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A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method: A rationale and effectiveness

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Despite all the new developments in cancer therapy, the life expectancy of patients with malignant anaplastic brain tumors and glioblastoma multiform (GBM) remains short. Since the establishment of the Di Bella Method (DBM) in cancer therapy, DBM was able to increase the survival rate and life quality, without overt toxicity, in comparison to what is described in the literature related to the analogous brain tumors, with the same immunohistochemical, histologic and clinical features. Therefore, we treated seven patients with malignant anaplastic brain tumors using the DBM protocol. DBM therapy consists of somatostatin and analogous (octreotide) all trans-retinoic acid (ATRA), β-Carotene, axerophthol dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT), proteoglycans-glycosaminoglycans, valproic acid, acetazolamide, diethyldithiocarbamate, hydroxyurea, and temozolomide. These molecules have either antiproliferative, antiangiogenic, cytostatic, antioxidant, antimetastatic (differentiative), and immunomodulating features. Moreover, the inclusion of ATRA, MLT, and glucosamine with sodium valproate, diethyldithiocarbamate and acetazolamide has reinforced antitumor properties of the therapy by extending them to cancer stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic dosage of hydroxyurea and temozolomide had increased the DBM therapy outcome by strengthening anti-tumor capability. The results of such treatment revealed that all seven patients were still alive after 5 to 8 years of starting DBM. In conclusion, the multi-strategic objectives of DBM are inhibiting the proliferative-invasiveness and neoplastic angiogenesis, silencing the survival system of cancer stem cells, enhancing the immunomodulatory and antioxidant activities, improving vitality and efficiency of normal cells, and depressing the efficiency and vitality of neoplastic ones.
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Neuroendocrinol Lett 2021; 42(7):464–483
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A retrospective observational study on cases
ofanaplastic brain tumors treated with the Di Bella
Method: A rationale and effectiveness
Giuseppe D B1, Vittoria B1, Elena C1
1 Di Bella Foundation, Bologna, Italy
Correspondence to: Dr. Giuseppe Di Bella,
Di Bella Foundation, Via Marconi 51, Post code 40122, Bologna, Italy
: +39 051 239662; +39 051230369, -: posta@giuseppedibella
Submitted: 2021-09-02 Accepted: 2021-12-02 Published online: 2021-12-00
Key words: Glioblastoma; Brain Tumors; Di Bella Method; Retinoic Acid; Somatostatin;
Vitamin D; D2 R agonists; Melatonin; Vitamin E; Prolactin; Growth Factor
Neuroendocrinol Lett 2021; 42(7):464–483 PMID: 35490357 NEL420721A09 © 2021 Neuroendocrinology Letters
Despite all the new developments in cancer therapy, the life expectancy of patients
with malignant anaplastic brain tumors and glioblastoma multiform (GBM)
remains short. Since the establishment of the Di Bella Method (DBM) in cancer
therapy, DBM was able to increase the survival rate and life quality, without
overt toxicity, in comparison to what is described in the literature related to the
analogous brain tumors, with the same immunohistochemical, histologic and
clinical features. Therefore, we treated seven patients with malignant anaplastic
brain tumors using the DBM protocol. DBM therapy consists of somatostatin and
analogous (octreotide) all trans-retinoic acid (ATRA), β-Carotene, axerophthol
dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT), proteoglycans-
glycosaminoglycans, valproic acid, acetazolamide, diethyldithiocarbamate,
hydroxyurea, and temozolomide. These molecules have either antiproliferative,
antiangiogenic, cytostatic, antioxidant, antimetastatic (differentiative), and
immunomodulating features. Moreover, the inclusion of ATRA, MLT, and
glucosamine with sodium valproate, diethyldithiocarbamate and acetazolamide
has reinforced antitumor properties of the therapy by extending them to cancer
stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic dosage
of hydroxyurea and temozolomide had increased the DBM therapy outcome by
strengthening anti-tumor capability. The results of such treatment revealed that
all seven patients were still alive after 5 to 8 years of starting DBM. In conclusion,
the multi-strategic objectives of DBM are inhibiting the proliferative-invasiveness
and neoplastic angiogenesis, silencing the survival system of cancer stem cells,
enhancing the immunomodulatory and antioxidant activities, improving
vitality and efficiency of normal cells, and depressing the efficiency and vitality
ofneoplastic ones.
AAAZ - Acetazolamide
ATRA - All Trans Retinoic Acid
ALDH - Aldehyde Dehydrogenase
Ca 9 - Isoenzyme of CAH
CAH - Carbonic Anhydrase
CCK - Cholecystokinin
C.M. - GH-induced chemotaxis of Monocytes
CSC - Cancer Stem Cells
DBM - Di Bella Method
EGF - Epidermal Growth Factor
EGFR - Epidermal Growth Factor Receptor
FGF - Fibroblastic Growth Factor
Neuroendocrinology Letters Vol. 42 No. 7 2021 • Article available online:
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
GBM - Glioblastoma Multiforme
gCSC - Glioblastoma Cancer Stem Cells
GF - Growth Factor
GH - Growth Hormone
GHR - Growth Hormone Receptor
HDAT - Histone deacetylase
HGF - Hepatocyte Growth Factor
HIF-1α - Hypoxia-Induced Oncogenic Factor
IGF1-2 - Insulin-like Growth Factor 1-2
IGFR - Insulin-like Growth Factor Receptor
IL8 - Interleukin 8
MRI - Magnetic Resonance Imaging
MLT - Melatonin
NGF - Nerve Growth Factor
NHL - Non-Hodgkin’s Lymphoma
NOSe - Endothelial nitric oxide synthase
PDGF - Platelet-Derived Growth Factor
PET - Positron Emission Tomography
PG2 - Prostaglandin 2
PRL - Prolactin
PRLR - Prolactin Receptor
RMN - Magnetic Resonance Imaging
SSN - National Health Service
SST - Somatostatin
SSTR - Somatostatin Receptor
TGF - Transforming Growth Factor
TRK - Tyrosine-kinase
VEGF - Vascular Endothelial Growth Factor
VIP - Vasoactive Intestinal Peptide
VPA - Valproic Acid
Malignant anaplastic brain tumors and glioblastoma
multiform (GBM) remain an unresolved clinical
problem. Furthermore, GBM is the most frequent
and aggressive type of cancer affecting different glial
cells of an adult brain. Although there are advance-
ments in the treatment of cancer, malignant brain
tumors and GBM treatments fall short. For instance,
Stupp’s regimen consists of the main course for treating
anaplastic astrocytoma and GBM patients. The regimen
consists ofsurgery followed by radiotherapy. However,
the overall median survival remains 15-18 months after
diagnosis and has not significantly improved in the
last decade (Delgado-López & Corrales-García 2016;
Lakomy et al. 2020). In addition, total resection (above
98% of tumor volume) increases survival compared
to subtotal or partial resection. On the contrary,
extended” subtotal resection does not confer any
advantage compared with partial resection or biopsy
(Laws et al. 2003). Generally, the one-year survival is
57%, decreasing to 16% at two years, and to 7% at three
years (Filippini et al. 2008). However, GBM patient
who lives more than three years is described as “long
survivor”, and this condition is often limited to subtotal
resection surgery.
Since cancer cells development is a multistep process
involving multiple abnormal signaling and genetic
pathways, treatment should be performed similarly.
Also, cancer stem cells (CSC) should be targeted to halt
the re-progression of cancer. Thus, the Di Bella Method
(DBM) was established (Di Bella et al. 1979a; Di Bella
et al. 1979b). The DBM consists of administrating
several specific molecules where each molecule is
chosen based on its mechanism of action against tumor
cells, CSC, proliferation and apoptosis, oncogenes,
angiogenesis, molecular analysis, and genetic muta-
tion. Besides, some molecules were chosen for their
preservative mechanisms on healthy cells, including cell
membrane integrity, DNA preservation, and mitochon-
drial function (Di Bella 2010).
For several years, we have been using the DBM for
treating several types of cancer including breast, head
and neck, and several others with success (Di Bella etal.
1979a; Di Bella et al. 1979b; Di Bella 1997; Di Bella &
Di Bella 1998; Di Bella 2005; Di Bella & Gualano 2006;
Di Bella 2010; Di Bella et al. 2013a; Di Bella et al.
2013b; Di Bella & Di Bella 2015; Di Bella et al. 2017;
Di Bella et al. 2018; Di Bella 2019). In brain cancer, the
percentage of CSC is associated with chemo and radio-
therapy resistance, and thus rapid re-progression of the
disease occurs. Since DBM protocol targets many steps
of cancer development as well as CSC, we treated seven
patients with malignant anaplastic brain tumors and
GBM. In addition, we mentioned how DBM compo-
nents halt tumor growth and enhance patients’ survival
with a brain tumor.
