Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease

CATANA protontherapy facility: The state of art of clinical and dosimetric experience

After nine years of activity, about 220 patients have been treated at the CATANA Eye Protontherapy facility. A 62MeV proton beam produced by a Superconducting Cyclotron is dedicated to radiotherapy of eye lesions, as uveal melanomas. Research and development work has been done to test different dosimetry devices to be used for reference and relative dosimetry, in order to achieve dose delivering accuracy. The follow-up results demonstrated the efficacy of proton beams and encouraged us in our activity in the fight against cancer

A 62 MeV proton beam for the treatment of ocular melanoma at Laboratori Nazionali del Sud-INFN (CATANIA)

At the Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali del Sud (INFN-LNS) in Catania, Italy, the first Italian protontherapy facility, named Centro di AdroTerapia e Applicazioni Nucleari Avanzate (CATANA) has been built in collaboration with the University of Catania. It is based on the use of the 62-MeV proton beam delivered by the K=800 Superconducting Cyclotron installed and working at INFN-LNS since 1995. The facility is mainly devoted to the treatment of ocular diseases like uveal melanoma. A beam treatment line in air has been assembled together with a dedicated positioning patient system. The facility has been in operation since the beginning of 2002 and 66 patients have been successfully treated up to now. The main features of CATANA together with the clinical and dosimetric features will be extensively described; particularly, the proton beam line, that has been entirely built at LNS, with all its elements, the experimental transversal and depth dose distributions of the 62-MeV proton beam obtained for a final collimator of 25-mm diameter and the experimental depth dose distributions of a modulated proton beam obtained for the same final collimator. Finally, the clinical results over 1 yr of treatments, describing the features of the treated diseases will be reported

Clinical and Research Activities at the CATANA Facility of INFN-LNS: From the Conventional Hadrontherapy to the Laser-Driven Approach

The CATANA proton therapy center was the first Italian clinical facility making use of energetic (62 MeV) proton beams for the radioactive treatment of solid tumors. Since the date of the first patient treatment in 2002, 294 patients have been successful treated whose majority was affected by choroidal and iris melanomas. In this paper, we report on the current clinical and physical status of the CATANA facility describing the last dosimetric studies and reporting on the last patient follow-up results. The last part of the paper is dedicated to the description of the INFN-LNS ongoing activities on the realization of a beamline for the transport of laser-accelerated ion beams for future applications. The ELIMED (ELI-Beamlines MEDical and multidisciplinary applications) project is introduced and the main scientific aspects will be described

Influence of Donor and Recipient Gender on Telomere Maintenanceafter Umbilical Cord Blood Cell Transplantation: A Study by the GruppoItaliano Trapianto Di Midollo Osseo

Physiological loss of telomerase activity in adult life determines progressive telomere length (TL) shortening. Inflammation and oxidative damage are established causes of TL loss; moreover, males have shorter telomeres compared to females. Despite these notions, mechanisms regulating TL maintenance are poorly defined. As umbilical cord blood (UCB) cells harbor very long telomeres, not yet exposed to environmental damages, UCB transplantation (UCB-T) provides a unique experimental setting to study determinants of TL in humans. TL dynamics was analyzed on peripheral blood mononucleated cells (MNCs) from 36 patients (median age: 42 yrs.) undergoing UCB-T. TL was studied at a median of 20 months since UCB-T. A significantly longer TL (mean 8,698 bp, range 6521-11960) was documented in UCB-T recipients compared to age-matched healthy controls (mean 7,396 bp, range 4,375-11,108) (p<0.01). Among variables potentially influencing TL maintenance, including recipient features, graft type, transplant procedure, and engraftment kinetics, only donor/recipient gender combination was associated to TL, with longest TL in females receiving a male UCB (mean 10,063 bp, range 8,381-11,960). To further investigate this trend, telomerase activation was assessed in vitro. Experiments showed that telomerase subunits were preferentially up-regulated in male-derived bone marrow MNCs exposed ex-vivo to estradiol as compared to female MNCs. This implies an increased sensitivity of male-derived MNCs to telomerase activation induced by estradiol. The results suggest that extrinsic and modifiable factors such as hormonal status and female milieu could be major determinants of TL in humans providing the rationale for investigating hormonal-based approaches to counteract telomere erosion and aging-related diseases

Orbital metastasis from thyroid cancer: a case report and review of the literature.

BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far. CASE DESCRIPTION: A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration. CONCLUSIONS: This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients

Quantitative Diffusion-Weighted MR Imaging: Is There a Prognostic Role in Noninvasively Predicting the Histopathologic Type of Uveal Melanomas?

