Complete objective response to biological therapy of plurifocal breast carcinoma
Complete objective response to biological therapy of plurifocal breast carcinoma (full PDF)
Abstract
In this case presentation, a woman with breast carcinoma who chose to try Prof. Luigi Di Bella’s biological therapy (DBM), was found, after seven months, to have a 50% reduction in objective measures of her carcinoma and was totally cured after 14 months. The patient’s recovery extended to bilateral axillary adenopathies, and took place without the toxicity normally associated with cancer treatment.
DBM entails the use of anti-proliferative molecules such as somatostatine, prolactin, and estrogen inhibitors, along with differentiating and apoptotic molecules such as melatonin, retinoids, vitamins C, D3, and E, calcium, and amino sugars, combined with minimal doses of chemotherapy. The hemato-chemical exams showed no damage, with a progressive reduction of prolactin, estradiol, IGF1, and maintenance of low levels of GH.
The achievement of objective results, without toxicity, in this case, proves the effectiveness of this therapy and confirms the positive results already published on the use of MDB for Low-Grade NHL, and pulmonary carcinomas in the 3rd and 4th stages. DBM, without the need for either hospitalization or day hospitalization, without toxicity, and without even minimally reducing the patient’s daily work routine, allowed the patient to avoid surgical trauma and the significant collateral effects of chemotherapy and radiotherapy.
Timely use of DBM as the first line therapy, in a patient which had not been debilitated by the mutagenic, toxic, and immuno-depressive effects of chemo- and radiotherapy, contributed greatly to the final outcome. We feel it is useful to highlight this case in an effort to stimulate interest and further study into the oncological potential of DBM biological and receptor therapy.
INTRODUCTION
The following is a case of complete remission of a multifocal mammary carcinoma in a 51 year old woman. The carcinoma had 3 distinct locations in the left breast, had infiltrated both ducts and lobes, and exhibited bilateral microfibrocystic alterations with evident bilateral reactive axillary lymphadenopathy. Additionally, 2 small cerebral lesions of, suspected, but unconfirmed metastatic origin were revealed by contrast MRI.
The following are the essentials of the DBM (Di Bella Method) biological therapy carried out, and the histological and hemato-chemical tests, in addition to the diagnostic tests, performed before and after MDB treatment. Additionally we provide an extremely synthesized description of the MDB rationale, with documentation of the scientific basis for the treatment.
CLINICAL CASE
The patient was 51 years old female, weighing 62 kg, and having 2 children. She was 11 years old at menarche, had a history of regular menstruation, and had taken estro-progestogen birth control pill since age 45. On examination the patient’s nipples appeared normal; ducts dilated, and absent secretions. The first symptoms appeared in January 2006.
Diagnosis and therapy, which was formulated by the “Centro Diagnostico Terapeutico per la Mammella” (Diagnostic Therapeutic Center for Breasts) - Oncology Institute of the University of Ferrara – Italy, reported the following: “Micro-cystic macro-cystic mastopathy with some macro-cystic areas and ductal ectasy, discrete adipose component, mainly pre-glandular. Axillary lymphadenopathy more pronounced on the left side with no evident architectural disorganization".
- Location: upper-internal left quadrant;
- Distance from cutis: 3.6 mm;
- Distance from nipple: 22 mm;
- Edges indistinct;
- Low echogenicity;
- Reduced subcutaneous adipose stratum;
- Age tumor appeared: 51 years;
- Distance from fascia: 1.0 mm;
- Dimensions (the largest of 3 neoplasms) 13.8 mm × 15.7 mm × 11 mm;
- Margins of neoplasm finely irregular;
- Cutaneous echogenicity normal;
- Reduced retro adipose stratum.
Proliferative processes
- Left breast in 9 a.m. ray 10 mm × 11 mm × 9.7 mm to 3.6 mm from cutis and to 2.6 mm from fascia, to 30 mm from nipple;
- From 11 a.m. ray to 11.30 of 13.6 mm × 11 mm × 15.7 mm of the upper-internal quadrant of left breast;
- Of upper left haemitelic line of 5.5 mm × 4.4 mm × 4.4 mm;
Core Biopsies of lesions 1) and 2) were performed and sent for examination to the University of Ferrara’s Department of Pathology and Oncology, which formulated the following histopathological diagnosis:
- "Infiltrating ductal carcinoma, coexisting pagetoid propagation of globular in situ carcinoma of ducts.";
- "Infiltrating ductal and lobular carcinoma; coexisting lobular in situ carcinoma.".
Six frustules of the core biopsy were sent for consultation to the Institute of Pathological Anatomy at the University of Bologna – Bellaria Hospital, which reported the following: "2nd degree invasive ductal carcinoma, associated with in situ carcinoma, probably globular (B5)!".