The DBM therapy for brain tumors consisted of admin-
istrating multiple drugs, vitamins and molecules as
outlined in Table 1. Each of the drugs or vitamins or
supplements used was based on our previous clinical
results on different types of cancer (Di Bella et al. 1979a;
Di Bella et al. 1979b; Di Bella 1997; Di Bella & Di Bella
1998; Di Bella 2005; Di Bella & Gualano 2006; Di Bella
2010; Di Bella et al. 2013a; Di Bella et al. 2013b; Di Bella
& Di Bella 2015; Di Bella et al. 2017; Di Bella et al. 2018;
Di Bella 2019).
Somatostatin and somatostatin analogues
In the DBM method, several molecules were used tohalt
cancer proliferation and growth. These molecules were
chosen based on scientific research. For instance,
cell proliferation, physiological or pathological, and
protein synthesis is closely dependent on the interac-
tion between prolactin (PRL) and growth hormone
(GH). GH is the primary inducer of growth (De Souza
et al. 1974; Lincoln et al. 1998; Friend 2000; Barnett
2003; Anthony & Freda 2009). GH is also the principal
mediator of postnatal cell growth and differentiation in
somatic cells following binding to its receptor, GHR (Le
Roith et al. 2001; Zhu et al. 2001). This binding acti-
vates pivotal pathways of cell growth and survival, such
as the JAK-2/STAT signaling pathway, p44/42 family
of mitogen-activated protein kinases (MAPKs), and
phosphoinositide 3-kinases (PI3Ks) family (Le Roith
etal. 2001; Zhu et al. 2001). On the other hand, GHRs
Copyright © 2021 Neuroendocrinology Letters ISSN 0172–780X
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
are widely distributed with varying concentrations in
different cell types, normal as well as neoplastic ones.
The fact remains - the more GHRs are expressed in
tumor cells, the more tumor cells possess invasive and
metastatic capabilities (Lincoln et al. 1994).
Besides, there are several GH-dependent mitogenic
molecules, such as EGF, FGF, HGF, IGF1, VEGF, PDGF
(Hagemeister & Sheridan 2008; Murray et al. 2004; Sall
et al. 2004; Szepesházi et al. 1999; Taslipinar et al. 2009),
and gastrointestinal (GI) specific growth factors, such as
VIP, CCK, G (Kath & Höffken 2000) that are involved in
many types of cancer. Furthermore, prolactin receptor
(PRLR) and GH receptor (GHR) are co-expressed on
cellular membranes, and through heterodimerization
they can physically and functionally interact, ampli-
fying proliferative pathways (Kelly et al. 1993). It has
been found that GH and PRL have akey role in the
development and in the progression ofhuman tumors,
especially in brain (De Souza et al.1974; Ben-Jonathan
et al. 2002; Batra et al. 1997; Cameron et al. 1979).
Tumor induction and progression are positively
related to GHR-PRLR expression, as demonstrated by
immunohistochemistry, Western blot, in situ hybrid-
ization and qPCR analyses. It’s well documented that
in tumor tissues GHR levels are higher than in physi-
ological or peritumoral ones, confirming the mitogenic
key role (Di Bella et al. 2018; Friend 2000; Gruszka et al.
2001; Lincoln et al. 1998; Zeitler & Siriwardana 2000).
Although the exact timing of etiopathogenesis is not
completely understood, it's conceivable that autocrine
and/or paracrine signaling could be accountable for
local production of GH, GHR, PRL, PRLR, and IGFI in
many tumors, including central nervous system ones.
IGF-1 is strongly dependent on GH (Daughaday
& Trivedi 1987). Moreover, it’s well known that GH
administration causes an increase of IGF-1 in human
tumor cells. A large amount of GHR could be observed
in cell lines during exponential cell growth and GH/
IGF-1 axes is the principal mediator of somatic growth
and has acrucial role in oncogenesis (Laban et al. 2003),
Tab. 1. DBM therapy for GBM
Somatostatin Peptide hormone
(14 years) 4 mg subcutaneous or into
a vein
(automatic infuser
during night)
Octreotide LAR Octreotide Acetate
(8 years) 20 mg intramuscular Every 20 days
Retinoid solution
All-Trans-Retinoic acid
Axerophthol Palmitate
α-Tocopherol acetate
0.5 g
0.5 g
2 g
1000 g
Per os daily (3 times per day)
Vitamin C L-Ascorbic Acid 4 g Per os Daily (lunch and dinner)
Vitamin D3 1,25-diOh-Tachysterol 30 drops=1 ml
around=1 mg Per os Daily (3 administrations)
Synachthen® Tetracosactide acetate 0.25 mg Subcutaneous 3 administrations per
week with infuser
Parlodel® Bromocriptine 2.5 mg Per os ½ tab 2 times a day
Dostinex® Cabergoline 0.5 mg Per os ½ tab 2 times a week
Chondroitin sulfate
D-Glucuronic Acid (GlcA)
Galactosamine (GalNAc)
500 mg Per os 2 times a day
Glucosamine D-Glucosamine 500 mg Per os 3 times a day
Deursil® Ursodeoxycholic Acid 300-450 mg Per os Daily
Melatonin 12%
Adenosine 51%
Glycine 37%
100 mg Per os Daily
Temodal® Temozolomide 20 mg Per os 2 times a day
Oncocarbide® Hydroxyurea 500 mg Per os Daily
Depakin Chrono® Sodium Valproate
(NaVP) 500 mg Per os 2 times a day
Diamox® Acetazolamide 250 mg Per os ½ tab 2 times a day
Disulfiram Diethyldithiocarbamate 200 mg Per os Daily
Neuroendocrinology Letters Vol. 42 No. 7 2021 • Article available online:
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
inhibiting apoptosis (Kusano et al. 2014; Perry et al.
2006), and stimulating the production EGF, FGF and
VEGF-A (Cattaneo et al. 1999; Brunet-Dunand et al.
2009; Vacas et al. 2016).
Furthermore, GH promotes migration and invasive-
ness of tumor cells via the endothelial to mesenchymal
transition (EMT) in tumor cells and down-regulating
plakoglobin, the cytoplasmic relocation of E-cadherin
and the activation of metalloproteinases 2 and 9 (MMP2
and MMP9) (Mukhina et al. 2004; Sommers et al. 1994;
Thiery 2002). Also, GH transduction leads to a signifi-
cant induction of several angiogenic genes, such as the
endothelial nitric oxide synthase (eNOS), the vascular
endothelial growth factor (VEGF), the basic fibroblast
growth factor (bFGF). Additionally, using immunohisto-
chemistry analyses, GH displays an increase in capillary
density and cellular proliferation (Kusano et al. 2007).
According to some studies, mRNA of GHR was
found in healthy brain cells and glioblastoma (Castro
etal. 2000). Overexpression of GH and GHRH in cancer
tissues such as glioblastoma, breast, lungs and others is
well documented (Lincoln et al. 1998). Several studies
confirmed the antitumor efficacy of somatostatin
analogues in glioblastoma, mainly by inhibiting GH and
GHRH release (Jaeckle et al. 2003; Kovács etal. 2010).
Somatostatin and its analogues downregulate GH
and GH-dependent growth factors, making their use
suitable for treatment of different kinds of cancer (Arena
et al. 2007; Di Bella 2010; Di Bella et al. 1979; Friend
2000; Lachowicz-Ochedalska et al. 2000; Lee etal. 2008;
Pawlikowski et al. 1999; Pollak 1997; Verhoef et al. 2008;
Vieira Neto et al. 2008). In different kinds ofcancer, not
only in neuroendocrine ones, an expression ofsoma-
tostatin receptor is well documented (Albérini et al. 2000;
Borgström et al. 1999; Briganti et al. 1997; Cattaneo et al.
1999; Corleto et al. 2009; Edelman et al. 2009; Faggiano
et al. 2008; Florio etal. 2000; Florio 2008; Friend 2000;
Fusco et al. 2008; Hassaneen et al. 2010; He et al. 2009;
Hubalewska-Dydejczyk et al. 2008; Ioannou et al. 2008;
Khanna et al. 2008; Kogner et al. 1997; Kwekkeboom
etal. 2008; Laklai et al. 2009; Li et al. 2008; Luboldt etal.
2010; Moertel et al. 1994; Orlando et al. 2001; Pisarek
etal. 2009; Ruscica et al. 2010; Sestini et al. 1996; Steták
et al. 2001; van Eijck etal. 1998; Watt et al. 2008).
Furthermore, the antiproliferative effect of soma-
tostatin and somatostatin analogues takes place by
inhibiting IGH pathways (Kiaris et al. 2005). Regression
and long survival with somatostatin in a primary glio-
sarcoma, a type of GBM but rare and has poor prog-
nosis, confirmed the efficacy of somatostatin in this
type of pathology (Anthony & Freda 2009; Barnett 2003;
De Souza et al. 1974; Friend 2000; Lincoln et al. 1998;
Trignani et al. 2013).
