A 65 year-old-female was admitted to Arcispedale Santa Maria Nuova, Reggio, Italy on December 5th, 2008 who presented with progressive memory loss, chronic headaches, and nausea. The symptoms were present, off-and-on, for about one month prior to diagnosis. Neurological examination showed mild left superior harm and facial paresis. The patient's family history included breast adenocarcinoma (mother), and ovarian carcinoma (sister). Past clinical history included post-pubertal headache, hysterectomy at the age of 37 years, chronic erosive gastritis and familial hypercholesterolemia controlled with lipid-lowering medication. The patient's blood pressure was 120/70, and within normal limits. Laboratory tests revealed an unremarkable complete blood count. Liver and renal functions were within normal limits. Blood biochemistry was essentially normal. Prior to therapeutic intervention, the patient's weight and height, were 64 kilograms (kg) (141 pounds) and 158 centimetres (62 inches), respectively. This height and weight related to an approximate body mass index (BMI) of 25.6 kg/m2.
On the day of admission, the patient underwent contrast-enhanced (contrast media: gadoteric acid, 0.2 ml/kg) magnetic resonance imaging (MRI), which disclosed a large multi-centric solid necrotic tumor in the right hemisphere (Figure ). The tumor showed extensive infiltration of the right temporal pole, the insular lobe, the frontal operculum, the putamen, and head of the caudate nucleus. Avid contrast enhancement characterized the tumor, which was surrounded by extensive edema. A shift to the left of the midline structures was noted. The tumor also compressed the right frontal horn. An electroencephalogram demonstrated abnormality with a generalized slowing background and frequent delta bursts on the right frontotemporal region. Anti-inflammatory steroidal therapy (dexamethasone, 16 mg/day i.v.) and anti-epileptic therapy (Topiramate, 50 mg/2×/day and Clobazam, 50 mg/day) were commenced. On December 15th, the patient underwent right frontal temporal craniotomy involving partial excision of the temporal pole with incomplete debulking.
Figure 1 MRI contrast enhanced images of a large multi-centric mass involving the right hemisphere pole. (A) Temporal pole, (B) frontal operculum, insular lobe, posterior putamen, (C) frontal operculum, head of caudate nucleus. Note the presence of peripheral (more ...)
The histopathological examination disclosed the patterns of GBM. Haematoxylin and eosin (H&E) analysis showed high cellularity, prominent vascularity, as well as areas of necrosis and hemorrhage. The tumor cells appeared poorly differentiated, hyperchromatic, pleomorphic, and displayed neoplastic pseudopalisades surrounding necrotic foci (Figure ). Extensive subpial infiltration was also noted. The histological characteristics were typical for GBM (WHO grade IV) [24
]. Methylation of the O6
-methylguanine-DNA methyltransferase (MGMT) promoter was also detectable according to standard procedures [26
]. The patient underwent computed tomography (CT) of the head during the immediate postoperative period, which showed an increasing edema-related shift to the left of the midline structures. During the immediate post-operative recovery period, the patient started a self-imposed water only fast (from December 16-17). The patient's average daily calorie intake, prior to fasting, was about 1700-1800 kcal/day. Blood glucose was 130 mg/dl while urine ketone levels were undetectable. After several days of modest food consumption, the patient again started a water-only fast on December 22. Blood glucose and urine ketones were monitored using a standard glucose kit and Keto-Stick kit (Ketur-Test®
). After three days of fasting (ketosis induction period), ketones were raised to the high level of +++, while blood glucose was reduced to 60 mg/dl. At this time (December 24), the patient's body weight and body mass index was 58.0 kg (127.6 lbs) and 23.23 kg/m2
, respectively. After the fast, a KD was administered in restricted amounts for 14 days (December 24 to January 7, 2009). This calorie restricted ketogenic diet (R-KD) delivered about 600 kcal/day in total and included 20 g of the KetoCal®
4:1 (fat/protein + carbohydrate) diet (SHS, International), 10 g medium chain triglyceride oil (MCT), 32 g protein, and 10 g carbohydrates. The diet contained a small amount of dietary fiber, and a total fat content of 42 g. The R-KD was supplemented with multivitamins including the B complex and minerals to maintain nutrient adequacy and to avoid metabolic abnormalities as previously described [27
Figure 2 Histopathological analysis of excised brain tumor tissue (H&E). A) Multiple zones of necrosis circumscribed by viable tissue (4 ×). B) Dense zone of small-cells with hyperchromatic nuclei and scant cytoplasm (10 ×). C) Zone of (more ...)