Histopathologically, uveal melanomas (UMs) can be classified as spindle cell, mixed cell and epithelioid cell type, with the latter having a more severe prognosis. The aim of our study was to assess the correlation between the apparent diffusion coefficient (ADC) and the histologic type of UMs in order to verify the role of diffusion-weighted magnetic resonance imaging (DWI) as a noninvasive prognostic marker. A total of 26 patients with UMs who had undergone MRI and subsequent primary enucleation were retrospectively selected. The ADC of the tumor was compared with the histologic type. The data were compared using both one-way analysis of variance (ANOVA) (assessing the three histologic types separately) and the independent t-test (dichotomizing histologic subtypes as epithelioid versus non-epithelioid). Histologic type was present as follows: the epithelioid cell was n = 4, and the spindle cell was n = 11, the mixed cell type was n = 11. The mean ADC was 1.06 ± 0.24 × 10−3 mm2/s in the epithelioid cells, 0.98 ± 0.19 × 10−3 mm2/s in the spindle cells and 0.96 ± 0.26 × 10−3 mm2/s in the mixed cell type. No significant difference in the mean ADC value of the histopathologic subtypes was found, either when assessing the three histologic types separately (p = 0.76) or after dichotomizing the histologic subtypes as epithelioid and non-epithelioid (p = 0.82). DWI-ADC is not accurate enough to distinguish histologic types of UMs

Potent in vivo anti-tumor activity of extracellular vesicles isolated from genetically engineered primary mesenchymal stromal cells expressing the trans-membrane TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Introduction: TNF-related apoptosis-inducing ligand (TRAIL) is a a wide variety of tumor cells with minimal effects on normal cells. Despite its in vitro activity, recombinant soluble TRAIL has so far shown limited efficacy in vivo. In contrast, recent reports have shown that significant apoptosis can be observed both in vitro and in vivo when TRAIL is expressed on the cell membrane (mTRAIL). A further innovation might be the delivery of bioactive proapoptotic TRAIL through its expression by extracellular vescicles (EVs), the nanovesicular organelles secreted by cells. In fact, EVs are viewed as an effective tool for intercellular cross-talk and receptor discharge. The trans-membrane expression of TRAIL ligand within the double layer exosomal membrane may induce a more potent death signal when compared with the soluble molecule. Material and Methods: Mesenchymal Stromal Cells (MSC) from bone marrow were cultured in vitro and used for EVs production. Cultured MSC in 75 cm2 flasks, at 80% confluence were infected with a lentivector encoding TRAIL, maintained in culture, and cell-supernatants repeatedly collected over several days, ultracentrifugated, with EVs-containing pellet harvested in PBS. EVs were produced also from uninfected MSC as control (EVs-CTRL). EVs were characterized by flow cytometry for expression of MSC markers and mTRAIL, EV size was evaluated by NanoSight technology. Total protein concentration was used to quantify EVs, Western Blot analysis was performed to characterize membrane-bound TRAIL. In vitro analysis was performed on SU-DHL-4 (human B cell lymphoma) and MEL-1300 (human melanoma) cell lines, exposed for 24 hours to 20-100 μg/ml EVs-TRAIL or EVs-CTRL. Annexin/propidium iodide assay was used to quantify apoptotic/necrotic cells. For the in vivo assessments, SU-DHL-4 and MEL-1300 cells were transduced with Luc-Lentiviral particles to obtain Luciferase positive cell lines. These cells were used to engraft NOD scid gamma (NSG) mice (2x106 SU-DHL-4 and 3x105 MEL-1300 cells for each subcutaneous injection point). To visualize tumor cells, mice were injected intraperitoneum with luciferin and analyzed with the Xenogen system. Mice bearing subcutaneous tumor nodules received single intravenous injections of 100, 200, 300 μg or multiple (x 3) 200 μg injections of either EVs-TRAIL or EVs-CTRL. Results: FACS analysis showed strong TRAIL expression on EVs from TRAIL-infected MSC compared to EVs-CTRL, with a high proportion of positive particles (median 85%, range 78-93). In addition, EVs-TRAIL displayed MSC membrane markers, i.e. CD 105, CD 90, CD73 and CXCR4. Western Blot analysis under non-reducing conditions showed the presence of TRAIL ligand, with strong prevalence of dimeric TRAIL isoform (barely detectable the trimeric isoform, undetectable monomeric isoforms). NanoSight analysis revealed that EVs had a variable size, up to approximately 400 nm in diameter, with a predominant peak at 273 nm. A strong and dose-dependent cytotoxic effect was observed on SU-DHL-4 cells exposed to EVs-TRAIL (annexin/PI+ve cells: up to 87% for 100 μg/ml EVs-TRAIL), compared to EVs-CTRL exposure (15% Annexin/PI+ve cells for 100 μg/ml EVs-TRAIL). A similar, albeit less pronounced in vitro cytotoxic effect of EVs-TRAIL was observed on the melanoma MEL-1300 cell line. The anti-tumor effect was remarkably strong when EVs-TRAIL were injected in vivo in mice bearing either SU-DHL-4 or MEL-1300 nodules. A marked reduction of the tumor luminescence from 1.2x1010 photon/sec to <108 photon/sec was observed at seven days since a single EVs-TRAIL injection at 200 and 300 μg. Multiple administrations of 200 μg EVs-TRAIL induced the strongest luminescence reduction, as observed in MEL-1300 bearing NSG mice. Histological examination of nodules from EVs treated mice showed necrosis areas along with extensive intra-tumor vascular disruption. Conclusion: EVs isolated from genetically engineered TRAIL-expressing MSC: i. do express mTRAIL; ii. display potent antitumor activity, inducing extensive apoptosis/necrosis both in vitro and in vivo in animal models bearing lymphoma and melanoma nodules. Thus, EVs-TRAIL may represent a promising strategy for delivering pro-apoptotic signals to tumor cells. Moreover, the results could pave the way to the use of EVs for therapeutic purposes