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1.  β3-adrenoreceptor and tumor microenvironment: a new hub 
Oncoimmunology  2015;4(11):e1026532.
The achievement of malignant traits in several cancers is associated with tumor microenvironment reactivity. New evidence show that the stress hormone noradrenaline enhances melanoma microenvironment reactivity, mainly acting through β3-adrenoreceptors (β2-ARs), favoring recruitment of cancer-associated fibroblasts, M2-macrophages, bone marrow-derived precursors, These events concur in sustaining a pro-inflammatory and pro-angiogenic milieu, finally boosting melanoma malignancy.
PMCID: PMC4589043  PMID: 26504670
beta-adrenoreceptors; cancer associated fibroblasts; inflammation; mesenchymal stem cells; stress; tumor microenvironment
2.  Sequential Use of 90Y Microspheres Radioembolization and 177Lu-Dotatate in Pluri-Metastatic Neuroendocrine Tumors: A Case Report 
90Y radioembolization and peptide-receptor radionuclide therapy (PRRT) with177Lu-DOTATATE are both effective treatments for patients with inoperable neuroendocrine metastatic tumors (NET). We report the case of a 72-year-old man with severe functional syndrome due to a metastatic NET. 68Ga-DOTATOC positron-emission tomography (PET) revealed high somatostatin receptor expression in a gross liver metastasis, in one abdominal lymph node and in several skeletal lesions. The patient underwent liver radioembolization with 90Y-resin microspheres followed by four cycles of PRRT with177Lu-DOTATATE. After 3 months, a complete remission of the functional syndrome was observed. 68Ga-DOTATOC PET demonstrated a complete response for skeletal and lymph nodal lesions with a residual bulky mass in the liver. Therefore a further 90Y radioembolization was performed as consolidation treatment for the hepatic lesion. Six months after these combined treatments, 68Ga-DOTATOC PET demonstrated complete metabolic response in liver and stable extrahepatic lesions. No significant long-term adverse reactions were registered. To our knowledge, the sequential use of 90Y radiembolization before and after PRRT in a liver-dominant advanced NET has not been reported in the literature and this case suggests that these combined treatments can be safe and effective.
PMCID: PMC4571666  PMID: 26396640
90Y radioembolization; 177Lu DOTATATE; Neuroendocrine tumors; Somatostatin receptors
3.  Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression 
Oncotarget  2014;6(7):4615-4632.
Stress has an emerging role in cancer and targeting stress-related β-adrenergic receptors (AR) has been proposed as a potential therapeutic approach in melanoma. Here we report that β3-AR expression correlates with melanoma aggressiveness. In addition, we highlight that β3-AR expression is not only restricted to cancer cells, but it is also expressed in vivo in stromal, inflammatory and vascular cells of the melanoma microenvironment. Particularly, we demonstrated that β3-AR can (i) instruct melanoma cells to respond to environmental stimuli, (ii) enhance melanoma cells response to stromal fibroblasts and macrophages, (iii) increase melanoma cell motility and (iv) induce stem-like traits. Noteworthy, β3-AR activation in melanoma accessory cells drives stromal reactivity by inducing pro-inflammatory cytokines secretion and de novo angiogenesis, sustaining tumor growth and melanoma aggressiveness. β3-ARs also play a mandatory role in the recruitment to tumor sites of circulating stromal cells precursors, in the differentiation of these cells towards different lineages, further favoring tumor inflammation, angiogenesis and ultimately melanoma malignancy. Our findings validate selective β3-AR antagonists as potential promising anti-metastatic agents. These could be used to complement current therapeutic approaches for melanoma patients (e.g. propranolol) by targeting non-neoplastic stromal cells, hence reducing therapy resistance of melanoma.
