The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models.

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).

Dosimetric analysis of the patterns of local failure observed in patients with locally advanced non-small cell lung cancer treated with neoadjuvant chemotherapy and concurrent conformal (3D-CRT) chemoradiation.

PURPOSE: Three-dimensional conformal radiation therapy (3D-CRT) represents an advance in the better delineation of the target contours and more accurate dose distributions. The purpose of this study was to identify local control prognostic factors in patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with 3D-CRT. MATERIAL AND METHODS: Between April 1995 and March 2002, 65 patients (NSCLC stage IIIA: 20%, IIIB: 77%) were treated with cisplatin-based induction and concurrent chemotherapy chemotherapy and hyperfractioned 3D-CRT (1.2Gy b.i.d.; median dose: 72.8 (range: 67-85.9). Clinical parameters (sex, age, performance status, stage, histology, tumor location), therapeutic factors (chemotherapy schedule, 3D-CRT dose, treatment response) and dosimetric factors (volume and dose of GTV, PTV-2, CTV and PTV-1) were evaluated. Local recurrences were divided into three dosimetric categories: those with more than 80% of their volume within high dose region (95% of prescription dose) were considered "central"; those between 20% and 80% were considered "marginal", and those with less than 20% of their volume within high dose region were considered "out-of-field". Local-failure free survival (LFFS) was obtained using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS: There were 18 local failures (nine central, eight marginal and one out-of-field). The 2 and 5 year LFFS were 73% and 53%, respectively. In multivariate analysis, PTV-1>1146cc (HR=2.9, CI 95%: 1.1-7.5, p=0.026) was the only factor associated with worse LFFS. CONCLUSIONS: This study shows that local control was independently related to PTV-1 size. The great majority of local recurrences were located in the high-dose region. Dosimetric parameters may contribute to improving radiotherapy results in multidisciplinary treatment for LA-NSCLC.

An independent algorithm to check the monitor units calculation in radiosurgery.

Double checking of the monitor units (MU) is an important step in the quality assurance (QA) process in radiosurgery. In this paper we propose the use of an independent algorithm constructed using the ellipsoid which best fits the measurements taken with the bubble head frame. The monitor units calculated by this independent algorithm and the commercial planning system were compared in 40 patients treated with radiosurgery (57 isocenters, 320 arcs). The average relative difference was -0.2% +/- 2.1 (k=1). These results are better for the variance, -0.4% +/- 1.8 (k=1), when all the depths of the bubble head frame are measured and no arcs are calculated by extrapolation or when only one of these factors appear. If there are missing values in the bubble head frame measurements and the model is extrapolated, the variance of the results is greater, 0.4% +/- 3.9 (k=1). The algorithm is reliable as a QA tool for linac radiosurgery.

Sampling size in the verification of manufactured-supplied air kerma strengths.

Quality control mandate that the air kerma strengths (S(K)) of permanent seeds be verified, this is usually done by statistics inferred from 10% of the seeds. The goal of this paper is to proposed a new sampling method in which the number of seeds to be measured will be set beforehand according to an a priori statistical level of uncertainty. The results are based on the assumption that the S(K) has a normal distribution. To demonstrate this, the S(K) of each of the seeds measured was corrected to ensure that the average S(K) of its sample remained the same. In this process 2030 results were collected and analyzed using a normal plot. In our opinion, the number of seeds sampled should be determined beforehand according to an a priori level of statistical uncertainty.

Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial.

PURPOSE: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

Intensity-modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) in locally advanced rectal cancer (LARC): dosimetric comparison and clinical implications.

PURPOSE: To compare target dose distribution, comformality, normal tissue avoidance, and irradiated body volume (IBV) in 3DCRT using classic anatomical landmarks (c3DCRT), 3DCRT fitting the PTV (f3DCRT), and intensity-modulated radiation therapy (IMRT) in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Fifteen patients with LARC underwent c3DCRT, f3DCRT, and IMRT planning. Target definition followed the recommendations of the ICRU reports No. 50 and 62. OAR (SB and bladder) constraints were D5 < or = 50 Gy and Dmax < 55 Gy. PTV dose prescription was defined as PTV95 > or = 45 Gy and PTVmin > or = 35 Gy. Target coverage was evaluated with the D95, Dmin, and Dmax. Target dose distribution and comformality was evaluated with the homogeneity indices (HI) and Conformity Index (CI). Normal tissue avoidance of OAR was evaluated with the D5 and V40. IBV at 5 Gy (V5), 10 Gy (V10), and 20 Gy (V20) were calculated. RESULTS: The mean GTV95, CTV95, and PTV95 doses were significantly lower for IMRT plans. Target dose distribution was more inhomogeneous after IMRT planning and 3DCRTplans had significantly lower CI. The V40 and D5 values for OAR were significantly reduced in the IMRT plans .V5 was greater for IMRT than for f3DCRT planning (p < 0.05) and V20 was smaller for IMRT plans(p < 0.05). CONCLUSIONS: IMRT planning improves target conformity and decreases irradiation of the OAR at the expense of increased target heterogeneity. IMRT planning increases the IBV at 5 Gy or less but decreases the IBV at 20 Gy or more.

Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson's disease.

The migration of peripheral bone-marrow-derived cells (BMDCs) to the brain was studied in a chronic mouse model of Parkinson's disease (PD). BMDCs expressing the enhanced green fluorescent protein (GFP) were aseptically obtained from C57 BL/6-EGFP-Tg mice and intravenously injected into C57 BL/6j mice which had received a total body irradiation of 8 Gy to induce bone marrow ablation. Implanted GFP-BMDCs replenished the bone marrow of irradiated mice, and progressively crossed the blood-brain barrier (BBB), penetrating different mesencephalic and telencephalic brain regions in the following months. The progressive degeneration of dopamine (DA) cells with a small daily dose (4 mg/kg/day for 20 days) of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) increased the penetration of GFP-BMDCs into the brain, particularly into those regions with marked DA innervation and which showed the clearest DA cell loss. BMDC penetration increased before the DA cell loss was evident and persisted for a long time after MPTP withdrawal. Under these conditions, most BMDCs differentiated into microglia (CD68 expression was observed in 50% of GFP cells 60 days after MPTP administration). BMDC-derived microglia showed morphological characteristics of cell activation, with the glial cell line-derived neurotrophic factor only being expressed in 3% of the cells. No differentiation into neurons (NeuN expression), astrocites (GFAP), cytotoxic lymphocytes (CD8) and T-helper lymphocytes (CD4) was observed. Taken together, the present data suggest that a significant portion of microglial cells is of a peripheral origin. Bearing in mind that microglial reaction is a significant part of the degenerative process in PD, the increase of BMDC penetration into DA-rich areas during DA cell degeneration and their differentiation into microglia suggest that cells coming across the BBB may participate in the neurodegeneration process. The precise role of such a cell inflow into the brain requires further study. Nevertheless, this may represent an opportunity to develop neuroprotective therapeutic strategies for PD.