68Ga-DOTATOC PET/CT Follow Up after Single or Hypofractionated Gamma Knife ICON Radiosurgery for Meningioma Patients.

68Ga-DOTATOC represents a useful tool in tumor contouring for radiosurgery planning. We present a case series of patients affected by meningiomas on who we performed 68Ga-DOTATOC positron emission tomography (PET)/CT pre-operatively, a subgroup of which also underwent a post-operative 68Ga-DOTATOC PET/CT to evaluate the standardized uptake value (SUV) modification after Gamma Knife ICON treatment in single or hypofractionated fractions. Twenty patients were enrolled/included in this study: ten females and ten males. The median age was 52 years (range 33-80). The median tumor diameter was 3.68 cm (range 0.12-22.26 cm), and the median pre-radiotherapy maximum SUV value was 11 (range 2.3-92). The average of the relative percentage changes between SUVs at baseline and follow up was -6%, ranging from -41% to 56%. The SUV was reduced in seven out of 12 patients (58%), stable in two out of 12 (17%), and increased in three out of 12 (25%), suggesting a biological response of the tumor to the Gamma Knife treatment in most of the cases. 68Ga-DOTATOC-PET represents a valuable tool in assessing the meningioma diagnosis for primary radiosurgery; it is also promising for follow-up assessment.

A straightforward multiparametric quality control protocol for proton magnetic resonance spectroscopy: Validation and comparison of various 1.5 T and 3 T clinical scanner systems.

PURPOSE: The aim of this study was to propose and validate across various clinical scanner systems a straightforward multiparametric quality assurance procedure for proton magnetic resonance spectroscopy (MRS). METHODS: Eighteen clinical 1.5 T and 3 T scanner systems for MRS, from 16 centres and 3 different manufacturers, were enrolled in the study. A standard spherical water phantom was employed by all centres. The acquisition protocol included 3 sets of single (isotropic) voxel (size 20 mm) PRESS acquisitions with unsuppressed water signal and acquisition voxel position at isocenter as well as off-center, repeated 4/5 times within approximately 2 months. Water peak linewidth (LW) and area under the water peak (AP) were estimated. RESULTS: LW values [mean (standard deviation)] were 1.4 (1.0) Hz and 0.8 (0.3) Hz for 3 T and 1.5 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficient of variation of LW and AP for different spatial positions of acquisition voxel were 43% (20%) and 11% (11%), respectively. The mean (standard deviation) phantom T2values were 1145 (50) ms and 1010 (95) ms for 1.5 T and 3 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficients of variation for repeated measurements of LW, AP and T2 were 25% (20%), 10% (14%) and 5% (2%), respectively. CONCLUSIONS: We proposed a straightforward multiparametric and not time consuming quality control protocol for MRS, which can be included in routine and periodic quality assurance procedures. The protocol has been validated and proven to be feasible in a multicentre comparison study of a fairly large number of clinical 1.5 T and 3 T scanner systems.

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

[This corrects the article on p. 223 in vol. 7, PMID: 28971066.].

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.

Multiparametric MRI Apparent Diffusion Coefficient (ADC) Accuracy in Diagnosing Clinically Significant Prostate Cancer.

AIM: To evaluate the accuracy of multiparametric magnetic resonance imaging apparent diffusion coefficient (mpMRI ADC) in the diagnosis of clinically significant prostate cancer (PCa). PATIENTS AND METHODS: From January 2016 to December 2016, 44 patients who underwent radical prostatectomy for PCa and mpMRI lesions suggestive of cancer were retrospectively evaluated at definitive specimen. The accuracy of suspicious mpMRI prostate imaging reporting and data system (PI-RADS ≥3) vs. ADC values in the diagnosis of Gleason score ≥7 was evaluated. RESULTS: Receiver operating characteristics (ROC) curve analysis gave back an ADC threshold of 0.747×10-3 mm2/s to separate between Gleason Score 6 and ≥7. The diagnostic accuracy of ADC value (cut-off 0.747×10-3 mm2/s) vs. PI-RADS score ≥3 in diagnosing PCa with Gleason score ≥7 was equal to 84% vs. 63.6% with an area under the curve (AUC) ROC of 0.81 vs. 0.71, respectively. CONCLUSION: ADC evaluation could support clinicians in decision making of patients with PI-RADS score <3 at risk for PCa.