In conclusion, the PRL/GH/IGF axis has a promi-
nent role in malignant growth, providing a rationale
for the use of anti-dopamine D2 receptor agonists in
combination with biological GH antagonists, such as
somatostatin and its analogues. Inhibiting such axis
downregulates GH-related mitogenic growth factor,
including IGF1 and 2 (Arena et al. 2007; Buckley &
Buckley 2000), EGF (Barrie et al. 1993; Watt et al. 2008),
FGF (Bonneterre et al. 1990), VEGF (Albini etal. 1999;
Ashino et al. 2003; Cascinu et al. 2001) PDGF (Cattaneo
et al. 1999) and their relative pathways, resulting in anti-
proliferative and pro-apoptotic signals for recipient cells
(Watt et al. 2008). This emerging way of viewing is well
documented in basic research, but it’s not yet translated
in clinical applications.
Disulfiram (Aldehyde dehydrogenase inhibitor)
We have integrated DBM with Disulfiram, an aldehyde
dehydrogenase (ALDH) inhibitor, known as a marker
of glioblastoma CSCs (Toledo-Guzmán et al. 2019;
Moreb 2008), that is involved in the renewal, differ-
entiation and auto-protection (Marcato P et al. 2011;
Marcato P et al. 2011). Glioblastoma CSCs (gCSC)
represent the chemical-resistant population responsible
for recurrence, with a relevant percentage in glioblas-
toma cellular population. The temozolomide (TMZ),
an alkylating agent, is a first line chemotherapy drug,
able to ameliorate patient survival, and the resistance
to it leads to treatment failure (Schäfer A et al. 2012).
It has been highlighted that “long noncoding RNAs
(lncRNAs)” are related to a significant positive regula-
tion of TP73-AS1 in gCSC, related to overexpression
ofALDH1A1, one of the predominant ALDH isozymes,
protein (Nikhil et al. 2019), hallmark of ill-fated prog-
nosis in GBM and in other cancer disease (Mazor et al.
2019). ALDH1A1 was found regularly in gCSC and it is
associated with chemoresistance to TMZ (Moreb 2008).
Biomolecular mechanisms involving ALDH1A1 were
highlighted. In gCSC, overexpression of ALDH1A1
increases their aggressiveness and resistance, making
them a target for therapeutic strategies (Safa et al. 2016;
Xu et al. 2015).
gCSCs characterized by mesenchymal phenotype
exhibit high intracellular of ALDH 1 Family Member
A3 (ALDH1A3) and are considered more aggressive
and more resistant to therapy (Chen et al. 2019). In a lot
of cancer types, such as breast and ovarian carcinomas,
neuroblastomas, retinoblastomas, etc., the presence
of CSC was demonstrated and related to overexpres-
sion of their specific marker ALDH1, leading to a poor
prognosis, enhanced aggressiveness and chemoresis-
tance (Flahaut et al. 2016; Kim et al. 2018; Marcato etal.
2011; Marcato et al. 2011; Seigel et al. 2015). In this
context, the introduction in DBM of disulfiram, a nega-
tive regulator of ALDH is a rational choice. Moreover,
Disulfiram is well tolerated without any toxicity at the
dosage of 200 mg per day.
Valproic Acid
VPA, an anti-convulsion medication, has been shown
to have antineoplastic activities by inhibiting histone
deacetylase and chromatin condensation (Krauze
et al. 2018), and allowing access to all transcription,
Copyright © 2021 Neuroendocrinology Letters ISSN 0172–780X
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
differentiation and cytostatic factors (Rudà et al. 2016).
Moreover, VPA activates tumor suppressor genes
(Garcia et al. 2018), and inhibits glioma proliferation in
vitro and in vivo, by increasing apoptosis and inducing
cell cycle arrest (Pan et al. 2017). Therefore, VPA was
considered a valid therapeutic option for GBM treat-
ment (Ishiguro et al. 2018).
Furthermore, VPA acts on downregulation
of O6-alkylguanine DNA alkyltransferase, inducing
expression of BMP2, BMP4, ACVR, and DLX2 mRNAs
and a simultaneous increase of Smad1/5 phosphoryla-
tion (Raja et al. 2017). VPA modifies the expression
of genes involved in differentiation, DNA repair and
apoptosis. In particular, VPA induces p21 expression,
blocks cell cycle in G2/S phase, and activates at the
same time an apoptotic cascade, through downregula-
tion of antiapoptotic protein Bcl-2 / Bcl-XL. Indeed, as
reported in recent studies, a reduction of the mitotic
index emerged after VPA treatment, confirming the
induction of the G1 block. Commonly, cell arrested in
G1 phase move toward differentiation and subsequent
apoptosis (Riva et al. 2014). Clinically, VPA administra-
tion with temozolomide led to an increase in survival
ofGBM patients (Kerkhof et al. 2013).
VPA has been shown to counteract the prolifera-
tion and mobility of gCSCs (Gefroh-Grimes & Gidal
2016) and potentiates the antitumor response with a lot
of mechanisms, including differentiation in different
types of tumor cells (Rudà et al. 2016). In gCSCs, VPA
induces a dose-dependent reduction of metabolic
activity. The efficacy of this drug is revealed, evaluating
the classification of gCSCs lines, from the more sensible
to less responsive: G166, G179 and G144, GBM2,
GBM7, GliNS2 (Riva et al. 2014).
Carboanhydrase inhibitors
The carbonic anhydrases (CAH), zinc metalloproteins,
are enzymes that can have a clinical relevance in cancer
therapy, because of their isoform specific for cell surface.
The Ca9, an isoform of CAH, is almost exclusively asso-
ciated to cancers, and it is involved in tumorigenesis.
Ca9 is overexpressed in many types of cancer, and it is
infrequently present in healthy tissues. Ca9 expression
is induced by hypoxia and acidification, both of which
present in neoplastic areas of solid tumors (Winum
et al. 2008; Said et al. 2010; Said et al. 2013; Supuran
& Winum 2015). Furthermore, overexpression of Ca9
represents a significant indicator of disease prognosis,
associated with increased aggressiveness, malignant
progression, metastasis and poor response to treat-
ment documented in various tumors (McDonald et al.
2019). Therefore, the inhibition of Ca9, mediated by
acetazolamide (AAZ), counteracts its carcinogenic role
(Pastorekova et al. 2008).
Melatonin (MLT) is a natural hormone produced from
the pineal gland and is associated with the control
ofsleep-awake cycle (Auld et al. 2017). Furthermore,
MLT has antioxidant, anti-aging and immunomodula-
tory properties. MLT has a relevant role in the hemato-
poiesis, mainly thrombogenesis, leukocytes regulation,
and synthesis of hemoglobin. Besides, MLT has a prom-
inent role in perfusion and in gaseous haemato-tissue
exchanges, preventing tissue ischemia’s, acidosis, and
hypoxia in neoplastic environment, with a consequent
over-expression of oncogenic genes, such as HIF-1α.
The relevant and non-toxic apoptotic, oncostatic, anti-
angiogenetic, antiproliferative properties of this indole
on all neoplastic pathologies are documented (Heldin
& Westermark 1991; Cos et al. 1996; Lissoni et al. 1996;
Bartsch & Bartsch 1997; Blask et al. 1997; Pawlikowski
et al. 1999; Lissoni et al. 2000; Czeczuga-Semeniuk
et al. 2002; Reiter & Korkmaz 2008; Sánchez-Barceló
et al. 2005; Skwarlo-Sonta 2002; Trubiani et al. 2005;
Vijayalaxmi et al. 2004; Watanabe et al. 2008; Fischer
etal. 2008; Bejarano et al. 2009; Matt et al. 2009; Ferreira
Cda et al. 2010;; Kim et al. 2013; Moradkhani et al.
2020). Clinically, MLT showed potential in treating
solid tumors (Di Bella 2005; Di Bella & Gualano 2006;
Di Bella et al. 2013a; Di Bella et al. 2013b; Nooshinfar
et al. 2017; Talib 2018; Di Bella 2019; Gil-Martín et al.
Retinoid solution
Retinoids are chemical compounds related to vitamin
A. Early studies had shown that retinoids regulate cell
proliferation and differentiation. Then, several studies
demonstrated that retinoids play a crucial role both
in prevention and therapy of cancer, limiting conse-
quences induced by cancer and usual anticancer thera-
pies (Abe et al. 2003; Adachi et al. 2001; Di Masi et al.
2015; Anthony & Freda 2009; Arany et al. 2003; Baroni
et al. 2003; Basu et al. 2000; Chambaut-Guérin et al.
2000; Chou et al. 2000; Dufner-Beattie et al. 2001; Kim
et al. 2009; Kini et al. 2001; Lee et al. 2008; Sharow etal.
2012; Song & Xu 2001; Wu et al. 2009; Ni et al. 2019;
Ying et al. 2011).
For instance, the all-trans retinoic acid (ATRA)
has been shown to help in differentiating blast cells
in haemtological malignancies (Hassan HT & Rees J
1990), decreasing the potential for neoplastic prolif-
eration and playing an important role in cell differen-
tiation, apoptosis and adhesion (Herreros-Villanueva
etal. 2015; Voigt et al. 2000). Furthermore, it has been
shown that retinoic acid can suppress the gene tran-
scription of oncogenic factors and promote the antipro-
liferative effect (Arnold et al. 1994), has anti-angiogenic
action (Majewski et al. 1994). Besides, retinoic acid
and temozolomide arrested cell cycle progression in
the G0/G1 phase and significantly induced apoptosis
of human glioma cells (Shi et al. 2017).
