CT images (which track glucose), CancerThera researchers believe the Warburg Effect may be one of the explanations. The tumor in the bone marrow consumes so much energy that it ends up competing with the brain for circulating glucose.
However, the brain adapts: it is capable of changing its “diet.” The lactate produced in excess by the tumor travels through the bloodstream, crosses the brain barrier, and begins to be used by neurons as an alternative fuel. In other words, the brain appears less bright on PET/CT not necessarily because it is shutting down, but because, faced with the “theft” of its preferred glucose by the tumor, it starts using the lactate produced by the tumor itself.
Study authors
- Maria Emilia Seren Takahashi, Marcos Paulo D. S. Silva e Felipe Cardoso de Souza
Instituto de Física Gleb Wataghin, Universidade Estadual de Campinas (Unicamp) - Tiago Pessolo dos Santos
Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp) - Christopher Cralcev, Eliana Cristina Miranda e Carmino Antonio de Souza
Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas (Unicamp) - José Barreto C. Carvalheira
Departamento de Radiologia e Oncologia, Universidade Estadual de Campinas(Unicamp) - Celso Dario Ramos
Serviço de Medicina Nuclear, Hospital de Clínicas, e Departamento de Radiologia e Oncologia, Universidade Estadual de Campinas (Unicamp)
Text: Romulo Santana Osthues | Images: Reproduction of exams provided by the researchers