Evaluation of erlotinib treatment response in non-small cell lung cancer using metabolic and anatomic criteria.

BACKGROUND: In this paper the clinical value of PET for early prediction of tumor response to erlotinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen is evaluated. The aim was to compare the early metabolic treatment response using European Organization for Research and Treatment of Cancer (EORTC) 1999 recommendations and PET Response Criteria in Solid Tumors (PERCIST), and the standard treatment response using Response Evaluation Criteria in Solid Tumors (RECIST). METHODS: Twenty patients with stage IV NSCLC were enrolled prospectively. PET/CT studies were performed before, then 48 hours, and 45 days after the initiation of erlotinib treatment. The lesion with the highest uptake in each patient was evaluated according to EORTC 1999 recommendations, PERCIST and RECIST to assess metabolic and anatomic response. Response classifications were compared statistically using Wilcoxon signed-rank test. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier Test. RESULTS: At 48 hours, the Kaplan-Meier analysis showed that EORTC proved to be a significant prognostic factor for predicting DFS and OS. At 45 days, there was a significant difference in response evaluation between RECIST and metabolic classifications. RECIST and PERCIST were significant prognostic factors for predicting DFS and OS. EORTC was not able to discriminate responder from non-responder patients. CONCLUSIONS: This study shows that, according to the EORTC protocol, the PET exam is able to provide early identification of patients who benefit from Erlotinib treatment. Used at the end of therapy, PERCIST could be considered an appropriate metabolic evaluation method to discriminate responders from non-responders.

Response of a radioresistant human melanoma cell line along the proton spread-out Bragg peak.

PURPOSE: To analyse changes of cell inactivation and proliferation under therapeutic irradiation conditions along the proton spread out Bragg peak (SOBP) with particular emphasis on its distal declining edge. MATERIALS AND METHODS: HTB140 cells were irradiated at four positions: plateau, middle, distal end and distal declining edge of the 62 MeV proton SOBP. Doses ranged from 2-16 Gy. They were normalised in the middle of SOBP and delivered following the axial physical dose profile. Survival, proliferation and cell cycle were assessed seven days after irradiation. RESULTS: Moving from proximal to distal irradiation position surviving fractions at 2 Gy (SF2) decreased from 0.88-0.59. Increased radiosensitivity of the cells was noticed for the doses below 4 Gy, resulting in two gradients of cell inactivation, stronger for lower and weaker for higher doses. Relative biological effectiveness (RBE) increased from 1.68-2.84 at the distal end of SOBP. A further rise of RBE reaching 7.14 was at its distal declining edge. Following the axial physical dose profile of SOBP the strongest inactivation was attained at its distal end and was comparable to that at its declining edge. CONCLUSIONS: Survival data confirmed very high radioresistance of HTB140 cells. An effect similar to low-dose hyper radiosensitivity (HRS) was observed for order of magnitude larger doses. Better response of cells to protons than to gamma-rays was illustrated by rather high RBE. Strong killing ability at the SOBP distal declining edge was the consequence of increasing proton linear energy transfer.

Anti-tumour activity of fotemustine and protons in combination with bevacizumab.

BACKGROUND: Metastatic melanoma is one of the most aggressive tumours and is also very resistant to current therapeutic approaches. The aim of this investigation was the in vitro study of the anti-proliferative effects of fotemustine (FM; 100 and 250 microM), bevacizumab (5 microg/ml) and proton irradiation (12 and 16 Gy) on resistant HTB140 human melanoma cells. METHODS: Viability was estimated by sulphorhodamine B assay, while cell proliferation was analyzed by 5-bromo-2-deoxyuridine assay. Cell cycle distribution and apoptosis were examined using flow cytometry. RESULTS: Cell viability and proliferation were reduced after all applied treatments. The level of apoptosis significantly increased after treatment with FM, protons or a combination of all agents, while the apoptotic index ranged from 1.2 to 9.2. Proton irradiation, as well as combined treatment with bevacizumab and protons or 100 microM FM, bevacizumab and protons, have reduced melanoma cell proliferation through the induction of G1 phase arrest. Single FM (250 microM) or bevacizumab treatment and their combination, as well as the joint application of these 2 agents with protons, reduced cell proliferation and provoked G2 phase accumulation. CONCLUSION: The analyzed treatments reduced cell viability and proliferation, triggered G1 or G2 cell cycle phase accumulation and stimulated apoptotic cell death.