Furthermore, the effect of retinoic acid on gCSCs
has been established. gCSCs are known to be the tumor
initiator and tumor propagator (Wang & Liu 2019;
Songthaveesin et al. 2018). It has been established
Neuroendocrinology Letters Vol. 42 No. 7 2021 • Article available online:
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
that glioma stem cells divide symmetrically, resulting
in the poor therapeutic effect of current glioma treat-
ments. If gCSCs are divided asymmetrically, the prolif-
erative capacity of the tumor containing such cells is
decreased, and if asymmetry is decreased in normal
stem cells, the neoplastic transformation increases
(Wang & Liu 2019). In that sense, it has been shown
that ATRA induce asymmetric gCSCs cell division in
U87MG glioblastoma cell line. These results suggest
a therapeutic effect of ATRA on glioma stem cells
(Wang & Liu 2019; Songthaveesin et al. 2018).
As presented in Table 1, retinoid solution contains
not only ATRA, but also axerophthol palmitate
(vitamin A), β-carotene, and α-tocopherol acetate.
These constituents also enhanced the anti-cancer
activities of ATRA. For instance, it has been shown
that vitamin A caused death to of the neoplastic cell by
apoptosis, through the activation of caspases and the
degradation of the general transcription factor Sp-1
(Piedrafita & Pfahl 1997; Kanungo 2017). On the other
hand, α-tocopherol (vitamin E) has a high antioxidant
and anti-free radical activity and directly affects a key
step in energy exchange and life itself: the transport
of electrons in the respiratory chain. Furthermore,
α-tocopherol inhibited the growth of various tumor
cell lines (Dalen & Neuzil 2003; Elattar & Virji 1999;
Fariss et al. 1994; Heisler et al. 2000; Inokuchi et al.
2003; Israel et al. 2000; Malafa et al. 2002; Malafa &
Neitzel 2000; Kerkhof et al. 2013; Neuzil et al. 2002;
Neuzil etal. 2001; Prasad et al. 1990; Prasad et al. 1994;
Prasad et al. 2003; Prasad & Kumar 1996; Pussinen et al.
2000; Ripoll et al. 1986; Rose & McFadden 2001; Sarna
et al. 2000; Shklar & Schwartz 1996; Tang & Meydani
2001; Turley et al. 1995; Wu et al. 2002; Yamamoto
etal. 2000; Yu et al. 2002; Yu et al. 1997; Yu et al. 1997;
Zhang et al. 2002). Besides, α-tocopherol enhanced the
anticancer action of various chemotherapy drugs such
as adriamycin, cisplatin and tamoxifen (Prasad et al.
1994; Ripoll et al. 1986) and protected bone marrow
cells from the lethal effects ofdoxorubicin (Fariss etal.
Vitamin C
Ascorbic acid, or vitamin C, has a great antioxidant
activities by reacting directly with single atomic
oxygen, hydroxides and superoxide radicals (Padh
1991; Sauberlich 1994). Biologically, vitamin C acts
as a hydrogen carrier in intermediary metabolism,
including cellular respiration processes (Ngo et al. 2019;
Pawlowska et al. 2019). Besides, vitamin C possess
anticancer therapeutic activities (Cameron et al. 1979;
Head 1998; Bendich & Langseth 1995; Aidoo et al.
1994; Lee et al. 2002; Blaszczak et al. 2019; Di Bella & Di
Bella 1998; Ohno et al. 2009; van Gorkom et al. 2019),
including anti-angiogenic activity (Ashino et al. 2003),
and anti-metastatic activities (Peterkofsky 1991; Pinnel
et al. 1987; Cameron & Pauling 1973; Utoguchi et al.
Vitamin D
Vitamin D is a fat-soluble molecule that is mainly
responsible for increasing intestinal calcium absorp-
tion and for calcium homeostasis. However, vitamin
D has many biological functions. Of these, vitamin
D is an important molecule to for differentiation
of cells (Marcinkowska 2001; Consolini et al. 2001).
Also, vitamin D induces phenotypic maturation
of tumor cells into functionally mature, differenti-
ated, physiologically normal cells (Barroga EF et al.
2000; Majewski et al. 1994). Vitamin D3 was found
to inhibit proliferation, and promoted differentiation
of various types oftumor cells, and prevented adhesion
of cellular migration from basal membrane. The latter
phenomenon was due to adownregulation of alpha-6
and beta-4 integrins, laminin receptors associated with
greatest cellular migration and invasiveness of prostatic
cancer cells in vivo (Yudoh et al. 1999; Sung & Feldman
2000). Furthermore, vitamin D inhibited angiogenesis
through inhibiting VEGF in a dose dependent manner
(Mantell et al. 2000).
Proteoglicans and glycosaminoglicans
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan
(GAG) composed of a chain of alternating sugars
(N-acetylgalactosamine and glucuronic acid). It is
used with glucosamine as a supplement for osteoar-
thritis. However, there are several studies that showed
chondroitin sulfate has anti-tumor and antimetastatic
activities (Fthenou et al. 2009; Kasten et al. 2018; Shi
et al. 2021). It has been found that chondroitin sulfate
inhibited the growth of a bladder cancer cell line by the
activation of caspases 3 and 9 and thereby inducing
apoptosis (Ferro et al. 2012). Besides, it has been shown
that combining chondroitin sulfate with the gene
ofmurine granulocyte macrophage-colony-stimulating
enhanced the survival of mice bearing ovarian cancer
(Hamada et al. 2012).
Glucosamine sulfate
Similar to chondroitin sulfate, glucosamine is used as
asupplement for osteoarthritis. Besides, several studies
have shown the potential of glucosamine sulfate in
cancer treatment mainly by inhibiting CSC (Hosea
etal. 2018; Hong et al. 2020). Furthermore, it has been
reported that glucosamine induced autophagic cell
death through stress stimulation of the endoplasmic
reticulum (ER) in human glioma cells. ER stress
induced by glucosamine was manifested by the induc-
tion of the expression of BiP, IRE1alpha and phospho-
eIF2alpha (Hwang & Baek 2010). Besides, glucosamine
suppressed the proliferation of the DU145 human
prostate cancer cell line through inhibition of STAT3
signaling. In DU145 cells, glucosamine reduced the
N-glycosylation of gp130, decreased the binding of IL-6
to cells, and altered the phosphorylation of JAK2, SHP2
and STAT3 (Chesnokov et al. 2014).
Copyright © 2021 Neuroendocrinology Letters ISSN 0172–780X
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
Furthermore, glucosamine has been documented
that glucosamine has anti-inflammatory activity via
regulating inhibiting nuclear factor κB (NF-κB) action
and therefore suppresses inflammatory cytokines
production (Dalirfardouei et al. 2016). Hence, it may
be used in treating inflammatory-induced tumors
(Al-Hanbali et al. 2009; Mansour et al. 2018).
Although D-glucosamine is safe, some studies have
presented the toxic effect of its conjugates on cancer
cells and have highlighted its application in targeting
glioma. The study revealed a significant effect on cyto-
toxicity and apoptosis in vitro as assessed on resistant
grade IV glioma cell lines. Furthermore, this effect was
not observed on normal human erythrocytes in the
haemolysis test. GC liposomes were not toxic to normal
brain tissues of healthy Sprague-Dawley rats tested.
The absence of histological and behavioral changes
together with the absence of caspase-3 in the brain
tissue confirmed the suitability of the system for direct
infusion into the brain (Yadav et al. 2019).
The expression of vitamin D receptors in glioma
tumors is associated with increased survival (Cataldi
et al. 2020; Norlin 2020). The 1,25-hydroxyvitamin
D3 has direct effects on nervous systems, influ-
encing steroidogenic pathways. In the human glioma,
Vitamin D3 stimulates the expression of aromatase
and the 3β-hydroxysteroid dehydrogenase as well as
the 17-hydroxylase/steroid lyase in the astrocytes, in
addition to providing neuroprotection. The expres-
sion of vitamin D receptors in glioma is associated with
ahigher survival, and 1,25 hydroxyvitamin D3 and its
analogous suppress the proliferation and the migration
in glioma cellular lines, expressing human vitamin D
receptors (Norlin 2020).
Although there are rationales for using each molecule in
DBM, the synergistic effect of the combination makes it
more powerful. For instance, the synergic effect ofMLT
and VPA enhances the cytotoxic effect of TMX in GBM
cells through the reduction of MGMT expression (Di
Bella et al. 2013a; Di Bella et al. 2013b; Lissoni et al.
1996; Rudà et al. 2016), and therefore increasing life
expectancy as seen in our patients (Zhang et al. 2016).
Furthermore, the combination of CAH inhibitors
with chemotherapeutic treatments for glioblastoma
increased survival.