Immunohistochemical diagnosis (Figures "Histological finds 1-4" below):
Estrogen Receptor: 99.5% positive;
Progesterone Receptor: 80.4% positive;
Expression of EGF Receptor: 0.00%.
Additional diagnostic tests (Figures "Mammogram 1-2" below):
February 9, 2006: X-ray (mammogram).
February 15, 2006: Breast ultra-sound (Figures "Ultrasound scans 1-3" below). Diagnostic conclusions from the University of Ferrara’s: “Left mammary neoplasia (infiltrating globular and ductal carcinoma), cerebral alteration of unidentified histological nature". The proposed therapy consisted of: total mastectomy with removal of axillary lymph nodes followed by radio-chemotherapy.
At the end of the clinical report, issued to the patient on March 14, 2006, the following was highlighted: “We strongly suggest that surgery not be postponed!".
March 22, 2006: The patient, refused the suggested treatment plan and began Prof. Luigi DiBella’s biological therapy (MDB).
Diagnostic tests carried out during MDB treatment.
October 18, 2006: Approximately 7 months after initiation of MDB treatment, an ultra-sound showed that the bilateral axillary adenopathy of 2 of the 3 neoplastic lesions had disappeared, and the residual tumor size had been reduced to 9 mm. Report: “Non-homogeneous glandular structures with small scattered cystic areas and ectatic ducts in the areolar areas. In the upper left sector of the left breast, at 11 a.m., a hypoechogenic area with irregular edges with a long axis of 9 mm. No other suspicious elements, with the exception of small areas of architectural disorder in the left inferomedial sector; no axillary, supraclavicular or, as far as can be seen, internal mammary adenopathies".
December 14, 2006: After an additional 2 months, (nine months total), an ultra-sound documented further reductions in tumor size; “The current examination compared to the previous one of February 2006, shows that the expansive infiltrative formation noted in the left breast at 11:30 a.m. is reduced in size and currently measures 6 mm. No pathological images on the right breast. We advise eco-mammography checks in view of the relative density of the glandular component".
April 5, 2007: Ultrasound: “No structural alterations in the right breast. In the upper internal quadrant of the left breast, near the median sagittal plane, the hypoechogenic area with irregular margins previously examined by needle aspiration, with extenuation of the ultra-sound tractus of 5.8 × 3.8 × 5.1 mm. The most superficial margin of this formation is one centimeter from the cutaneous plane and approximately 3 mm from the muscular fascia. No lymphadenopathy suspected in the axillary and supraclavicular regions".
August 28, 2007: Bilateral MRI (Magnetic Resonance Imaging) with and without contrast: “In the T2 sequence weighed in the context of both glandular bodies, some minute cystic formations can be seen. After administration of the contrast substance, there were no areas with bilaterally suspect enhancement. Specifically there were no expansive formations in correspondence to the hypoechogenic area with posterior acoustic obstruction as previously described in the ultra-sound exam".
September 18, 2007: Total corporeal bone and articular scintigraphy: negative! (Figure below).
September 20, 2007: Chest X-ray: negative!
September 20, 2007: Complete abdominal ultrasound: negative!
October 12, 2007: PET confirms the absence of neoplastic lesions: “The PET with 18 F-FDG did not show the presence of areas of pathological accumulation of the radiopharmaceutical ascribable to lesions with high metabolic activity.” (Figure below).
October 22, 2007: Mammographic ultrasound and X-ray were also negative and confirm remission: “Breasts rich in glandular tissue with galactophorous ducts in evidence and some periareolar galactocele without nodular images, suspected micro-calcifications, or infiltrative signs. Ultra-sound showed the presence of some cysts of maximum 5.6 mm diameter in the right breast. No solid nodular formations." (Figure "Mammogram 3, 4" below).
March 3, 2008: Breast ultrasound shows disappearance of neoplastic lesions, and stable result: “Breasts rich in glandular tissue with galactophorous ducts in evidence and also periareolar galactocele prevalent on the left. Scattered cysts are present in all quadrants with a maximum diameter of 3 mm but with no solid nodular images or infiltrative signs. Check-up advised in approximately 6 months.” (Figure "Ultrasound scans 4, 5" below).