Effects of fotemustine or dacarbasine on a melanoma cell line pretreated with therapeutic proton irradiation.

BACKGROUND: Considering that HTB140 melanoma cells have shown a poor response to either protons or alkylating agents, the effects of a combined use of these agents have been analysed. METHODS: Cells were irradiated in the middle of the therapeutic 62 MeV proton spread out Bragg peak (SOBP). Irradiation doses were 12 or 16 Gy and are those frequently used in proton therapy. Four days after irradiation cells were treated with fotemustine (FM) or dacarbazine (DTIC). Drug concentrations were 100 and 250 microM, values close to those that produce 50% of growth inhibition. Cell viability, proliferation, survival and cell cycle distribution were assessed 7 days after irradiation that corresponds to more than six doubling times of HTB140 cells. In this way incubation periods providing the best single effects of drugs (3 days) and protons (7 days) coincided at the same time. RESULTS: Single proton irradiations have reduced the number of cells to approximately 50%. FM caused stronger cell inactivation due to its high toxicity, while the effectiveness of DTIC, that was important at short term, almost vanished with the incubation of 7 days. Cellular mechanisms triggered by proton irradiation differently influenced the final effects of combined treatments. Combination of protons and FM did not improve cell inactivation level achieved by single treatments. A low efficiency of the single DTIC treatment was overcome when DTIC was introduced following proton irradiation, giving better inhibitory effects with respect to the single treatments. Most of the analysed cells were in G1/S phase, viable, active and able to replicate DNA. CONCLUSION: The obtained results are the consequence of a high resistance of HTB140 melanoma cells to protons and/or drugs. The inactivation level of the HTB140 human melanoma cells after protons, FM or DTIC treatments was not enhanced by their combined application.

Assessment of the inhibitory effects of different radiation qualities or chemotherapeutic agents on a human melanoma cell line.

The correlation between time dependent viabilities, after applying two radiation qualities and two alkylating agents on HTB140 melanoma cells, has been studied. Irradiations were performed with gamma-rays and 62 MeV protons, close to the Bragg peak maximum, delivering doses of 8-24 Gy. Treatments with fotemustine (FM) and dacarbazine (DTIC) were carried out with concentrations of 0.05-2mM. High radio-resistance of HTB140 cells revealed by a clonogenic assay was confirmed by microtetrasolium and sulforhodamine B, through the surviving fraction at 2 Gy (SF2), being 0.961-0.956 for gamma-rays and 0.931-0.887 for protons. A better efficiency of protons was illustrated by relative biological effectiveness at 2 Gy (RBE), ranging from 1.69 to 1.89. A kinetic study of concentration dependent cytotoxicity indicated that the best effect of the drugs, estimated as the concentration that produces 50% of growth inhibition (IC(50)), was obtained at 48 h, having values of 76 microM for DTIC and 145 microM for FM. The cytostatic ability of the drugs pointed out that the presence of DTIC at 24h, compared to FM, was insufficient to produce an effect. Protons and FM demonstrated their pro apoptotic capacity. Cross-resistance between treatments applied to the HTB140 cells was observed, protons being the most efficient, while DTIC, FM and gamma-rays demonstrated a lower level of cell inactivation.

Viability of a human melanoma cell after single and combined treatment with fotemustine, dacarbazine, and proton irradiation.

Viability of human HTB140 melanoma cells after being exposed to fotemustine (FM) and dacarbazine (DTIC) as well as to proton irradiation was studied. Effects of 100 and 250 microM drugs were assessed after incubation of 6, 24, 48, 72, and 96 h. Irradiations were performed with 62 MeV therapeutic protons, delivering to the cell monolayer single doses of 2, 4, 8, 12, and 16 Gy. Viability was evaluated 7 days after irradiation. Inactivation level was estimated using microtetrasolium (MTT) and sulforhodamine B (SRB) assays. Combined effects of each drug and protons, were carried out using the same drug concentrations. Proton doses applied were those used in therapy, that is, 12 and 16 Gy. With the increase of drug concentration or irradiation dose, level of cell inactivation reached approximately 60%, 48 h after drug treatment or 7 days after irradiation at 16 Gy. Considering the rate of drug concentrations used, as well as the level of doses applied, it appears that HTB140 cells are more resistant to proton irradiation than to alkylating agents tested. The combined treatment with FM or DTIC and protons did not show significant changes of cell viability as compared to the effects of single agents. Since the time point for measuring cumulative effects of drug and irradiation was 48 h post irradiation, it seems that the obtained level of viability could be attributed primarily to the effects of drugs.