We noticed that the integration of AAZ in a multi-
therapeutic context contributed to reducing cortisone
administration due to its diuretic and anti-edema prop-
erties. Besides, administrating AAZ and VPA reduced
epileptic episodes and improved the prognosis.
Interaction between MLT and other DBM molecules
opposes several processes characterizing neoplastic
phenotype, mutation and proliferation, progression
and/or dissemination. All these features suggest the use
of this molecule as a treatment for cancer (Di Bella etal.
2017; Gil-Martín et al. 2019; Nooshinfar et al. 2017;
Talib 2018).
Many research papers confirm the preventive and
therapeutic activity of vitamin D in neoplastic patholo-
gies (Jeon & Shin 2018). Various synthetic analogues
ofVitamin D, called deltanoids, are designed specifi-
cally to potentiate antiblastic activity, and at the same
time reducing several collateral effects (Negri et al.
2020). Synergism of Vitamin D, Vitamin C, Vitamin E,
and MLT was found in several clinical studies, showing
their antiproliferative, antiangiogenic, and differentia-
tive properties.
Furthermore, we hypothesize that the combination
of Calcitriol and ATRA (All-Trans Retinoic Acid) and
Temozolomide could be a safer approach to benefit
from vitamin D in high degree glioma cancer manage-
ment. The addition of acetazolamide to this protocol
can reduce the risk of brain pseudotumors, because
of vitamin D and a surplus of vitamin A can lead
tointracranial hypertension; this approach can provide
benefits due to antitumoral activity of acetazolamide
(Elmaci et al. 2019).
The Patient’s age, diagnosis, and initial treatment used
before DBM are summarized in Table 2. Below is abriefing
about each case and the follow-up results after DBM.
Patient ID: 5833
Date of birth: 29/07/1989
DIAGNOSIS 20/06/2012 (23 years old) ANAPLASTIC
unmethylated-MGMT; mutated IDH1; EGFRvIII
negative; overexpressed VEGF.
20/06/2012 – SURGICAL RESECTION (bilobed
space-occupying lesion, around 4 cm)
26/07/2012 – Brain MRI: ...small residue of the most
caudal part of the left parietal glial lesion...
30/07/2012 – RT + TMZ 135 mg (up to 06/11/2012)
21/11/2012 – TEM 370 mg/12 courses
27/12/2012 – PET: …hypodense nodular area, caudally
to the surgical cavity, in the left parietal region...
05/03/2013 – Brain MRI: ...disease residue along the
edges of the seemingly stable surgical cavity, even though
the rCBV values are increased compared to the previous
05/10/2013 – Brain MRI: ...further signal alteration
located in the left parietal corona radiata, suspected to be
mild infiltrative disease progression...
05/11/2013 – START DBM
20/06/2014 – Brain MRI: ...morphology and exten-
sion of the infiltrative disease residue along the lower
edge ofthe surgical cavity are unaltered... the small area
of signal alteration located in the left parietal corona
radiata is also unaltered”
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Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
25/06/2014 – PET: ...reduction in radio-compound
uptake at the hypodense nodular area, previously
reported caudally to the surgical cavity in the left parietal
29/12/2017 – PET: ...the PET-CT scan has not shown
any amino acid tracer distribution abnormalities that
could be related with certainty to a neoplastic disease...
23/03/2018 – Brain MRI: ...morphology and size
ofthe surgical cavity are unaltered... the areas of signal
alteration are also unaltered, T2/FLAIR hyperintensi-
ties on the edges of the cavity, without contrast agent
uptake. No documented increase in rCBV values at these
18/10/2018 – MRI: Unaltered diagnosis
10/06/2019 – MRI: Stable disease diagnosis with unal-
tered main MRI findings
10/01/2020 – PET-CT: ...has not shown any amino acid
tracer distribution abnormalities that could be related
to a neoplastic disease, particularly at the edges of the
surgical resection in the left parietal region. No further
areas of focal uptake of 11C-Methionine at cortical and
subcortical regions and in the cerebral hemispheres.
26/06/2020 – Brain MRI: Stable disease diagnosis with
unaltered main MRI reports.
26/06/2020 – Brain MRI with Contrast Agent: ...
shows non-significant increase in perfusion in some ROIs
and choline peaks in some voxels on spectroscopy. No
significant enhancement after contrast agent. Ended due
to the absence of recurrent disease.
10/10/2020 – Histological exam: “Fragment of squa-
mous epithelioma in situ (pTis UICC 2017)”
Patient ID: 6245
Date of birth: 04/12/1982
DIAGNOSIS 21/05/2007 (25 years old)
unmutated IDH1; mutated IDH2; methylated-MGMT;
1p/19q codeletion
21/05/2007 – 1st SURGICAL RESECTION
31/05/2013 - 2nd SURGICAL RESECTION
21/10/2014 - 3rd SURGICAL RESECTION (2nd recur-
rence) – RX + TEM 75 mg
25/11/2014 – START DBM
20/07/2015 – Brain MRI: pathological alterations
shown in the sequences performed after Gadolinium
30/03/2016 – Brain MRI: ...findings essentially
21/11/2017 – Brain MRI: ...findings essentially
02/05/2018 – Brain MRI: ...findings essentially
Tab. 2. Patient’s age, diagnosis, and treatments before initiation of DBM
Patient ID
Age (y)
atthe time
ofdiagnosis Diagnosis Mutation/
Therapy after
Survival after
5833 23 Jun 2012
Surgery +
Nov 2013 >7 years
6245 23 May 2007 Oligoastrocytoma (II)
mutated IDH2;
MGMT; 1p/19q
Surgeries +
Nov 2014 > 6 years
6572 27 Feb 2015 Anaplastic
astrocytoma (III)
Surgery +
Chemotherapy Mar 2015 > 5 years
9691 19 Nov 2010 Oligoastrocytoma (II)
IDH1; IP53
GFAP positive;
Surgeries Aug 2014 > 6 years
4835 40 Nov 2012 GBM (IV) mutated IDH1 Surgery Dec 2012 > 8 years
5371 49 May 2013 Anaplastic glioma (III) ND - Sept 2013 > 7 years
5251 43 Nov 2012 Oligodendroglioma (?) ND - Apr 2013 > 7 years
Copyright © 2021 Neuroendocrinology Letters ISSN 0172–780X
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
27/11/2018 – Brain MRI: ...findings essentially
22/05/2019 – Brain MRI: “stable neuroradiological
diagnosis compared to previous”
12/05/2020 – Brain and brain stem MRI: Stable
13/05/2020 – Oncology Visit: “In light of the recent
instrumental reassessment that documented significant
disease stability, and optimal and stable general clinical
conditions, it is recommended to keep monitoring the
18/11/2020 – Brain and brain stem MRI: “Today’s find-
ings appear completely unaltered. [...] All the remaining
findings are essentially unaltered.
Patient ID: 6572
Date of birth: 21/02/1988
DIAGNOSIS 02/02/2015 (27 years old) ANAPLASTIC
Mutated-IDH1; methylated-MGMT; GFAP positive
16/01/2015 – SURGICAL RESECTION (no CT/2 RT
27/02/2015 – Brain MRI: ...centimetric residual area
of T1 hyperintensities and T2 hypointensities is observed
with a diffuse oedema. Adjacent to the previous finding,
millimetric area of T1 hyperintensities as well as the
enhanced area after contrast agent...
16/03/2015 – START DBM
20/04/2016 – Brain MRI: ...slightly less evident, the
small area of signal alteration refers to the residual lesion
after contrast agent...
03/10/2017 – Brain MRI: pathological enhance-
ment after administration of the contrast agent...
02/07/2018 – Brain MRI: ...No areas of pathological
enhancement attributed to residues/recurrences are
06/02/2019 – Brain MRI: “The findings are essentially
unaltered... no significant areas of pathological enhance-
ment are observed”
09/10/2019 – Brain MRI: compared to the previous
scan on 30/01/19: findings unaltered; left frontal region
with an area of T2 hyperintensities. Frontal horn of left
lateral ventricle remains wide. Diffusion and perfusion
imaging do not show areas of ADC reduction and rCBV
increase at the aforementioned area of T2 hyperintensi-
ties. Remaining findings are unaltered, particularly in
the malacic area affecting the right cerebral hemisphere
and left thalamic ischaemic cavity, as well as the likely
nodule of grey matter heterotopia along the wall of the
right lateral ventricle chamber. No areas of pathological
enhancement after contrast agent.
15/07/2020 – Brain MRI: “Compared to the exam
observed on 09/10/2019, the baseline and post-contrast
enhancement MRI findings are perfectly comparable.
Currently no images are observed that are consistent with
neoplastic recurrence.
Patient ID: 9691
Date of birth: 20/11/1991
DIAGNOSIS: 30/11/2010 (19 years old)
unmutated IDH1; IP53 negative; GFAP positive;
NOGO-A positive
16/11/2010 - 1st SURGICAL RESECTION (5 cm
15/02/2013 – 2nd SURGICAL RESECTION (recur-
rence) – diagnosis: OLIGODENDROGLIOMA WHO II
10/06/2013 – Brain MRI: ...residual lesion...
