Comparative real-world outcomes of dupilumab versus endoscopic sinus surgery in the treatment of severe CRSwNP patients.

INTRODUCTION: Management of severe chronic rhinosinusitis with nasal polyps (CRSwNP) has changed significantly in recent years, with different treatments now available including biologics and endoscopic sinus surgery (ESS), although there are still few comparative studies. We aimed to compare 1-year outcomes of patients with severe CRSwNP treated with dupilumab or ESS plus intranasal corticosteroids (INCS). METHODS: In this retrospective, real-life, observational, cohort study, we enrolled 101 patients with severe CRSwNP who were treated with INCS and either ESS (n = 49) or dupilumab (n = 52). The following outcomes were considered: nasal polyp score (NPS), Sino Nasal Outcome Test-22 (SNOT-22), visual analogue scale (VAS) for specific symptoms, Sniffin' Sticks identification test (SSIT), need for oral corticosteroids (OCS) and local eosinophilia detected by nasal cytology. RESULTS: ΔNPS was significantly higher in the surgery group up to 12 months when the difference with dupilumab group was no longer significant (ΔNPS: 4 vs. 4.1). ΔVAS rhinorrhoea, ΔVAS smell and ΔSNOT-22 were significantly higher in the dupilumab group at 12 months (p < .05). SSIT scores were significantly better in the dupilumab group starting from the first month of follow-up (p < .05). In the dupilumab group, only 6.1% of patients had detectable local eosinophilia compared to 57% in the surgery group alongside with a lower need for OCS (16.3% vs. 61%). CONCLUSIONS: Both dupilumab and ESS were effective in improving outcomes in patients with severe CRSwNP over 12 months. Nevertheless, patients treated with dupilumab had greater improvement in terms of SNOT-22, VAS rhinorrhoea, VAS smell and SSIT scores, with better control of local inflammation and less need for OCS.

How to manage recurrences after surgery in CRSwNP patients in the biologic era: a narrative review.

Objective: This narrative review analyses factors affecting recurrence of Chronic rhinosinusitis with nasal polyps (CRSwNP) after surgery, such as type, extension and completeness of endoscopic sinus surgery (ESS). We also described new implications in the management of recurrences after the advent of biologics. Methods: We identified four topics: definition of disease state; factors linked to recurrence of polyps; evaluation and management of recurrence in clinical practice. Results: We analysed the differences between exacerbation and recurrence, as well as the concept of "controlled disease". We focused on potential predictors of recurrence after ESS, such as type 2 inflammation, asthma, aspirin-exacerbated respiratory disease, incomplete initial surgery and lack of adherence to long-term post-operative local corticosteroids. We discussed the new aspects of diagnosis and treatment of recurrences after surgery, summarising our suggestions in a detailed algorithm for practical management of patients with recurrent disease. Conclusions: The results emphasised the importance of accurate evaluation of patients with CRSwNP recurrence, focusing on the reasons of failure and risk of disease progression, in order to guide personalised interventions. It is crucial to define the concept of appropriate surgery, which affects the choice between starting a biologic or repeating surgery.

A retrospective observational study on cases of osteosarcomas treated with a multitherapy: The rationale and effectiveness.

BACKGROUNDS: The prognosis of patients with osteosarcoma in many cases remains poor, and life expectancy with lung metastases is around 12 months. Chemotherapy and radiotherapy can only temporarily control neoplastic progression, followed by developing chemo and radioresistant tumours. METHODS: This is a retrospective observational study on 15 patients diagnosed with osteosarcoma and treated by a multitherapy approach. The multitherapy consisted of somatostatin and analogous (octreotide) all-trans-retinoic acid (ATRA), ß-Carotene, axerophthol dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT), proteoglycans, glycosaminoglycans, hydroxyurea, and sodium butyrate. RESULTS: This multitherapy increased the survival rate and life quality, without overt toxicity, compared to the standard treatment for osteosarcomas. The agents in this approach have several functions. They exert antiproliferative, antiangiogenic, cytostatic, antioxidant, antimetastatic, and immunomodulating features. Moreover, the inclusion of ATRA, MLT, and sodium butyrate has reinforced antitumor properties on cancer stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic hydroxyurea dosage increased the biological therapy outcome by strengthening antitumor capability. FINDINGS: This multitherapy approach is effective against osteosarcoma. INTERPRETATION: The multistrategy of this multitherapy therapy 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.