Response of a human melanoma cell line to low and high ionizing radiation.

Effects of single irradiation with gamma rays and protons on human HTB140 melanoma cell growth were compared. Exponentially growing cells were irradiated close to the Bragg peak maximum of the unmodulated 62 MeV protons, as well as with (60)Co gamma rays. Applied doses ranged from 8 to 24 Gy. Viability of cells and proliferation capacity were assessed 7 days after irradiation. Induction of apoptosis and cell cycle phase redistribution were observed 6 and 48 h after irradiation. Significant inhibitory effects of both irradiation qualities were detected 7 days after irradiation. Important reduction of HTB140 cell viability was observed after irradiation with protons. Almost linear and highly significant (P < 0.001) decrease of cell proliferation was observed 7 days after irradiation with gamma rays and protons, as compared to nonirradiated controls. Protons induced apoptosis, both 6 and 48 h after irradiation. With the increase of post-irradiation incubation time, number of apoptotic cells decreased. Exposure of HTB140 cells to gamma rays did not provoke apoptotic cell death. Important number of cells in G1-S phase, detected by the cell cycle phase redistribution analyses, suggested high metabolic activity of irradiated melanoma cells within the first 48 h. Both irradiation qualities caused modest G2-M arrest 6 and 48 h after irradiation, thus supporting results that illustrated high radioresistance of HTB140 cells.

Radiobiological analysis of human melanoma cells on the 62 MeV CATANA proton beam.

PURPOSE: To measure the ability of protons and gamma-rays to effect cell viability and cell survival of human HTB140 melanoma cells. MATERIALS AND METHODS: Exponentially growing HTB140 cells were irradiated close to the Bragg peak maximum of the 62 MeV protons or with 60Co gamma-rays with single doses, ranging from 8 - 24 Gy. Cell viability using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay was evaluated at 6 h, 24 h, 48 h or 7 days after irradiation and clonogenic survival was assessed at 7 days after irradiation. Cell cycle phase redistribution and the level of apoptosis were evaluated at 6 h and 48 h after irradiation. RESULTS: The study of cell viability as a function of time (cell survival progression) and cell survival, using a clonal assay, demonstrated the considerably stronger inactivation effect of protons compared to gamma-rays with a relative biological effectiveness (RBE) of approximately 1.64. Cell cycle phase distribution and apoptosis levels with time enabled us to investigate the development and the character of the damage induced by irradiation. Due to the high radio-resistance of HTB140 cells, cell cycle phase redistribution exhibited only a modest cell accumulation in G2/M phase. Protons but not gamma-rays induced apoptosis. CONCLUSIONS: It appears that protons reduce the number of HTB140 cells by apoptosis as well as by severe DNA damage, while gamma-rays eliminate viable cells primarily by the production of irreparable DNA damage. Protons have an increased RBE relative to gamma-rays.

Preliminary investigation on the use of the MOSFET dosimeter in proton beams.

Metal Oxide Semiconductor (MOS) device structures can be used to measure ionizing radiation through the mechanism of hole trapping in the oxide layer leading to changing of electrical characteristic of the device. They are a new type of direct reading semiconductor dosimeters. Due to their extremely small physical size, ability to permanently store the accumulated dose, dose-rate independence and their ease of use make them very promising for in vivo dosimetry. They are attractive for dosimetry in small radiation fields used in modern radiation oncology modalities, as conformal radiotherapy, IMRT, stereotactic radiotherapy/radiosurgery and proton therapy. Preliminary results on the use of commercial MOSFET dosimeters (TN-502RD, Thomson & Nielsen Electronics Ltd, Canada) irradiated on therapeutic 62 MeV proton beams are presented. Linearity with absorbed dose, sensibility and energy dependence were investigated. Moreover, the possibility to use of MOSFET dosimeters in order to measure the Output Factors (OF) for very small irradiation fields was verified. The comparison of OF obtained using MOSFETs and other dosimetry systems is reported.