After 14 days of the R-KD, the concomitant radiation plus chemotherapy (temozolomide) regimen was initiated on January 8, 2009, according to standard procedures [2
]. All steroidal medication was terminated at this time. The patient's body weight was 55 kg (121 lbs) at the start of the standard treatment, which extended to February 17, 2009. On January 27, the patient developed a mild hyperuricemia of 6.2 mg/dl (normal values: 2.4-5.7 mg/dl). The plasma uric acid levels gradually increased reaching a maximum value of 10.9 mg/dl by February 7. Transient hyperuricemia can occur following implementation of ketogenic diets [28
]. Allopurinol (100/mg/day) treatment was commenced to control the uric acid levels, which gradually returned within normal ranges. Due to the hyperuricemia the patient was gradually shifted to a calorie restricted non-ketogenic diet, which also delivered a total of about 600 kcal/day. This diet maintained low blood glucose levels and slightly elevated (++) urine ketone levels due to the low calorie content of the diet. The changes in circulating glucose and ketone levels during this period are shown in Figure . More comprehensive blood analysis was not conducted. It is important to mention that the patient did not experience hypoglycemia (blood glucose levels below 45 mg/dl) at any time during the course of fasting or ketogenic diet therapy.
Figure 3 Levels of circulating glucose (black line) and urinary ketones (red line) in the patient during the period from January 8 to February 7, 2009. The values are within normal physiological ranges for people who maintain low calorie dieting .
During the concomitant chemotherapy, laboratory tests revealed abnormalities in complete blood count to include leukocytes 2.86 ×1000/mm3, erythrocytes 3.56 million/mm3, hemoglobin 10.5 g/dl, and hematocrit 32%. The patient also developed lymphopenia 0.332 ×1000/mm3. The concomitant treatment was terminated on February 17th. One week later (February 24, 2009), the patient underwent an MRI. No evidence of either the tumor or the associated edema was apparent (Figure ). Porencephaly was seen in the right frontal region at the tumor site. Ex vacuum enlargement of the right frontal horn and lack of mass effect represented indirect confirmation of tumor regression. Restitutio ad Integrum of the insular lobe, caudate nucleus, and putamen were noted with only minimal damage to the blood brain barrier (Figure ). On March 3, the patient developed mild hypoproteinemia (5.1 g/dl). This was corrected by increasing dietary protein to about 7 g/day for one month, which returned protein levels to the normal range (6.4 gr/dl). On April 21, the patient underwent positron emission tomography with fluoro-deoxy-glucose (FDG-PET), which included delayed acquisition. No evidence of recurrent disease was detected (Figure ). An MRI, performed on July 22, was stable over the comparison time from February 24 with no clear evidence of disease recurrence. At that time, the patient weighed 50 kg (110 pounds, BMI 20.0 kg/m2), was in good general health, and had no neurological complications. The patient's Karnofsky performance status was at 100% during the course of the diet. Caloric intake was not strictly followed after July 22. An MRI performed on October 9, 2008 showed tumor recurrence. The patient was then treated with CPT11 (Irinotecan) and bevacizumab (Avastin) therapy. A schematic diagram showing the clinical time course of dietary treatments with dates of MRI and PET is presented in Figure .
Brain MRI taken a few days after ending the standard radiotherapy plus concomitant temozolomide therapy together with KD-CR protocol. No clear evidence of tumor tissue or associated edema was seen. Arrow indicates porencephaly.
Positron emission tomography with fluoro-deoxy-glucose (FDG-PET) imaging showing no evidence of recurrent tumor.
Timeline of clinical course with dates of dietary treatments, MRI, and PET