Enhancement of antitumor immune response by radiation therapy combined with dual immune checkpoint inhibitor in a metastatic model of HER2-positive murine tumor.

PURPOSE: Treatments for metastatic human epidermal growth factor receptor 2 (HER2)-positive tumors are improving but remain inadequate. We investigated activating antitumor immune response by combining radiation therapy with immune checkpoint inhibitors using mouse tumors overexpressing HER2, a pivotal driver oncogenic antigen, to develop new immunotherapies for metastatic HER2-positive tumors. MATERIALS AND METHODS: NT2.5 cells were inoculated into the two mammary fat pads of FVB/N mice, which were divided into four groups: no treatment (Non), anti-PD-1 and anti-CTLA4 antibodies (P1C4), irradiation of the large tumor (Rad), and combination (R + P1C4) groups. Tumor growth, immunostaining of tumor-infiltrating lymphocytes, and the proportion of HER2-tumor antigen-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were analyzed. RESULTS: In the Rad group, unirradiated and irradiated tumors shrank after treatment. Besides the directly irradiated tumors, the unirradiated tumors in the R + P1C4 group shrank the most. In the unirradiated tumors, CD8-positive T cells and FOXP3-positive T cells accumulated significantly more in the R + P1C4 group than in the P1C4 and the Rad groups (all p < 0.001). CD4-positive helper T cells accumulated significantly more in the R + P1C4 group than in the Rad group (p < 0.05), but this was not significantly different from the P1C4 group. HER2-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were significantly increased in the R + P1C4 group compared to the P1C4 and Rad groups (all p < 0.0001). CONCLUSION: Irradiation of HER2-positive tumors induced an antitumor immune effect against the unirradiated tumor, which was enhanced by the combined use of immune checkpoint inhibitors and was mediated by enhanced recruitment of HER2-tumor antigen-specific cytotoxic T lymphocytes at the tumor site in an HER2-positive mouse tumor model. Harnessing the distant antitumor immune response induced by the combination of radiation therapy and immune checkpoint inhibitors could be a promising treatment strategy for metastatic HER2-positive tumors.

MR Imaging-based Evaluation of Mesenteric Ischemia Caused by Strangulated Small Bowel Obstruction and Mesenteric Venous Occlusion: An Experimental Study Using Rabbits.

PURPOSE: This study assessed the MRI findings of strangulated small bowel obstruction (SBO) and mesenteric venous occlusion (MVO) in a rabbit model using 3T MRI. MATERIALS AND METHODS: Twenty rabbits were included in this study. The strangulated SBO and MVO models were generated via surgical procedures in nine rabbits, and sham surgery was performed in two rabbits. The success of generating the models was confirmed via angiographic, macroscopic, and microscopic findings after the surgical procedure. MRI was performed before and 30 min after inducing mesenteric ischemia. T1-weighted images (T1WIs), T2-weighted images (T2WIs), and fat-suppressed T2WIs (FS-T2WIs) were obtained using the BLADE technique, and fat-suppressed T1WIs (FS-T1WIs) were obtained. The signal intensities of the affected bowel before and after the surgical procedures were visually categorized as high, iso, and low intense compared with the findings for the normal bowel wall on all sequences. Bowel wall thickness was measured, and the signal intensity ratio (SI ratio) was calculated using the signal intensities of the bowel wall and psoas muscle. RESULTS: Angiographic, macroscopic, and microscopic findings confirmed that all surgical procedures were successful. The ischemic bowel wall was thicker than the normal bowel. The bowel wall was thicker in the MVO model (3.17 ± 0.55 mm) than in the strangulated SBO model (2.26 ± 0.46 mm). The signal intensity and SI ratio of the bowel wall were significantly higher after the procedure than before the procedure on all sequences in both models. The mesentery adjacent to the ischemic bowel loop exhibited a high signal intensity in all animals on FS-T2WIs. CONCLUSION: Non-contrast MRI can be used to evaluate mesenteric ischemia caused by strangulated SBO and MVO. FS-T2WIs represented the best modality for depicting the high signal intensity in the bowel wall and mesentery caused by ischemia.

A phantom study for ground-glass nodule detectability using chest digital tomosynthesis with iterative reconstruction algorithm by ten observers: association with radiation dose and nodular characteristics.

OBJECTIVE: To compare detectability of simulated ground-glass nodules (GGNs) on chest digital tomosynthesis (CDT) among 12 images obtained at 6 radiation doses using 2 reconstruction algorithms and to analyze its association with nodular size and density. METHODS: 74 simulated GGNs [5, 8 and 10 mm in diameter/-630 and -800 Hounsfield units (HU) in density] were placed in a chest phantom in 14 nodular distribution patterns. 12 sets of coronal images were obtained using CDT at 6 radiation doses: 120 kV-10 mA/20 mA/80 mA/160 mA, 100 kV-80 mA and 80 kV-320 mA with and without iterative reconstruction (IR). 10 radiologists recorded GGN presence and locations by continuously distributed rating. GGN detectability was compared by receiver operating characteristic analysis among 12 images and detection sensitivities (DS) were compared among 12 images in subgroups classified by nodular diameters and densities. RESULTS: GGN detectability at 120 kV-160 mA with IR was similar to that at 120 kV-80 mA with IR (0.614 mSv), as area under receiver operating characteristic curve was 0.798 ± 0.024 and 0.788 ± 0.025, respectively, and higher than six images acquired at 120 kV (p < 0.05). For nodules of -630 HU/8 mm, DS at 120 kV-10 mA without IR was 73.5 ± 6.0% and was similar to that by the other 11 data acquisition methods (p = 0.157). For nodules of -800 HU/10 mm, DS both at 120 kV-80 mA and 120 kV-160 mA without IR was improved by IR (56.3 ± 11.9%) (p < 0.05). CONCLUSION: CDT demonstrated sufficient detectability for larger more-attenuated GGNs (>8 mm) even in the lowest radiation dose (0.17 mSv) and improved detectability for less-attenuated GGNs with the diameter of 10 mm at submillisievert with IR. Advances in knowledge: IR improved detectability for larger less-attenuated simulated GGNs on CDT.

[Waldenström macroglobulinemia complicated with chylothorax].

An 81-year-old male had been diagnosed with Waldenström macroglobulinemia (WM) eight years previously and had thus been administered appropriate treatment. Left chylothorax later developed at 3 years and 8 months after the initial diagnosis. He was hospitalized with severe anemia, general fatigue, and appetite loss one year prior to this presentation and died due to a severe fungal infection. Autopsy revealed the presence of 1,300 ml chylothorax and infiltration of lymphoplasmacytic lymphoma (LPL) cells throughout his entire body. LPL cells were found to have invaded the excitation conducting system in the heart. In an evaluation of a resected lung tissue specimen of pneumothorax, subpleural infiltrated lymphoid cells were observed to show immunohistochemical positivity for IgM and bcl-2. Although these lymphoid cells were initially considered to be non-neoplastic lymphocytes, they were later determined to be LPL cells, which thus induced dilatation and proliferation of the lymph vessels. Chylothorax complications in patients with WM are rare events and only six such cases have so far been reported. The present case is considered to be an instructive one in which autopsy suggested the invasion of LPL cells to be involved in the development of arrhythmia, pneumothorax, and chylothorax before death.