08/07/2014 – Brain MRI: ...extension of the residual
lesion is unaltered, but diffusion imaging shows a 2-fold
ADC increase compared to the white matter, and perfu-
sion also shows an rCBV value that is 5 times that of the
reference white matter...
08/08/2014 – First revision: Prof. Giangasparo
Umberto I – Policlinico di Roma [Umberto I Polyclinic
18/08/2014 – START DBM
28/08/2014 Brain MRI: ...slight increase in exten-
sion of the area of signal alteration, hyperintense on
T2-weighted sequences, affecting the nervous tissue
surrounding the surgical wound, that seems to contra-
laterally infiltrate through the trunk of the corpus
11/09/2014 – Second Revision Ist. Besta di Milano
[Besta Institute of Milan] of histological findings from
2010 and 2013
16/09/2014 – 31/10/2014 – RT (33 sessions): Refused
chemotherapy treatment.
03/12/2014 – Brain MRI: ...size and characteristics
ofthe signal in the area of T2 hyperintensities are essen-
tially unaltered...
03/06/2015 – Brain MRI: ...the area of T2 hyperinten-
sities is essentially comparable... diffusion imaging shows
this at the area of signal alteration. Increased ADC values
(2.6) compared to white matter (1); perfusion imaging
does not detect significantly increased rCBV values”
09/09/2015 – Brain MRI: areas of pathological
contrast enhancement are observed after administration
of the contrast agent...
22/11/2016 – Brain MRI: ...findings unaltered... diffu-
sion and perfusion imaging do not show areas of ADC
reduction or rCBV increase...
28/03/2017 – Brain MRI: ...the diagnosis remains
01/09/2017 – PET: “no areas of significant uptake at the
known lesion, outlined in the MRI scan on 29/03/2017,
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Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
in the left parasagittal posterior frontal hemisphere...the
scan did not show the presence of areas of pathological
radiopharmaceutical uptake that could be related to the
primary disease...
The patient reduced the doses of the medicinal product
on their own initiative, followed by some seizures and
worsening of general conditions.
31/07/2018 – Brain MRI: ...stable radiological find- apparent recurrence of the known space-occu-
pying lesion from their medical history...
Resumption of somatostatin intravenous infusion treat-
ment at full doses, resolution of seizures
Improvement in quality of life.
09/07/2020 – Brain MRI: “Compared to the previous
MRI on 20/02/2020, the onset of an area of patho-
logical contrast enhancement in the left parietal intra-
axial region is observed, likely neoplastic with irregular
morphology and around 20 mm in diameter. Perfusion
imaging shows rCBV values that are increased 3-fold
at this area of pathological enhancement compared
tothose of the contralateral white matter, likely in rela-
tion to signs of neoangiogenesis. A small perilesional
oedema is associated with this area of pathological
enhancement. Increased extension of the known area
of left high-frontal signal alteration [...]posterosuperi-
orly to the known surgical cavity, rCBV values that are
increased 2/3-fold are observed compared to those of the
contralateral white matter. Compared to the abovemen-
tioned previous MRI scan, the onset of multiple small
and markedly hypointense areas are observed at the
same area on the T2*-weighted GE images, such as the
presence of haemosiderin, suspected to be multiple small
radiation-induced cavernomas. The morphovolumetrics
of the ventricular system and the size of the subarach-
noid spaces of the convexity and the base are essentially
21/10/2020 – Brain MRI with Contrast Agent: ...
slight size reduction in the known area of pathological
contrast enhancement, of irregular morphology and in
the left parietal region, is observed with a decrease in
the associated perilesional oedema. Perfusion imaging
shows rCBV values that are persisting and currently
increased 5-fold at this area of pathological enhance-
ment compared to those of the contralateral harmless
white matter, such as neoangiogenesis. The spectroscopy
documents a slight increase in choline compounds in
this region and amoderate reduction in NAA compared
to the homologous sampling collected from the contra-
lateral region, without signal alteration. The extension
of the left superior frontal area of signal alteration is
essentially unaltered, with T2/FLAIR hyperintensities,
surrounding the surgical cavity and extending to the
underlying centrum semiovale and corona radiata:
at the latter, rCBV values remain significantly poorly-
defined, more apparent alongside the lateral ventricle.
The ventricular morphovolumetrics and remaining
finding are stable, in the absence of new areas of patho-
logical contrast enhancement.
The patient-initiated suspension of essential compo-
nents of the cure these days has resulted in severe
disease progression.
Patient ID: 4835
Date of birth: 26/05/1972
DIAGNOSIS: 15/11/2012 (40 years old)
GLIOBLASTOMA (WHO IV) (with a peripheral part
of diffuse astrocytoma) mutated IDH1
RESECTION (70/80%): ...the large lateral and anterior
parts are removed. The neoplastic part infiltrating the
premotor–motor and contralateral regions is left in situ.
70/80% of tumor removal is estimated...
18/12/2012 – START DBM
04/01/2013 – MRI: ...known residual lesion in the left
frontal paramedian region whose signal, area of infil-
tration and contrast enhancement characteristics do
not appear to be substantially altered compared to the
previous scan...
09/11/2015 – MRI: ...the radiological findings appear
to be essentially unaltered... in particular, the known
space-occupying lesion located at the cingulate gyrus,
which affects both hemispheres, is still significant...” “...
no areas of intra- or extraparenchymal pathological
enhancement are observed at either the lesion or the
remaining sub- and supratentorial parenchyma after
administration of the contrast agent...
29/04/2016 – MRI: ...the sizes and signal characteris-
tics of the known space-occupying lesion located at the
cingulate gyrus, which affects both hemispheres, remains
essentially unaltered...
02/11/2016 – MRI: ...during today’s scan, after adminis-
tration of the contrast agent, the abovementioned poorly-
defined area of contrast enhancement at the lesion in the
right paramedian region, appears to be less apparent...
15/02/2018 – MRI: signs of locoregional recurrence
are detected as a result of removing the glioblastoma
that was previously located at the cingulate gyrus with
bihemispheric involvement...
29/05/2019- MRI: ...the onset of signs of locoregional
disease recurrence are not observed...Remaining findings
are unaltered...
19/03/2020 – Brain MRI: absence of enhancement
attributed to signs of disease recurrence. Diffuse leukom-
alacia persists at the centra semiovale and in the periven-
tricular region, unaltered compared to the previous scan.
Sub- and supratentorial ventricular system of normal
morphology, volume and location. Slight enlargement
ofthe vault fluid spaces. Developmental venous anomaly
in the left cerebellar region. No intra- and extra-axial
pathological enhancement detected after contrast agent.
Mucosal thickening of left maxillary sinus. Turbinate
Patient ID: 5371
Date of birth: 22/06/1964
Copyright © 2021 Neuroendocrinology Letters ISSN 0172–780X
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
DIAGNOSIS: 06/05/2013 (49 years old) PROGRESSIVE
06/05/2013 – MRI: “...extensive cerebral tumor involving
the entire bulbo-medullary junction with diffusion tothe
inferior cerebellar peduncles, right middle cerebellar
peduncle, and infiltration of the 4th ventricle on which it
already determines the mass effect...
10/09/2013 – START DBM
“Progressive anaplastic glial tumor, grade III infil-
trating glioma” DIAGNOSIS, exacerbated by the
highest functional dignity of the affected area, crossed by
10cranial nerves, from the 3rd to 12th (excluding the optic
and olfactory nerves) and the 4th ventricle, site of the vital
nerve, respiratory and cardiovascular centres that can be
easily made inactive by compression (for tumor progres-
sion, and/or postoperative or post-therapeutic cerebral
oedema). The location and extension caused paresis and
disability. A court-appointed Technical Advisor, who the
patient had asked to get DBM, excluded radiotherapy,
operation, and confirmed the possibility of palliative treat-
ment with a prognosis of less than a year.
DBM achieved remission in the majority of the tumor and
stability, blocking progression of the residual tumor cells
that are no longer proliferating, finally enabling functional
recovery and self-sufficiency in a patient that was previ-
ously known for disability and assistance.
29/01/2019 – Brain MRI: “the extension of the neoplastic
infiltration detected at the bulbocervical region remains
stable, bilaterally with an increase in volume of the
anatomic structures in question and inhomogeneous
signal alteration”.
17/04/2019 – FDG-PET: compared to the MRI on
29/01/2019: the presence of inhomogeneous metabolic
tracer uptake is detected, with various degrees of mild
to moderate uptake at the alteration detected on the
MRI. The uptake is reported to be more accentuated on
the right-hand side. Moreover, moderate-severe uptake
is detected at the right column, of uncertain significance
(aspecific? Other?); useful assessment in characterized
field. There is nothing else to report in the remaining
examined body regions, particularly in the lung paren-
chyma and the liver. The PET findings suggest the pres-
ence of heteroplastic tissue with moderate carbohydrate
metabolism at the bulbocervical junction and proximal
segment of the cervical cord. N.B. in the hypermetabolic
region, the activity is defined as mild-moderate-severe
compared to the hepatic metabolic activity, pursuant
toEANM guidelines.