PMCID: PMC4467103  PMID: 25474135
β-adrenergic receptors; melanoma; tumor microenvironment; cancer associated fibroblasts; macrophages; mesenchymal stem cells
4.  The role of 18F-FDG positron emission tomography in the follow-up of liver tumors treated with 90Yttrium radioembolization 
In the last years, radioembolization (RE) has emerged as a novel technique for the treatment of malignant hepatic lesions using 90Y embedded in spheres, which are infused directly into the hepatic arterial circulation. 90Y-spheres, once implanted in liver, can release a significant radiation burden to neoplastic cells with a relative low dose to normal parenchyma. 90Y RE results as a combination of embolization and radiation therapy, thus the standard radiologic follow up modalities may be not sufficiently accurate to assess tumor response to treatment. 18Fluoro-deoxyglucose Positron Emission Tomography (18F-FDG PET) detects glucose uptake and metabolic activity in tumor cells. 18F-FDG PET has become a well established diagnostic tool in many oncological scenarios. Furthermore, PET response criteria (PERCIST) have been recently introduced to categorize the metabolic response to therapy of cancer patients. Several semiquantitative parameters, such as SUVmax and its changes, the Functional Tumor Volume and the Total Lesion Glycolysis can be useful to accurately assess tumor changes after therapy. The purpose of this article is to present the literature on the role of 18F-FDG PET in the evaluation of patients with primary and secondary liver tumors treated with 90Y RE.
PMCID: PMC4446391  PMID: 26069856
Liver tumors; 90Y radioembolization; PET-CT; PERCIST; total lesion glycolysis; function tumor volume
5.  An unusual case of spleen metastasis from carcinoma ex pleomorphic adenoma of the parotid gland 
Carcinoma ex pleomorphic adenoma is a rare tumor arising from the salivary glands that spreads through direct extension, through the lymphatic vessels, and, rarely, hematogenously. When distant metastases have been found, they have been reported mainly in the lung. We present an unusual case of carcinoma ex pleomorphic adenoma of the parotid gland with splenic metastases. The patient presented with a primary carcinoma ex pleomorphic adenoma of the parotid gland and he underwent a total parotidectomy with laterocervical lymphadenectomy ipsilateral and adjuvant radiation therapy to the right parotid area. One year later, the patient showed an ipsilateral supraclavicular lymph node recurrence, treated with surgery and radiation therapy. Two more years later, the patient developed lung and splenic lesions, detected through CT and PET. He underwent splenectomy and pathologic assessment of the specimen showed metastatic carcinoma ex pleomorphic adenoma. To our knowledge, there is no reported case of a carcinoma ex pleomorphic adenoma metastasizing to the spleen. Patients treated for carcinoma ex pleomorphic adenoma should be investigated for distant metastases with a long-term follow-up examination for local and distant metastases and new splenic lesions in these patients should be investigated.
PMCID: PMC3905163  PMID: 24456816
Carcinoma ex pleomorphic adenoma; Parotid tumours; Pleomorphic adenoma; Splenic metastases
6.  Heart Rate and Arterial Pressure Changes during Whole-Body Deep Hypothermia 
ISRN Pediatrics  2013;2013:140213.
Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn. This retrospective study describes how DH modified the heart rate and arterial blood pressure if compared to mild hypothermia (MH). Fourteen in DH and 17 in MH were cooled within the first six hours of life and for the following 72 hours. Hypothermia criteria were gestational age ≥36 weeks; birth weight ≥1800 g; clinical signs of moderate/severe hypoxic-ischemic encephalopathy. Rewarming was obtained in the following 6–12 hours (0.5°C/h) after cooling. Heart rates were the same between the two groups; there was statistically significant difference at the beginning of hypothermia and during rewarming. Three babies in the DH group and 2 in the MH group showed HR < 80 bpm and QTc > 520 ms. Infant submitted to deep hypothermia had not bradycardia or Qtc elongation before cooling and after rewarming. Blood pressure was significantly lower in DH compared to MH during the cooling, and peculiar was the hypotension during rewarming in DH group. Conclusion. The deeper hypothermia is a safe and feasible, only if it is performed by a well-trained team. DH should only be associated with a clinical trial and prospective randomized trials to validate its use.
PMCID: PMC3649319  PMID: 23691350
7.  Expression of β-adrenergic receptors in pediatric malignant brain tumors 
Oncology Letters  2012;5(1):221-225.
β-adrenergic receptors (β-ARs) are G protein-coupled receptors that activate signal transduction pathways involved in angiogenesis, resulting in enhanced tumor vascularization and more aggressive growth. In this study, we evaluated the expression of β-ARs in a population of 12 children affected by malignant primary brain tumors. We found a significant expression of β1- and β2-ARs in all 12 samples as well as the 3 cell lines tested (U87MG, T98G and DAOY). The mean absolute β1-AR mRNA level standardized to GAPDH was 5.81 (range, -7.91 to 11.29) for brain tumors and 8.59 (range, 6.046 to 12.59) for cell lines (U87MG, DAOY and T98G), respectively. The mean absolute β2-AR mRNA level was 4.74 (range, −9.30 to 8.45) for tumor specimens and 7.64 (range, 5.85 to 8.88) for cell lines. These real-time quantitative (qRT)-PCR expression data were confirmed by immunohistochemical analysis. Our study evaluated the presence of β1- and β2-ARs in malignant pediatric brain tumors and brain tumor cell lines.