RESULTS
Therapy and Clinical Course
The patient, after having refused a total mastectomy followed by chemo- and radiotherapy, which had been proposed by the Diagnostic Therapeutic Center for Breasts - Oncology Institute of the University of Ferrara (Italy), asked to be treated with the DiBella Method, which entails the synergic use of molecules with cytostatic, apoptotic, and antiproliferative differentiating action with an increase in immune system activity and in addition, for apoptotic reasons, minimum doses (non cytotoxic, cytolytic and therefore non mutagenic) of hydroxyurea. Hydroxyurea was used as a substitute for 100 milligrams of cyclophosphamide (which is normally part of the MDB protocol) to treat the cerebral lesions of repetitive neoplastic nature in view of its ability to overcome the hematoencephalic barrier. Continuous administration of 1000 milligrams per day of hydroxyurea, over a period of approximately 10 months could have proven toxic had it not been for the concomitant administration of MLT, vitamin E, retinoids, vitamins C and D3, which effectively countered hydroxyurea toxicity. It did not cause any changes in hemopoiesis or medullar dynamics. The patient administered the therapy at home while maintaining a quality of life that allowed her to continue her intense and busy entrepreneurial activities.
Active Ingredients [components of the prescribed therapy (MDB)]:
- Somatostatine (14 amino acids) (SST):Injected under the skin at night over the space of 10 hours with a programmable infusion pump, extended infusions were necessary due to short half-life of SST (about 3 minutes) and to coincide with the nighttime peak of incretion of GH;
- Octreotide, analogous to somatostatine (eight amino acids) and lag time formulation, 30 mg intramuscular every 25 days, for complete receptor and temporal saturation, with the same anti-proliferative and pro-apoptotic objective as somatostatine;
- Bromocriptine 2.5 mg 1\2 tablet morning and evening to inhibit prolactin, a powerful and ubiquitous mitogenic hormone;
- Cabergoline 1\2 tablet, 2 times a week, to reinforce the effects of bromocriptine, cabergoline also has a markedly longer half-life;
- Vitamin solution, according to Prof. DiBella’s formula: Betacarotene 2g - Palmitate axerophthol 1g - All-trans retinoic acid (ATRA) 1g - Alpha-tocopherol 1000g. One medium spoonful (100 mg × Kg of body weight), at least 15 minutes before eating, 3 times a day;
- Dihydrotachysterol (Vitamin D3 synthesis): 10 drops in the same spoon along with the vitamin compounds (i.e. 30 drops per day);
- Chemically complexed melatonin (2 mg) with adenosine (by means of a hydrogen link) and glycine, according to Prof. DiBella’s formula [12% melatonin, 51% adenosine, and 37% glycine]: 12 tablets per day;
- Anastrozole (Aromatase inhibitor) 1 mg , one tablet per day;
- Hydroxyurea 500 mg tablet, one tablet twice a day (morning and evening) for approximately 10 months;
- Calcium 1 g, 2 times a day, taken with ascorbic acid;
- Ascorbic Acid 2 g, taken with calcium in a glass of water, 2 times a day with meals;
- Glucosamine sulfate + Galactosamine sulfate 1500 mg, 3 times a day.
Prof. Luigi DiBella’s neuro-immune-endocrine biological therapy (MDB) slowly and progressively obtained a complete, objective response, without toxicity, with a mechanism of receptor differentiating apoptotic and anti-proliferative actions, with criteria, aims and mechanisms of action completely different from the usual cytotoxic and cytolytic therapy. The success of which demonstrates its ability to substitute for surgery, radiotherapy and/or chemotherapy; keeping in mind that radiotherapy and/or chemotherapy are not substitutes for surgery, but can precede and/or follow it.
In this case, due to the multifocal neoplasms (with bilateral axillary adenopathy) a surgical solution with a total mastectomy with axillary lymph node removal followed by chemo-radio therapy was planned and strongly advised by the university oncology institute, and which was subsequently refused by the patient. The objective response of DBM (Di Bella Method or MDB Metodo Di bella - Italian language) went as far as resolving both the axillary lymphadenopathy and the endocranial lesions of dubious secondary nature.
DISCUSSION
Rationale of the therapy
The loss of differentiation and proliferation, even if to different extents, are common denominators of all neoplasms. The ubiquitous receptor expression of prolactin [9, 23] and GH [32, 14] are one of the confirmations of the direct and generalized mitogenic role of this molecule.
Cellular proliferation is highly dependent on prolactin and GH, both powerful growth factors, and on GH dependent mitogenic molecules which are positively regulated by it, such as EGF, FGF, HGF, [IGF1-2, NGF, PDGF] VEGF, and TGF in addition to growth factors produced by the gastrointestinal tract, such as VIP, CCK, and PG. Both physiological as well as neoplastic cellular proliferation take place by means of these same molecules, which the neoplastic cells use to an exponential extent compared to healthy ones. Biological antidotes of GH such as somatostatine and similar compounds, reduce not only the expression and transcription of highly mitogenic growth factors, such as IGF1-2 [12, 50, 53], EGF [22], and FGF [42], but extend their negative regulation to the respective receptors with evident anti-proliferative and anti-angiogenic effects [56, 43].