Patient ID: 5251
Date of birth: 06/03/1969
DIAGNOSIS: November 2012 (43 years old)
17/12/2012 – CT ANGIOGRAM and MRI: show
atumor with “progressive tendency” (compared with an
MRI from 2006 in which it is barely noticeable, so much so
that it was not taken into account at the time), with severe
vascularization and sticking closely to the sylvian artery,
therefore “surgery is not recommended”. Considering
the progressive characteristics and the spectroscopy and
perfusion imaging findings, the diagnostic hypothesis puts
19/04/2013 – START DBM
20/03/2014 – MRI: ...the presence of a space-occupying
lesion, 1.95 x 1.59 cm in size, is confirmed... with mild
enhancement after contrast agent...
20/03/2014 – PET: ...the lesion, composed of solid and
calcified portions, has no substantive changes compared
towhat was previously documented...
09/11/2015 – PET: ...the scan does not show areas
ofpathological tracer uptake and, in particular, the previ-
ously reported lesion, which appears to be characterized by
a coarse shell-like calcification and without a perilesional
oedema that could be related to calcified meningioma
17/10/2017 – MRI: ...the scan has not shown the evolu-
tion of the left temporosylvian lesion...
22/11/2018 – MRI: ...lesion completely stable...
27/10/2020 – Brain MRI, perfusion imaging and
spectroscopy: “The left temporosylvian lesion remains
completely unaltered, with extensive calcified parts and
asmaller parenchymatous part.
Three of the seven patients treated with DBM are still
alive after 5 to 6 years, and the other four patients are
still alive after seven years of starting DBM (Table 2). In
3 cases (IDs 5833, 6245, 6572), DBM began after the
failure of Stupp protocol, i.e., when disease recurrence
was detected. After DBM treatment, disease progression
was arrested.
The patient with GBM (ID 4835) had incomplete
surgical resection then adapted DBM as first-line
therapy a month later. After eight years of DBM, the
patient is still alive and has neither symptoms nor disease
progression. Furthermore, patient 5371, who had inop-
erable aplastic glial neoplasm received neither surgery
nor Stupp protocol, started DBM as first-line therapy
during tumor progression. After seven years, the patient
did not develop recrudescence and is cancer-free. Also,
patient 5251, with inoperable oligoastrocytoma, didn’t
start Stupp therapy and didn’t have surgery. Eight years
following DBM, the patient is still alive after eight years
with free-tumor progression and living a normal life.
In malignant brain tumors and GBM, the prognosis
remains poor despite surgery, chemo- and radiotherapy,
with a median survival of 14-18 months after diagnosis
Neuroendocrinology Letters Vol. 42 No. 7 2021 • Article available online:
Di Bella et al: A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method
(Delgado-López & Corrales-García 2016). In our study,
DBM improved life expectancy and quality of life and
avoided relevant toxicity (Di Bella et al. 2017; Di Bella
et al. 2013a; Di Bella et al. 2013b; Di Bella 2005; Di Bella
2019; Di Bella 2010; Di Bella et al. 2018; Di Bella et al.
1979a; Di Bella et al. 1979b; Di Bella 1997; Di Bella &
Di Bella 2015; Di Bella & Gualano 2006; Di Bella & Di
Bella 1998).
During most tumors’ progression, with more
evidence in brain ones, the percentage of CSCs
compared with other cellular components of the
neoplastic population is high, and it’s associated with
chemo and radiotherapy resistance and the rapid
progression of the disease. For this reason, we have
gradually increased the dosage ofmolecules that nega-
tively affect CSCs and reprograms CSCs.
Unlike Stupp’s protocol, the metronomic administra-
tion in DBM of temozolomide (20 mg in the morning
and the evening) and hydroxyurea (500 mg at lunch)
has enhanced proliferation control and invasiveness
ofcancer cells. Besides, the daily administration of MLT
(100mg) with the retinoid solution in vitamin E reduced
the myelotoxicity of temozolomide and hydroxyurea
(Di Bella et al. 2013a; Di Bella et al. 2013b; Di Bella &
Di Bella 2015; Di Bella & Gualano 2006).
The DBM, in contrast with a classical oncological
point of view, moves the therapeutic axis from cyto-
lytic, toxic, and immunosuppressive mechanisms to the
contrast of negatively regulating oncogenesis through
different mechanisms (Di Bella et al. 2018; Perry et al.
2008). Furthermore,
differentiating components of DBM, such as a reti-
noid solution in vitamin E, vitamins C, D, and MLT,
counteract the mutagenic capability of tumor cells,
based on a defense system and a survival program
that allows efficient and rapid repair of DNA damages
induced by chemo- and radiotherapy. For instance, the
prokaryotes, the first forms of life, are still surviving
until the present day. Thanks to a defense system devel-
oped during evolution based on a mutational program,
DNA repair in case of adverse events. The prokaryotes
survival program termed the state of emergency, “SOS
program,” has been passed to the somatic cells (Radman
1975). In addition, it has been shown that the SOS
program is activated in tumor cells, and many homolo-
gies in neoplastic cell genes and bacterial ones have
been identified (Israel 1996).
Cancer cells in acute stress implement DNA repair
systems and express or silence genes according totheir
needs, selecting and retaining for each mutation
awhole series of advantages with speed and efficiency
far superior to bacterial cells. The SOS system allows the
neoplastic population to progressively become insus-
ceptible to different oncotherapeutic drugs through
DNA repair and recombination.
The SOS system is silenced and inactivated in stable
biological conditions, transcriptionally stopped by
arepressor, the LEX-A protein. When severe damages
occur in a somatic cell DNA, the transcriptional
repressor LEX-A is turned off by the positive regulator
REC-A. The SOS activation carries along with a series
of mutations that repair but, at the same time, modify
the DNA, leading to carcinogenesis. The mutating
cells start a progression of the SOS program, in which
a continuous selection and retention of mutations
confers a series of advantages, as confirmed by (Lambert
et al. 2011) and recently by (Russo et al. 2019).
In conclusion, the multi-strategic objectives ofDBM
are inhibiting the proliferative-invasiveness and
neoplastic angiogenesis, and silencing the SOS survival
system through differentiated components, like the reti-
noid solution in vitamin E, MLT, vitamin C, and D, etc.
Besides, the differentiative components of DBM display
trophic, immunomodulatory, and antioxidant activi-
ties, improve vitality and efficiency of normal cells and
depress the efficiency and vitality of neoplastic ones.
The DBM is expanding its activity to numerous vital
responses typical of neoplastic biology. DBM moves
the therapeutic axis from a merely cytotoxic and cyto-
lytic activity that expected a utopian and elusive life-
long eradication of all tumor cells in the body to an
immuno-neuro-endocrine homeostasis recovery.
A more physiologic strategy thought the reconver-
sion of vital functions that deviate in cancer cells, the
differentiation of tumor cells, and the reprogramming
of cancer stem cells.
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The aim of this retrospective study is to provide real-world evidence in glioblastoma treatment and to compare overall survival after Stupp's regimen treatment today and a decade ago. A current consecutive cohort of histologically confirmed glioblastoma irradiated from 1/2014 to 12/2017 in our cancer center was compared with an already published historical control of patients treated in 1/2003–12/2009. A total of new 155 patients was analyzed, median age 60.9 years, 61% men, 58 patients (37%) underwent gross total tumor resection. Stupp's regimen was indicated in 90 patients (58%), 65 patients (42%) underwent radiotherapy alone. Median progression-free survival in Stupp's regimen cohort was 6.7 months, median OS 16.0 months, and 2-year OS 30.7%. OS was longer if patients were able to finish at least three cycles of adjuvant chemotherapy (median 23.3 months and 43.9% of patients lived at 2 years after surgery). Rapid early progression prior to radiotherapy was a negative prognostic factor with HR 1.87 (p = 0.007). The interval between surgery and the start of radiotherapy (median 6.7 weeks) was not prognostically significant (p = 0.825). The median OS in the current cohort was about 2 months longer than in the historical control group treated 10 years ago (16 vs. 13.8 months) using the same Stupp's regimen. Taking into account differences in patient's characteristics between current and historical cohorts, age, extent of resection, and ECOG patient performance status adjusted HR (Stupp's regimen vs. RT alone) for OS was determined as 0.45 (p = 0.002).