PMCID: PMC3525361  PMID: 23255924
β-adrenergic receptors; medulloblastoma; anaplastic ependymoma; glioblastoma multiforme; brain tumor cell lines
8.  Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI) 
BMC Pediatrics  2012;12:144.
Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.
Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.
This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.
Trial registration
Current Controlled Trials ISRCTN62175998; Identifier NCT01241019; EudraCT Number 2010-018627-25
PMCID: PMC3478965  PMID: 22950861
Neonatal hypoxic-ischemic encephalopathy; Therapeutic hypothermia; Topiramate
9.  New developments in the treatment of hyperammonemia: emerging use of carglumic acid 
Hyperammonemia is a true neonatal emergency with high toxicity for the central nervous system and developmental delay. The causes of neonatal hyperammonemia are genetic defects of urea cycle enzymes, organic acidemias, lysinuric protein intolerance, hyperammonemia–hyperornithinemia– homocitrullinemia syndrome, transient hyperammonemia of the newborn, and congenital hyperinsulinism with hyperammonemia. In some of these conditions the high blood ammonia levels are due to the reduction of N-acetylglutamate, an essential cofactor necessary for the function of the urea cycle, or to the reduction of carbamoyl-phosphate synthase-I activity. In these cases, N-carbamylglutamate (carglumic acid) can be administered together with the conventional therapy. Carglumic acid is an analog of N-acetylglutamate that has a direct action on carbamoyl-phosphate synthase-I. Its effects are reactivation of the urea cycle and reduction of plasma ammonia levels. As a consequence it improves the traditional treatment, avoiding the need of hemodialysis and peritoneal dialysis. In this review we evaluate the possible field of application of carglumic acid and its effectiveness and safety.
PMCID: PMC3056327  PMID: 21403788
hyperammonemia; N-carbamylglutamate; carglumic acid; urea cycle disorder; metabolic disorders
10.  Study protocol: safety and efficacy of propranolol in newborns with Retinopathy of Prematurity (PROP-ROP): ISRCTN18523491 
BMC Pediatrics  2010;10:83.
Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment.
In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy.
Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests.
This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies.
Trial Registration
Current Controlled Trials ISRCTN18523491; Identifier NCT01079715; EudraCT Number 2010-018737-21
PMCID: PMC2993687  PMID: 21087499
11.  Dopamine versus dobutamine in very low birthweight infants: endocrine effects 
To compare the endocrine effects of dopamine and dobutamine in hypotensive very low birthweight (VLBW) infants.
Non‐blinded randomised prospective trial.
Level III neonatal intensive care unit.
35 hypotensive VLBW infants who did not respond to volume loading, assigned to receive dopamine or dobutamine.
Haemodynamic variables and serum levels of thyroid stimulating hormone (TSH), total thyroxine (T4), prolactin (PRL) and growth hormone were assessed during the first 72 h of treatment and the first 72 h after stopping treatment.
Demographic and clinical data did not significantly differ between the two groups. Necessary cumulative and mean drug doses and maximum infusion required to normalise blood pressure were significantly higher in the dobutamine than in the dopamine group (p<0.01). Suppression of TSH, T4 and PRL was observed in dopamine‐treated newborns from 12 h of treatment onwards, whereas levels of growth hormone reduced significantly only at 12 h and 36 h of treatment (p<0.01). TSH, T4 and PRL rebound was observed from the first day onwards after stopping dopamine. Dobutamine administration did not alter the profile of any of the hormones and no rebound was observed after stopping treatment.
Dopamine and dobutamine both increase the systemic blood pressure, though dopamine is more effective. Dopamine reduces serum levels of TSH, T4 and PRL in VLBW infants but such suppression is quickly reversed after treatment is stopped. Further research is required to assess if short‐term iatrogenic pituitary suppression has longer‐term consequences.
PMCID: PMC2675359  PMID: 17329276
dopamine; dobutamine; preterm newborn; hypotension

Results 1-11 (11)