Sinonasal Biomarkers Defining Type 2-High and Type 2-Low Inflammation in Chronic Rhinosinusitis with Nasal Polyps.

The complex pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) generates a spectrum of phenotypes with a wide variety of inflammatory states. We enrolled 44 very-likely-to-be type 2 CRSwNP patients in order to evaluate the load of inflammation and to analyze human interleukins in nasal secretion. Clinical data were collected to evaluate the severity of the disease. High levels of IL-5, IL-4, IL-6, and IL-33 were detected in all type 2 CRSwNP patients. By analyzing type 2 cytokine profiles and local eosinophil count, we identified two coherent clusters: the first was characterized by high levels of IL-4, IL-5, IL-6, and a high-grade eosinophil count (type 2-high); the second had lower levels of cytokines and poor or absent eosinophilic inflammation (type-2 low). IL-5 levels were significantly higher within the type 2 cytokine and it was the most reliable biomarker for differentiating the two clusters. In type 2-high inflammatory profile clinical scores, the mean number of previous surgeries and need for systemic corticosteroids were significantly higher compared to type 2-low. Our research demonstrated the potential role of type 2 biomarkers, and in particular, of IL-5 in identifying patients with a more severe phenotype based on a high inflammatory load.

Effectiveness of Dupilumab in the Treatment of Patients with Severe Uncontrolled CRSwNP: A "Real-Life" Observational Study in the First Year of Treatment.

The aim of this study was to evaluate the efficacy of dupilumab in the treatment of severe uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), with or without asthma as add-on therapy with intra-nasal corticosteroids in a real-life setting over the first year of treatment. Our data demonstrated that subcutaneous 300 mg dupilumab administered at home via a pre-filled auto-injector every two weeks, based on indications set by the Italian Medicines Agency, was rapidly effective in reducing the size of polyps, decreasing symptoms of disease, improving quality of life, and recovering olfaction. Significant improvement was observed after only 15 days of treatment, and it progressively increased at 6 and 12 months. Dupilumab was also effective in reducing the local nasal eosinophilic infiltrate, in decreasing the need for surgery and/or oral corticosteroids, and in improving control of associated comorbidities such as chronic eosinophilic otitis media and bronchial asthma. After 12 months of treatment, 96.5% of patients had a moderate/excellent response. From our data, it was evident that there was a group of patients that showed a very early response within one month of therapy, another group with early response within six months from baseline, and a last group that improved later within 12 months. The results of this study support the use of dupilumab as an effective option in the current standard of care for patients affected by severe uncontrolled CRSwNP.

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

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), ß-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.

Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes.

Breast cancer is a worldwide commonly found malignancy in women and effective treatment is regarded as a huge clinical challenge even in the presence of several treatment options. Extensive literature is available demonstrating polyphenols as phytopharmaceutical anticancer agents. Among the polyphenols, quercetin and curcumin have been reported to have a strong potential against breast cancer. However, so far, no comprehensive study has been performed to demonstrate the anticarcinogenic effects of curcumin, quercetin, and their combinations with somatostatin on the fatty acid profile of breast cancer cell membranes. We used MCF-7 and MDA-MB231 breast cancer cells incubated with curcumin and quercetin for 24 h, in the absence and presence of somatostatin, at their EC50 concentrations to evaluate membrane fatty acid based functional lipidomics together with the followup of EGFR and MAPK signaling pathways. The two cell lines gave different membrane free fatty acid reorganization. In MCF-7 cells, the following changes were observed: an increase of ω6 linoleic acid in the cells incubated with somatostatin + quercetin and quercetin and a decrease of ω3 acids in the cells incubated with somatostatin + curcumin compared to somatostatin and significant increases of monounsaturated fatty acid (MUFA), mono-trans arachidonic acid levels and docosapentaenoic acid for the cells incubated with somatostatin + quercetin compared to the control cells. In MDA-MB231 cells, incubations with curcumin, quercetin, and somatostatin + quercetin induced the most significant membrane remodeling with the increase of stearic acid, diminution of ω6 linoleic, arachidonic acids, and ω3 (docosapentaenoic and docosahexaenoic acids). Distinct signaling pathway changes were found for these cell lines. In MCF-7 cells, separate or combined incubations with somatostatin and quercetin, significantly decreased EGFR and incubation with curcumin decreased MAPK signaling. In MDA-MB231 cells, incubation with curcumin decreased AKT1 and p-AKT1 (Thr308) levels. Incubation with curcumin and quercetin decreased the EGFR levels. Our results showed that cytostatic and antioxidant treatments can be combined to induce membrane fatty acid changes, including lipid isomerization as specific free radical driven process, and to influence signaling pathways. This study aimed to contribute to the literature on these antioxidants in the treatment of breast cancer to clarify the effects and mechanisms in combination with somatostatin.

Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes.

BACKGROUND: Vitamin C (Vit C) is an important physiological antioxidant with growing applications in cancer. Somatostatin (SST) is a natural peptide with growth inhibitory effect in several mammary cancer models. OBJECTIVE: The combined effects of SST and Vit C supplementation have never been studied in breast cancer cells so far. METHODS: We used MCF-7 and MDA-MB231 breast cancer cells incubated with SST for 24h, in the absence and presence of Vit C, at their EC50 concentrations, to evaluate membrane fatty acid-profiles together with the follow-up of EGFR and MAPK signaling pathways. RESULTS: The two cell lines gave different membrane reorganization: in MCF-7 cells, decrease of omega-6 linoleic acid and increase of omega-3 fatty acids (Fas) occurred after SST and SST+Vit C incubations, the latter also showing significant increases in MUFA, docosapentaenoic acid and mono-trans arachidonic acid levels. In MDA-MB231 cells, SST+Vit C incubation induced significant membrane remodeling with an increase of stearic acid and mono-trans-linoleic acid isomer, diminution of omega-6 linoleic, arachidonic acid and omega-3 (docosapentaenoic and docosadienoic acids). Distinct signaling pathways in these cell lines were studied: in MCF-7 cells, incubations with SST and Vit C, alone or in combination significantly decreased EGFR and MAPK signaling, whereas in MDA-MB231 cells, SST and Vit C incubations, alone or combined, decreased p- P44/42 MAPK levels, and increased EGFR levels. CONCLUSION: Our results showed that SST and Vit C can be combined to induce membrane fatty acid changes, including lipid isomerization through a specific free radical-driven process, influencing signaling pathways.

The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity.

The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1-2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to overcome the need for continuous infusion regimes. Multilamellar liposomes made of natural phosphatidylcholine were used for the incorporation of a mixture of somatostatin and sorbitol dissolved in citrate buffer at pH = 5. Lyophilization and reconstitution of the suspension were carried out, showing the flexibility of this preparation. Full characterization of this suspension was obtained as particle size, encapsulation efficiency and retarded release properties in aqueous medium and human plasma. Liposomal somatostatin incubated at 37 °C in the presence of Fe(II) and (III) salts were used as a biomimetic model of drug-cell membrane interaction, evidencing the free radical processes of peroxidation and isomerization that transform the unsaturated fatty acid moieties of the lipid vesicles. This study offers new insights into a liposomal delivery system and highlights molecular reactivity of sulfur-containing drugs with its carrier or biological membranes for pharmacological applications.

The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature.

The interaction between pituitary hormones, GH - PRL, and Growth Factors, GF, plays a fundamental role in the physiological and neoplastic mechanisms of growth, the latter using these factors to a much greater extent compared to the former, with a direct dose-dependent effect on the speed of local or metastatic expansion. In hormone-dependent tumours, the respective male and female sex hormones interact with GH - PRL - GF to sustain the expansion of the tumour. We carried out a review of the literature on the relationship between the expression of GH and GHR in tumour tissues compared to healthy tissues, and on the correlation between this expression and tumour aggressiveness. An over-expression of GH and GHR in tumours was a constant finding. In more than a thousand cases published in various clinical, observational, retrospective studies investigating cervico-facial tumours, lymphoproliferative diseases, breast cancer, prostate cancer, non-small-cell lung cancer, neuroblastomas, oesophageal cancer, glioblastomas, and sarcomas, we constantly found an improvement in objective response, quality of life and survival, compared to conventional oncological protocols, by inhibiting GH and correlated GF using somatostatin.

Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast.

Breast cancer is the most common cancer and the leading cause of cancer death among women. Despite all efforts, about 11,939 deaths and 50,000 new diagnoses for breast cancer were estimated among Italian women in 2016. Therefore new approaches are needed to improve the survival and higher remission rates. We present a case of a woman with carcinoma of the breast and multiple metastases after right mastectomy, axillary dissection, repeated cycles of chemo and radiotherapy, and estrogen block. Biological method formulated by Prof. L. Di Bella (DBM) produced a complete and stable objective response without toxicity. The DBM includes antiproliferative molecules, such as somatostatin, prolactin and estrogen inhibitors together with differentiating and apoptotic molecules such as melatonin (MLT), Retinoids, Vitamin E, D3, Vit. C, Calcium, Amino sugars, associated with metronomic microdoses of chemotherapy drugs. The blood tests did not show any damage but a progressive reduction of Prolactin, Estradiol, and IGF1, and continuing low levels of GH. The objective result of this case, in the absence of toxicity, demonstrates the efficacy of the treatment and is in agreement with the positive results already published on the use of the DBM. Not requiring hospital or day hospital admission, and with no significant toxicity, the DBM avoided the significant side effects of chemo- and radiotherapy. We believe that this case can encourage more interest and more in-depth studies on the possibilities that have been opened up in oncology by the DBM treatment of the metastatic breast cancer.

Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings.

Melatonin has shown the potential to inhibit growth of different tumors, both in vitro and in vivo. There is clear evidence that the administration of melatonin alone or in combination with chemo and radiotherapy in cancer patients with advanced solid tumors has been associated with improved outcomes of tumor regression and survival. Moreover, chemotherapy has been shown to be better tolerated in patients treated with melatonin. However, there are different ways of preparation and administration of melatonin to the patient. This review article aims to offer the insight into the preparation, biological features and clinical findings in its use in cancer patients. Melatonin (MLT) can only be solubilized in water at 40-45 °C; at other temperatures it can only be solubilized in alcohol. It is absorbed in the human body complexed with adenosine by a hydrogen bond. It acts on two common denominators: proliferation and differentiation; in addition to anticancer homeostasis, MLT has a documented antidegenerative and immunomodulatory role. It also plays an important role in limiting oxidative stress, affecting blood and bone marrow constituent ratio, leukocyte formula regulation, hemoglobin synthesis, platelet genesis, aggregation and in erythrocyte resistance. Despite of all these important roles, most well-known features are probably the least important ones, such as sleep and wakefulness regulation and its effect on jet lag. In the preparation formulated by Prof. Di Bella, melatonin with adenosine at a ratio of 1:4, stabilized with 30% of glycine (MLT-DBM), has been used since 1994 in many patients with various indications and positive therapeutic responses and a total absence of toxicity. This method can be a good alternative to commercially produced preparations, as it was scientifically proved and published worldwide at conferences and in various medical journals.

Recurrent Glioblastoma Multiforme (grade IV - WHO 2007): a case of complete objective response - concomitant administration of Somatostatin / Octreotide, Retinoids, Vit E, Vit D3, Vit C, Melatonin, D2 R agonists (Di Bella Method.

In a 41 year old man, with Glioblastoma Multiforme (Grade IV - WHO 2007) and loco-regional recurrence, treated conventionally with surgery, radio-therapy and Temolozomide, a complete objective response was subsequently achieved by means of the well-tolerated concomitant administration of Somatostatin + slow-release Octreotide, Melatonin, Retinoids solubilized in Vitamin E, Vit D3, Vit C, D2 R agonists, and Temolozomide. In addition to the positive and previously unreported therapeutic finding, this result allowed the patient to avoid further surgical trauma and the correlated risks, achieving an excellent quality of life and working capacity.

