The impact of the radiotherapy technique in sparing the heart substructures in central tumor irradiation in lung cancer

Introduction: In thoracic radiotherapy (RT), heart sparing is very essential, as the high cardiac dose is associated with poor survival in patients with locally advanced non-small-cell lung cancer (NSCLC). The study aims to determine the doses exposed to heart substructures and coronary arteries by different RT techniques in central tumor irradiation in lung cancer. Methods: Twenty patients with NSCLC, irradiated between January 2018 and December 2020 in our department, were included in this study. Patients whose primary tumor was centrally located in the left lung were selected. The heart substructures [left atrium, right atrium (RA), left ventricle, and right ventricle] and coronary arteries (left main, left anterior descending, circumflex, and right coronary arteries) were delineated by the same physician. The doses of 60 Gy external RT were prescribed in 30 fractions using three-dimensional conformal radiotherapy (3D-CRT), static intensity-modulated radiotherapy (s-IMRT), and dynamic intensity-modulated radiotherapy (d-IMRT) techniques in all patients. The obtaining plans using three different techniques were compared. Results: The d-IMRT plans were statistically the best optimal plan for planning target volume (PTV) [Dmean (p = 0 04), Dmax (p < 0 0001), V95 (p < 0 0001), V107 (p < 0 0001), CI (p < 0 0001) and HI (p < 0 0001)]. The s-IMRT plans were significantly superior to 3D-CRT plans for PTV. RA Dmax and V45 were not different between the three techniques [Dmax (p = 0 148) and V45 (p = 0 12)]. The d-IMRT technique was significantly better in other heart substructures and coronary arteries. Conclusions: Compared to 3D-CRT and s-IMRT techniques, the d-IMRT technique provided the best protection in all heart substructures except for a few parameters (RA Dmax and V45 doses).

Green's Function Solutions of 1- and 2-D Dual-Phase-Lag Laser Heating Problems in Nano/Microstructures

Lasers and laser heating have a wide variety of applications such as spectroscopy, laser welding, laser cutting, and even biological applications like tumor irradiation and surgery. Theoretical modeling of laser heating has proven to be quite difficult, and classical heating equations have shown to be inaccurate due to the large temperature gradients created by the laser heating. Furthermore, the commonly-used Fourier's Law assumed the speed for a thermal wave to propagate as infinite; this is unrealistic in any medium and especially in domains with slow propagation speeds such as biological media and in fast nano/microscale heating applications. This study helps fill some of the gaps in accurate model of laser heating by presenting unique 1-D and 2-D models of the analytically solved Dual-Phase-Lag (DPL) heating equations which can much more accurately describe the temperature of such interactions in both the temporal and spatial domains.

Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses

Although radiotherapy has been used for over a century to locally control tumor growth, alone it rarely induces an abscopal response or systemic antitumor immunity capable of inhibiting distal tumors outside of the irradiation field. Results from recent studies suggest that combining immune checkpoint blockades to radiotherapy may enhance abscopal activity. However, the treatment conditions and underlying immune mechanisms that consistently drive an abscopal response during radiation therapy combinations remain unknown. Here, we analyzed the antitumor responses at primary and distal tumor sites, demonstrating that the timing of αPD-1 antibody administration relative to radiotherapy determined the potency of the induced abscopal response. Blockade of the PD-1 pathway after local tumor irradiation resulted in the expansion of polyfunctional intratumoral CD8+ T cells, a decrease in intratumoral dysfunctional CD8+ T cells, expansion of reprogrammable CD8+ T cells, and induction of potent abscopal responses. However, administration of αPD-1 before irradiation almost completely abrogated systemic immunity, which associated with increased radiosensitivity and death of CD8+ T cells. The subsequent reduction of polyfunctional effector CD8+ T cells at the irradiated tumor site generated a suboptimal systemic antitumor response and the loss of abscopal responses. Therefore, this report maximizes the potential synergy between radiotherapy and αPD-1 immunotherapy, information that will benefit clinical combinations of radiotherapy and immune checkpoint blockade.

The Tumor Suppressor MTUS1/ATIP1 Modulates Tumor Promotion in Glioma: Association with Epigenetics and DNA Repair

Glioblastoma (GBM) is a highly aggressive brain tumor. Resistance mechanisms in GBM present an array of challenges to understand its biology and to develop novel therapeutic strategies. We investigated the role of a TSG, MTUS1/ATIP1 in glioma. Glioma specimen, cells and low passage GBM sphere cultures (GSC) were analyzed for MTUS1/ATIP1 expression at the RNA and protein level. Methylation analyses were done by bisulfite sequencing (BSS). The consequence of chemotherapy and irradiation on ATIP1 expression and the influence of different cellular ATIP1 levels on survival was examined in vitro and in vivo. MTUS1/ATIP1 was downregulated in high-grade glioma (HGG), GSC and GBM cells and hypermethylation at the ATIP1 promoter region seems to be at least partially responsible for this downregulation. ATIP1 overexpression significantly reduced glioma progression by mitigating cell motility, proliferation and facilitate cell death. In glioma-bearing mice, elevated MTUS1/ATIP1 expression prolonged their survival. Chemotherapy, as well as irradiation, recovered ATIP1 expression both in vitro and in vivo. Surprisingly, ATIP1 overexpression increased irradiation-induced DNA-damage repair, resulting in radio-resistance. Our findings indicate that MTUS1/ATIP1 serves as TSG-regulating gliomagenesis, progression and therapy resistance. In HGG, higher MTUS1/ATIP1 expression might interfere with tumor irradiation therapy.

Correction: Synergistic effects of magnetic drug targeting using a newly developed nanocapsule and tumor irradiation by ultrasound on CT26 tumors in BALB/c mice

Correction for ‘Synergistic effects of magnetic drug targeting using a newly developed nanocapsule and tumor irradiation by ultrasound on CT26 tumors in BALB/c mice’ by Ali Shakeri-Zadeh et al., J. Mater. Chem. B, 2015, 3, 1879–1887, DOI: 10.1039/C4TB01708K.

Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY)

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher “immunogenic potential”. This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.