PMC8200410_01
MRI images of the patient's brain tumour. Panel 1. Fluid Attenuated Inversion Recovery (FLAIR) images show the IDH1-mutant GBM at diagnosis in August 2014 (A-D) and ~8 months later, at the last follow-up MRI examination (December 2016) prior to surgical excision of the enhancing nodule (E-H). The lesion discovered on August 2018 is centered in the right inferior frontal lobe (A,B, arrowheads), and abuts the premotor cortex (C, arrowhead). There is an enhancing nodule within the lesion, as seen in the magnified post-contrast image (D) (arrow). This enhancing lesion measured 1.25 mL, which is calculated using the V = ABC/2 formula. Follow-up MRI (E-H) demonstrates interval progression of the non-enhancing tumor (arrowheads). Interval increase in size of the enhancing lesion, measuring 5.97 mL, was also observed (H, arrow). Panel 2 shows the evolution of the lesion between the May 2017 surgical excision (A-C), and in the most recent MRI evaluation, dated March 2020 (D-F). T2-weighted images indicate the residual GBM (arrowheads). (B) shows the T2-hyperintense GBM filling the surgical cavity. The lesion in the premotor cortex is clearly seen in (C). Please note that the surgical debulking involved only the enhancing tumor, while the largest non-enhancing part of the GBM was not excised by the neurosurgeon. The most recent brain MRI (D-F) shows interval increase in size of the GBM (arrowheads), which remains circumscribed to the right frontal region without infiltrating the white matter tracts.
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F1
The lesion, which was mainly non-enhancing and solid, disclosed the presence of an eccentric contrast enhancing nodule (Figure 1, Panel 1, D). Signal change also extended into the precentral gyrus (Figure 1, Panel 1, C). MRIs preformed on April 14, 2015; July 17, 2015; November 16, 2015; February 20, 2016; July 9, 2016; and October 29, 2016 revealed evidence of interval slow contrast-enhanced tumor progression over that seen on the original 2014 MRI. MRI evidence of contrast-enhancing disease progression was more concerning on the follow-up MRI from December 15, 2016 (Figure 1, Panel 1, H). However, the largest T2 hyperintense part of the GBM remained untouched (Figure 1, Panel 2, A-C).
Histopathological analysis of excised brain tumor tissue. (A) Diffusely-infiltrating astrocytic tumor (star) with focal microvascular proliferation (arrows). Tissue taken from 2014 biopsy, H&E stain 200x. (B) Immunohistochemistry using MIB-1 antibody showing a proliferation index of ~4-6%. Tissue taken from 2014 biopsy, Immunostain 200x. (C) Section showing necrosis and palisading of astrocytic tumor cells around the necrotic area (arrows). Tissue taken from 2017 biopsy, H&E stain 200x. (D) Section showing glomeruloid vascular proliferation (arrows). Tissue taken from 2017 biopsy, H&E stain 400x.
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There was focal micro-calcification and focal microvascular proliferation (Figure 2A), but no necrosis was about present. The MIB-1 (Ki67) proliferation index was 4-6% (Figure 2B). However, the largest T2 hyperintense part of the GBM remained untouched (Figure 1, Panel 2, A-C). Histological analysis of the tumor tissue showed a diffusely invasive astrocytic tumor with infrequent/rare mitosis, prominent microvascular proliferation (Figure 2C) and areas of necrosis (Figure 2D).
The patient's blood glucose, ketone, and GKI values from 2014 to 2019. (A) Blood glucose, and ketone (beta-OHB) values determined using Precision Xtra blood glucose & ketone meter as described in text. (B) GKI values were determined from the individual glucose and ketone values in A using the glucose ketone index calculator, as previously described. Individual values were pooled over 3-month time intervals and are expressed as means +- 95% confidence intervals (CI). The number of readings for each data point in A and B ranged from a high of n = 151 (July-September, 2017), to a low of n = 7 (April-June 2018), and are given in the Supplementary Tables 1A-F arranged by year from 2014 to 2019.
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The patient's blood glucose and beta-OHB values are shown in Figure 3A over an almost 5-year period, and his computed GKI values over this period are shown in Figure 3B.
Timeline of clinical course with dates of dietary treatments and MRI.
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Facebook page that provides updates on his health status (http://www.childhoodcancer2018.org.uk/speakers/pablo-kelly.asp). Figure 4 presents a schematic diagram showing the clinical time course of MRI analysis and dietary treatment.