Congenital fibrosarcoma in complete remission with Somatostatin, Bromocriptine, Retinoids, Vitamin D3, Vitamin E, Vitamin C, Melatonin, Calcium, Chondroitin sulfate associated with low doses of Cyclophosphamide in a 14-year Follow up.

At birth, a male child presented a 6 cm tumour in the right leg. The tumour was partially removed after just 12 days. Histology showed a congenital fibrosarcoma associated with reactive lymphadenitis. A first cycle of adjuvant chemotherapy did not prevent the rapid progression of the disease. Subsequent evaluation for surgical removal raised serious concerns due to the need for a major operation involving total amputation of the right leg and hemipelvectomy. Since surgery could not exclude the possibility of disease recurrence and since the traditional cycles of chemotherapy did not offer any possibility of a cure, the parents opted for the Di Bella Method. The combined use of Somatostatin, Melatonin, Retinoids solubilized in Vit. E, Vit. C, Vit. D3, Calcium, and Chondroitin sulfate associated with low doses of Cyclophosphamide resulted in a complete objective response, still present 14 years later, with no toxicity and without the need for hospitalization, allowing a normal quality of life and perfectly normal adolescent psycho-physical development.

Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy.

OBJECTIVE: The aim of the liposoluble vitamin solution in the DBM formulation is to enhance the biovailability, the stability, the half-life and the therapeutic efficacy of the components without resorting to excessive or toxic doses. METHOD: The DBM vitamin solution contains 0.5 grams of vitamin A palmitate ester, 0.5 grams of all-trans-retinoic acid (ATRA), and 2 grams of ß-Carotene, in 1 000 grams of vitamin E acetate ester which stabilizes the other components, protecting them from oxidation. The solution is administered before meals at the dose of 90 to 150 mg per kg of body weight. The quantities have a determining value for a pharmacological result. No phenomena of overdose and/or toxicity have ever been detected in the tens of thousands of people who have used the solution with this formulation and dosage. RESULTS: Thanks to the synergic effect of the components and their antioxidant, free antiradical, cell-membrane stabilizing, differentiating and cytostatic properties, this solution has constantly produced positive therapeutic responses. Favourable effects have been observed in the prevention and treatment of neoplastic diseases, as well as on immunity, physiological growth, trophism and functionality of tegumental, respiratory, digestive, urogenital and exocrine gland epithelia. A significant antidegenerative effect has also been observed in pretumoral stages. Studies have been published reporting 754 cases of various types of tumor which have greatly benefited from the use of this vitamin solution synergically and factorially reinforced by the other components of the DBM, such as Melatonin, Vitamins D and C, D2 receptor agonists, and GH inhibitors like Somatostatina and analogs. CONCLUSIONS: In view of the documented results achieved, we believed it useful to provide the scientific community with the details of the formulation, preparation, posology, rationale, mechanism of action, biochemical, molecular and physiological bases, indications and clinical findings relating to the DBM liposoluble vitamin solution.

Melatonin anticancer effects: review.

Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases.

Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report.

OBJECTIVE: The current strategies for the treatment of breast cancer are essentially based on surgery, preceded and/or followed by chemotherapy often supplemented by radiotherapy and/or the administration of hormonal therapy and monoclonal antibodies. Their combined use has made it possible to increase an overall survival but they are still penalized by adverse effects and toxicity. The marked anti-cancer effects of biological molecule such as somatostatin, melatonin, retinoid, vitamin D3 and prolactin inhibitors have been studied and documented for several decades. Their integrated and synergic action have been demonstrated, but only a few studies have as yet been carried out on their combined application in humans. The aim of the present investigation was to evaluate both the objective clinical response and toxicity of the biological multimodal treatment named Di Bella Method (DBM). MATERIAL AND METHODS: The clinical data from a total of 20 women with a certified diagnosis of breast cancer,defined disease stage, and who independently decided to follow the DBM as first-line treatment, were retrospectively reviewed. RESULTS: The mean age of the patients was 51 years (min 30; max 73). Twelve (12) patients (60%) presented an early stage disease, while the other 40% had a locally advanced/metastatic stage. An overall clinical benefit was achieved in 75% of cases, with 55% of complete response and 20% of partial response. For metastatic patients, the overall survival rate was 71%. The main toxicity effects included leukopenia, gastrointestinal phenomena and drowsiness. CONCLUSIONS: The preliminary results of this report confirm the positive action of the biological treatment in terms of efficacy and survival, showing a more than favorable profile of tolerability.

