Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route (control arm). The total dose can either administered once a day or through a refracted schedule

Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route.The total dose can either administered once a day or through a refracted schedule.
The same patients subjected at a metformin. Metformin initial dosage will be 850 mg per day, and will be escalated based on patient tolerability up to a maximum of 2550 mg daily (experimental arm).

Brain Metastases

Melanoma

Lung Cancer

Breast Cancer

A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.

Dexamethasone

A minimum daily dosage of Dexamethasone 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day and 2550 mg daily (maximum dose), oral administration (OS) of Metformin; starting dose will be 850 mg/day, to be progressively increased to 1700 mg/day on day 4 and 2550 mg/day on day 7, if well tolerated.

Metformin

Fondazione IRCCS Istituto Nazionale dei Tumori

Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases

Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study

To evaluate the efficacy of metformin in preventing precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast cancer.

To study the efficacy of metformin in preventing dexamethasone-induced diabetes at 7 and 30 days after dexamethasone initiation, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast

To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone

To evaluate the efficacy of metformin in modifying the local disease control rate (brain) in patients treated with radiation therapy (RT) plus dexamethasone at 1 month

To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.

Patient QoL will be evaluated through the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C-30 version 3.0. The EORTC QLQ.C30 instrument will be scored according to the EORTC guidelines.

To investigate the potential impact of metformin on absolute counts of immune cell populations

To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes

To investigate the potential impact of metformin on activated antitumor lymphocytes

To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation

To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation

To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)

To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)

To evaluate the impact of metformin on gut microbiota populations (30 days)

To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation

Filippo de Braud

Professor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

University of Milan

Eligible patients will be randomized in a 1:1 ratio. Randomization will be stratified by means of minimization technique according to the following factors: primary tumor (melanoma versus lung versus breast cancer), dexamethasone dosage (8-12 mg vs >12 mg daily), baseline (pre-enrollment) fasting glycemia (< 100 versus 100-125 mg/dl). Patients randomized to the experimental arm will discontinue metformin after 30 days, unless diabetes has developed in the meanwhile and the physician believes that metformin is still required for its management. Patients randomized to the control arm who develop steroid-induced diabetes will be prescribed metformin, unless contraindicated, as the preferred therapy option for the management of hyperglycemia. In both treatment arms, dexamethasone will be administered until necessary and at the required dosage in the judgment of the treating physician.

the intervention will consist of 3 phases: a one week run-in period, 24 weeks strict KD and 24 weeks Modified Atkins Diet.
Every day, 40 g of KetoCal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals and to ensure ketosis during the night (some patients drink some sips of the shake during the night). During this run-in period, patients will become familiar with their diet and, in particular, they will learn which foods are allowed and which are not.

During the run-in period, the dietician will discuss the diet and maintenance of an isocaloric diet with the patients. As such, the diet of the control group will not change from their normal dietary pattern, unless a patient is following an Atkins-like diet. In the latter case, the patient will be asked to change the diet to a normal Belgian diet.

Lymphedema

Ketogenic Dieting

Ketocal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals will be used. After 24 weeks a Modified Atkins diet will be started.

Ketogenic diet

Isocaloric diet

UZ Leuven

Ketogenic Diet: a Novel Metabolic Strategy to Treat Lymphedema Patients?

measured with QOL questionnaire, a scale from 0-10 on 16 items, how higher the score, how higher the QOL

measured with Lymph ICF (international classification of functioning, disability and Health), a scale from 0-10 on 29 items, total score ranged from 0-100, 0-4: indicate no problem; 5-24 a small problem; 26-49: moderate problem; 50-95: severe problem; 96-100: very severe problem

Universitaire Ziekenhuizen Leuven

After baseline assessment, patients will be randomized in one of the treatment groups.
Randomization is performed according to 'www.randomization.com'. This free generator randomizes each subject to a single treatment by using the method of randomly permuted blocks.
Assessments are performed by a person blinded to the treatment allocation groups.
Randomization will be stratified for baseline lymphedema volume (3-9.9%, 10.0-19.9% and ≥20%), affected limb (arm or leg) and gender (females or males). The staff members who perform the measurements are blinded for the allocation.

The staff members who perform the measurements are blinded for the allocation.

The intervention consists in 5-day FMD (Fasting Mimicking Diet) to be followed for one cycle (Cohorts A and B) or for 4 consecutive every-four week cycles postoperatively.