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Increasing interest in studying the role of vitamin D in cancer has been provided by the scientific literature during the last years, although mixed results have been reported. Vitamin D deficiency has been largely associated with various types of solid and non-solid human cancers, and the almost ubiquitous expression of vitamin D receptor (VDR) has always led to suppose a crucial role of vitamin D in cancer. However, the association between vitamin D levels and the risk of solid cancers, such as colorectal, prostate and breast cancer, shows several conflicting results that raise questions about the use of vitamin D supplements in cancer patients. Moreover, studies on vitamin D supplementation do not always show improvements in tumor progression and mortality risk, particularly for prostate and breast cancer. Conversely, several molecular studies are in agreement about the role of vitamin D in inhibiting tumor cell proliferation, growth and invasiveness, cell cycle arrest and inflammatory signaling, through which vitamin D may also regulate cancer microenvironment through the activation of different molecular pathways. More recently, a role in the regulation of cancer stem cells proliferation and short non-coding microRNA (miRNAs) expression has emerged, conferring to vitamin D a more crucial role in cancer development and progression. Interestingly, it has been shown that vitamin D is able not only to potentiate the effects of traditional cancer therapy but can even contribute to overcome the molecular mechanisms of drug resistance—often triggering tumor-spreading. At this regard, vitamin D can act at various levels through the regulation of growth of cancer stem cells and the epithelial–mesenchymal transition (EMT), as well as through the modulation of miRNA gene expression. The current review reconsiders epidemiological and molecular literature concerning the role of vitamin D in cancer risk and tumor development and progression, as well as the action of vitamin D supplementation in potentiating the effects of drug therapy and overcoming the mechanisms of resistance often triggered during cancer therapies, by critically addressing strengths and weaknesses of available data from 2010 to 2020.
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The poor therapeutic effect of the current treatments for malignant glioma may be attributed to glioma stem cells (GSCs), which have been demonstrated to divide symmetrically. All-trans retinoic acid (ATRA)-induced differentiation is considered to target GSCs and has been reported to have the capability of eradicating cancer stem cells in specific malignancies. The aim of the present study was to investigate the effects of ATRA on the division mode of GSCs isolated from the U87MG glioblastoma cell line of unknown origin. The expressions of the GSC markers CD133 and nestin were detected using immunocytochemistry to identify GSCs. In addition, the differentiation potency of these GSCs was observed by detecting the expression of glial fibrillary acidic protein, β-tubulin III and galactosylceramidase using immunofluorescent staining. The Numb protein distribution was analyzed in two daughter cells following a GSC division. The results of the present study demonstrated that Numb protein is symmetrically segregated into two daughter cells during GSC division. Furthermore, the present study demonstrated that treatment with ATRA increased the asymmetric cell division of GSCs. In conclusion, these results suggest a therapeutic effect from ATRA-induced asymmetric division of GSCs from the U87MG cell line.
As a major therapeutic approach for cancer treatment, the effectiveness of chemotherapy is challenged by multidrug resistance (MDR). Herein, we fabricated novel redox-responsive, chondroitin sulfate-based nanoparticles that could simultaneously deliver quercetin (chemosensitizer), chlorin e6 (photosensitizer) and paclitaxel (chemotherapeutic agent) to exert enhanced chemo-photodynamic therapy for overcoming MDR and lung metastasis of breast cancer. In vitro cell study showed that nanoparticles down-regulated the expression of P-glycolprotein (P-gp) on MCF-7/ADR cells and thereby improved the anticancer efficacy of PTX against MCF-7/ADR cells. Moreover, NIR laser irradiation could induce nanoparticles to generate cellular reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and meanwhile facilitating lysosomal escape of drugs. Importantly, the novel nanoplatform exhibited effective in vivo MDR inhibition and anti-metastasis efficacy through enhanced chemo-photodynamic therapy. Thus, the study suggested that the multifunctional nanoplatform had good application prospect for effective breast cancer therapy.
Conjugation of D-glucosamine with lipophilic moiety can ease its application in surface modification of liposomes. Interestingly, although D-glucosamine is safe, studies have shed light on “toxic effect” of its conjugates on cancer cells and highlighted its application in targeting glioma. However, understanding the safety of such conjugates for local delivery to the brain is unavailable. Herein, after successful synthesis of D-glucosamine conjugate (GC), the toxicity of functionalized liposome was evaluated both in vitro and in vivo. The study revealed a significant effect on cytotoxicity and apoptosis in vitro as assessed on grade IV-resistant glioma cell lines, SF268, U87MG, using MTT assay and PI staining. Additionally, this effect was not observed on normal human erythrocytes in the hemolysis assay. Furthermore, we demonstrated that GC liposomes were non-toxic to the normal brain tissues of healthy Sprague-Dawley rats. Successful functionalization yielded liposome with uniform particle size, stability, and cellular uptake. With < 10% hemolysis, all the liposomal formulations demonstrated hemato-compatibility but led to high glioma cytotoxicity. The surface density of conjugate played an important role in tumor toxicity (0.5 < 1.0 ≤ 2.0% molar ratio). PI staining revealed that compared to control cell, functionalization led 26-fold increase in induction of apoptosis in glioma cells. Absence of histological and behavioral changes along with the absence of caspase-3 in brain tissue confirmed the suitability of the system for direct infusion in the brain. Thus, this study will aid the future development of clinically useful local chemotherapeutic without “add-in” side effects.
A cross-kingdom tale of drug resistance Physicians who treat bacterial infections and those who treat cancer often face a common challenge: the development of drug resistance. It is well known that when bacteria are exposed to antibiotics, they temporarily increase their mutation rate, thus increasing the chance that a descendant antibiotic-resistant cell will arise. Russo et al. now provide evidence that cancer cells exploit a similar mechanism to ensure their survival after drug exposure (see the Perspective by Gerlinger). They found that human colorectal cancer cells treated with certain targeted therapies display a transient up-regulation of errorprone DNA polymerases and a reduction in their ability to repair DNA damage. Thus, like bacteria, cancer cells can adapt to therapeutic pressure by enhancing their mutability. Science , this issue p. 1473 ; see also p. 1458
The active vitamin D hormone, 1,25‐dihydroxyvitamin D3, exerts many physiological actions in the body, including effects on the nervous system. Studies of steroidogenesis in cells of the nervous system and elsewhere indicate that 1,25‐dihydroxyvitamin D3 affects steroidogenic pathways but suggest varying responses in different cell types. For instance, 1,25‐dihydroxyvitamin D3 stimulates expression of aromatase in human glioma but not in human neuroblastoma cells or rat astrocytes. However, in astrocytes 1,25‐dihydroxyvitamin D3 suppresses 3β‐hydroxysteroid dehydrogenase (3β‐HSD) and steroid 17‐hydroxylase/lyase (CYP17A1). Other studies indicate crosstalk between vitamin D signaling and signaling of estrogens, progesterone or glucocorticoids. Reported data indicate synergistic effects of combinations of 1,25‐dihydroxyvitamin D3 and other steroid hormones on neuroinflammation, neurite outgrowth and neuroprotection. Also, dysregulation of steroid pathways affecting brain cells is found in vitamin D deficiency. Thus, several studies suggest that active vitamin D may affect steroid hormone synthesis and/or signaling in the nervous system, though potential mechanisms for these responses remain unclear. 1,25‐Dihydroxyvitamin D3 suppresses proliferation in several cell types and is therefore of interest in cancer treatment. Also, epidemiological studies associate vitamin D levels with cancer risk or outcomes. Reported data on tumors of the nervous system are mainly on glioma, a common type of brain cancer. Expression of the vitamin D receptor (VDR) in glioma tumors is associated with improved survival. Several studies show that 1,25‐dihydroxyvitamin D3 and vitamin D analogs (synthetic vitamin D‐like compounds) suppress proliferation and migration in human VDR‐expressing glioma cell lines. Studies on mechanisms for actions of 1,25‐dihydroxyvitamin D3 or its analogs indicate regulation of cell cycle proteins and senescence markers. These compounds also show synergism in combinations with other cancer therapies treating glioma. From the data available vitamin D analogs emerge as interesting candidates for future improved treatment of human glioma and maybe also other cancers of the nervous system.
Melatonin is a ubiquitous indole amine that plays a fundamental role in the regulation of the biological rhythm. Disrupted circadian rhythm alters the expression of clock genes and deregulates oncogenes, which finally promote tumor development and progression. An evidence supporting this notion is the higher risk of developing malignancies among night shift workers. Circadian secretion of the pineal hormone also synchronizes the immune system via a reciprocal association that exists between the immune system and melatonin. Immune cells are capable of melatonin biosynthesis in addition to the expression of its receptors. Melatonin induces big changes in different immune cell proportions, enhances their viability and improves immune cell metabolism in the tumor microenvironment. These effects might be directly mediated by melatonin receptors or indirectly through alterations in hormonal and cytokine release. Moreover, melatonin induces apoptosis in tumor cells via the intrinsic and extrinsic pathways of apoptosis, while it protectsthe immune cells. In general, melatonin has a profound impact on immune cell trafficking, cytokine production and apoptosis induction in malignant cells. On such a basis, using melatonin and resynchronization of sleep cycle may have potential implications in immune function enhancement against malignancies, which will be the focus of the present paper. Melatonin as an important antioxidant regulates immune cells including lymphocytes, T cells, B cells, T‐reg and NK cells through controlling chemokine release and cortisol production. Melatonin can also change tumor microenvironment through mitochondrial regulation, apoptosis induction and suppression of oncogenes.