The Di Bella Method (DBM) in the treatment of prostate cancer: a preliminary retrospective study of 16 patients and a review of the literature.

OBJECTIVE: To evaluate the objective clinical response and the safety of the combined administration of somatostatin, melatonin, retinoids, vitamin D3, dopamine subtype 2 receptor (D2R) agonists and low doses of cyclophosphamide, associated with androgen ablation, in patients with a histological diagnosis of prostate adenocarcinoma (Pac). MATERIALS AND METHODS: The clinical data of 30 patients with non-invasive and metastatic prostate cancer, who attended our institution over a period of more than 5 years, were retrospectively reviewed. RESULTS: 16 patients satisfied the evaluation criteria. Median age: 64 years. Disease stages: 8 patients (50%) were in Stage II. For advanced stages (Stage IV), secondary lesions were located in the bones and lymph nodes. Taken together, an overall objective response (OR) [Complete response (CR) + Partial Response (PR)] was achieved in 69% of the patients, with 88% of objective clinical benefit [CR+PR+SD]. For local Prostate Cancer group, an OR was achieved in 87.5% of patients (7 cases; 53-98; 95% CI), with CR in 62.5% (5 cases, 31-86; 95% CI). In metastatic disease, the OR was 50% (4 cases; 21-78; 95% CI), with a 20% of CR (2 cases; 7-59; 95% CI) and 75% of clinical benefit. CONCLUSIONS: This preliminary study shows that patients with early and advanced forms of prostate cancer, not previously treated by surgery and/or chemo-radiotherapy, can achieve a more than positive clinical benefit with the protocol foreseen by the Di Bella Method. Further clinical investigations are strongly recommended.

Laudatio for centenary of the birth of Luigi Di Bella, MD, PhD.

On the centennial of the birth of Luigi Di Bella, the desire to memorialise, at least in part, his thoughts has prompted us to write this tribute, in the hope that one day his dreams may come true. Throughout his research for a treatment of cancer, he deemed it necessary to employ a complex array of substances that, by acting centripetally on neoplastic cells, could in turn be capable of affecting, either simultaneously or sequentially, the myriad of biological reactions supporting their lives. Hence, not a substance but a method (Di Bella Method, DBM). These brief hints at some aspects of Prof. Di Bella's multifaceted scientific vision are aimed not only at reasserting the truth, but also at giving a modest contribution to a novel and free direction in experimental and clinical science.

The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck.

In 23 cases of carcinoma of the head and neck, the combined use of Somatostatin and/or its analogue Octreotide, prolactin inhibitors, Melatonin, Retinoids, Vitamin E, Vitamin D3, Vitamin C, Calcium, chondroitin-sulphate, and minimal oral doses of cyclophosphamide (50-100 mg/day) led to a decided increase in survival with respect to the median values reported in the literature for the same tumours and stages, together with an evident improvement in the quality of life, partial or complete objective responses and, in some cases, complete and stable cure with functional recovery. The rationale and the mechanisms of molecular biology of the treatment are discussed, showing that the treatment has a differentiating, apoptotic, antiproliferative, antiangiogenic and antimetastatic effect, and, unlike chemo- and/or radiotherapy, preserves and enhances the trophism and functionality of organs, tissues and immunitary and antitumoral homeostasis. This result, achieved without toxicity, demonstrates the efficacy of this biological multitherapy (Prof. Luigi Di Bella's method or DBM) and is in agreement with the positive results already published on the use of the DBM in various neoplastic diseases. We believe it is of use to report these cases to invite greater interest in the possibilities opened up by this biological multitherapy.