Melanoma, Malignant

The Fasting Mimicking Diet (or FMD) consists in a 5-day plant-based, low-calorie (about 600 Kcal on day 1, followed by about 300 KCal/day on days 2 to 5), low-carbohydrate low-protein diet

Impact of Dietary Intervention on Tumor Immunity: the DigesT Trial

Impact of Dietary Intervention on Tumor Immunity: the DigesT Trial.

Absolute and relative changes in PBMCs by 10-color cytofluorimetry before and after the FMD.

Phenotypic modifications in PBMCs, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Functional modifications in PBMCs, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Functional modifications in tumor-infiltrating lymphocytes, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Phenotypic modifications in tumor-infiltrating lymphocytes, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Functional modifications of immune cell populations in LNs, as detected by single-cell "mass cytometry" (CyTOF).

Gene expression profiling (through mRNA quantification) in tumor cells (Cohort A).

Gene expression profiling (through mRNA quantification) in PBMCs and immune cell populations inside lymph nodes (Cohort B).

miRNA profiling in tumor cells (Cohort A)

miRNA profiling in PBMCs and immune cell populations inside lymph nodes (Cohort B).

Changes in the expression of selected metabolic genes (including hexokinase 1, phosphofructokinase 1, pyruvate kinase 2) through mRNA quantification in PBMCs before and after the FMD.

FMD-induced changes in blood (glucose, triglycerides, fatty acids, cholesterol, amino acids)

FMD-induced changes in urine metabolites (ketone bodies)

FMD-induced changes in serum growth factors.

Qualitative changes in the type of tumor-infiltrating immune cell populations before and after the diet in breast cancer patients undergoing curative surgery (Cohort A).

Quantitative changes in the number of tumor-infiltrating lymphocytes, machrophages, MDSCs before and after the diet in breast cancer patients undergoing curative surgery (Cohort A).

Changes in tumor proliferation index (Ki67) IHC in breast cancer patients (Cohort A).

Changes in tumor cell apoptosis (caspase 3 by IHC) in breast cancer patients (Cohort A).

Changes in tumor levels of glycolytic enzymes by IHC (Glut1, HK1, PFK1/2, PK2) in breast cancer patients (Cohort A).

Changes in expression of estrogen and/progesterone receptor and HER2 oncoprotein by IHC in breast cancer patients (Cohort A).

Changes in the type of immune cells (CD8+ T-lymhocytes, CD 4+ lymphocytes, Treg) found in lymph node suspensions of melanoma patients undergoing one FMD cycle before lymph node dissection (Cohort B).

Quantitative changes in the absolute and relative amount of immune cell populations in lymph node suspensions of melanoma patients undergoing one FMD cycle before lymph node dissection (Cohort B).

Changes in genome-wide DNA methylomic profiles with high-density arrays in lymph node specimens from patients undergoing the FMD before surgery (Cohorts A and B).

Changes in genome-wide DNA methylomic profiles with high-density arrays in tumor specimens from patients undergoing the FMD before surgery (Cohorts A and B).

Changes in type of gut bacteria populations, as detected through 16S ribosomal RNA sequencing

Short-term (before vs after each FMD cycle) modification of blood nutritional parameters (levels of plasma cholesterol, prealbumin, transferrin, total lymphocytes)

Long-term (along subsequent FMD cycles) modification of blood nutritional parameters (levels of plasma cholesterol, realbumin, transferrin, total lymphocytes)

Short-term and long-term modification of BMI

FMD-induced changes in neutrophils, macrophages, lymphocytes

Assessment of patient compliance to the FMD, as measured by quantifying the number of major and minor deviations of patients' diet relative to the prescribed FMD scheme

Assessment of FMD tolerability, as defined by the occurrence of G3-G4 adverse events, or serious adverse events (SAEs)

Correlation between FMD-induced changes in serum metabolites and changes in PBMCs, their activation status, and characteristics of tumor cell and immune infiltrate.

Correlation between FMD-induced metabolic and immunological changes with patient diet evaluated at study enrollment through food diaries.

ketone/rintasyöpä

Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases

Ketogenic Diet: a Novel Metabolic Strategy to Treat Lymphedema Patients?

Impact of Dietary Intervention on Tumor Immunity: the DigesT Trial

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