The extent of the GH-IGF1 axis influence on neoplastic biological development is worth noting. The IGFRs respond mitogenically to IGF. The suppressive effect of the SST and similar ones, on serum levels of IGF1, is both direct, by inhibiting the IGF1 gene, as well as indirect by suppressing GH and thus its hepatic induction of IGF1. Angiogenesis is essential to neoplastic progression. Angiogenesis is in turn regulated by the fall of monocytes, interleukin 8, and by growth factors such as VEGF, TGF, IGF1, FGF, HGF, and PDGF. Each of these factors is negatively regulated by somatostatine and similar drugs [2, 5, 12, 18, 26, 59, 60, 62, 63].
The inhibition of angiogenesis induced by SST is synergistically enhanced by MLT [33, 15, 16], retinoids [40, 28, 36], Vitamin D3 [29, 39], Vitamin E [55, 57, 45], vitamin C [3], prolactin inhibitors [59], and components of the extra-cellular matrix [34, 47].
Likewise the cytostatic, anti-proliferative, and antimetastatic effect of somatostatine is effectively synergized by MDB’s other components:
- Retinoids [20, 61, 48, 46];
- Melatonin [7, 31, 41, 35, 13];
- Vitamin D3 [25, 6, 11];
- Cabergoline and Bromocriptine (prolactin inhibitors) [19, 9, 33, 30, 38];
- Glucosamine sulphate, Galactosamine sulphate, components of the extra-cellular matrix [51, 8];
- Vitamin E [58, 24, 37, 45, 55];
- Vitamin C [21, 44, 10].
The causal relationship between GH’s receptor expression and tumor induction and progression has been shown [32], histochemically demonstrating markedly higher concentrations of GHR in tumor tissues compared to physiological tissues, thus showing the powerful mitogenic role of GH with proliferative indices depending on dose. This is direct, via receptors, as well as indirect, by inducing hepatic expression of IGF1, which is GH dependent. The GH-IGF1 axis has a decisive role in the biological behavior of many neoplasms. In a very high percentage of neoplastic cells, IGF1 receptors have been identified which respond mitogenically to the ligand. Somatostatine exerts an antiblastic effect both directly, by inhibiting the IGF1 gene’s expression, as well as indirectly, by suppressing GH, which is needed for IGF1 incretion [50, 53, 54].
The SST inhibiting activity on EGF, another powerful mitogenic growth factor, with multiple mechanisms, has also been thoroughly documented:
- Depending on the dosage, inhibition of tyrosine phosphorylation induced by the activation of EGFR by EGF [43];
- Reduction of EGFR in tumor cells [56];
- Reduction of EGF’s expression [22];
- Reduction of EGF’s plasma concentration [12].
Mitogens produced by the gastrointestinal tract such as VIP, CCK, and PG are strongly inhibited by somatostatine and/or octreotide [27].
It has been shown that breast tumors express SSTR1, SSTR2, and SSTR3, and less frequently SSTR5 [1, 52], which in at least 50% of cases are scintigraphically visible, while in over half of the negative scintigraphs histochemical examinations revealed the presence of SSTR. Therefore the presence of SSTR [1, 4, 49, 17], and of neuro-endocrine receptors in a significant percentage of these carcinomas constitutes a further rational indication for using SST, which in any case has already been extensively justified by the above-cited negative effect of SST on GH, GH-correlated oncogenes and angiogenesis. The efficacy of somatostatine and/or octreotide is enhanced by a factorial synergic mechanism with MDB’s other components. The literature thus confirms the differentiating anti-neoplastic, anti-proliferative, anti-angiogenic, and anti-metastatic action mechanisms of all MDB’s components. In this case the hematochemical exams did not show any damage, but rather a progressive reduction of prolactin, estradiol, and IGF1 and maintenance of low levels of GH. The objective result, in the absence of toxicity, by progressively reducing, to disappearance, the 3 initial neoplastic lesions, the axillary adenopathy, the suspected cerebral lesions, and blockage of all metastatic dissemination, proves the effectiveness of the therapy and agrees with the positive results already published on the use of MDB on low level NHL and pulmonary carcinomas in the 3rd and 4th stages. MDB, without the need for hospitalization or even day hospitalization, in the absence of toxicity and without even a minimal reduction in the patient’s daily work routine, avoided surgical trauma and the significant collateral effects of chemo- and radio-therapy.
We believe the timely use of MDB, as the first line treatment, in patients which have not been debilitated by the toxic, mutagenic, or immuno-depressive effects of chemo-radiotherapy, can greatly facilitated the results. We feel it is useful to highlight this case in order to stimulate greater interest, study, and investigation into the possibilities opened up in oncology by MDB’s immuno-neuro-endocrine, biological and receptor therapy.
Complete objective response to biological therapy of plurifocal breast carcinoma
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