Efficacy of retreatment with polatuzumab vedotin in combination with rituximab in polatuzumab vedotin-resistant DLBCL models.

Polatuzumab vedotin (Pola) was approved for first-line and relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in many countries. This means that retreatment with Pola for r/r DLBCL could be considered after first-line Pola treatment; however, there is currently no evidence on the effectiveness of Pola-retreatment. To address this, we established two Pola-resistant cells from DLBCL cells (SU-DHL-4 and STR-428) and evaluated the combination efficacy of Pola plus rituximab (Rit), the key component of DLBCL therapy. MDR1 overexpression and decreased Bim expression were suggested to be the resistant mechanisms to Pola in Pola-resistant SU-DHL-4 and Pola-resistant STR-428, respectively. In these cells, Pola significantly increased Rit-induced CDC sensitivity either with increased MAC formation or reduced Mcl-1 expression. Additionally, treatment with Pola + Rit significantly enhanced antitumor activity in Pola-resistant STR-428 xenograft mouse models. Based on these results, Pola + Rit retreatment could have preserved efficacy because of the effect of Pola on sensitizing cells to Rit.

In vivo imaging of acute physiological responses after treatment of cancer with near-infrared photoimmunotherapy.

PURPOSE: Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer phototherapy using an antibody-photosensitizer conjugate (Ab-IR700). By NIR light irradiation, Ab-IR700 forms a water-insoluble aggregation on the plasma membrane of cancer cells, leading to lethal membrane damage of cancer cells with high selectivity. However, IR700 produces singlet oxygen, which induces non-selective inflammatory responses such as edema in normal tissues around the tumor. Understanding such treatment-emergent responses is important to minimize side effects and improve clinical outcomes. Thus, in this study, we evaluated physiological responses during NIR-PIT by magnetic resonance imaging (MRI) and positron emission tomography (PET). PROCEDURES: Ab-IR700 was intravenously injected into tumor-bearing mice with two tumors on the right and left sides of the dorsum. At 24 h after injection, a tumor was irradiated with NIR light. Edema formation was examined by T1/T2/diffusion-weighted MRI and inflammation was investigated by PET with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). Because inflammation can increase vascular permeability via inflammatory mediators, we evaluated changes in oxygen levels in tumors using a hypoxia imaging probe, [18F]fluoromisonidazole ([18F]FMISO). RESULTS: The uptake of [18F]FDG in the irradiated tumor was significantly decreased compared to the control tumor, indicating the impairment of glucose metabolism induced by NIR-PIT. MRI and [18F]FDG-PET images showed that inflammatory edema with [18F]FDG accumulation was present in the surrounding normal tissues of the irradiated tumor. Furthermore, [18F]FMISO accumulation in the center of the irradiated tumor was relatively low, indicating the enhancement of oxygen supply due to increased vascular permeability. In contrast, high [18F]FMISO accumulation was observed in the peripheral region, indicating enhancement of hypoxia in the region. This could be because inflammatory edema was formed in the surrounding normal tissues, which blocked blood flow to the tumor. CONCLUSIONS: We successfully monitored inflammatory edema and changes in oxygen levels during NIR-PIT. Our findings on the acute physiological responses after light irradiation will help to develop effective measures to minimize the side effects in NIR-PIT.

Influence on [18F]FDG uptake by cancer cells after anti-PD-1 therapy in an enforced-immune activated mouse tumor.

BACKGROUND: Anti-programmed cell death 1 (PD-1) antibody is an immune checkpoint inhibitor, and anti-PD-1 therapy improves the anti-tumor functions of T cells and affects tumor microenvironment. We previously reported that anti-PD-1 treatment affected tumor glycolysis by using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET). That study showed that anti-PD-1 therapy in a mouse B16F10 melanoma model increased glucose metabolism in cancer cells at the point where anti-PD-1 therapy did not cause a significant inhibition of tumor growth. However, the B16F10 melanoma model is poorly immunogenic, so it is not clear how anti-PD-1 treatment affects glucose metabolism in highly immunogenic cancer models. In this study, we used a cyclic dinucleotide GMP-AMP (cGAMP)-injected B16F10 melanoma model to investigate the effect of anti-PD-1 therapy on [18F]FDG uptake in a highly immune activated tumor in mice. RESULTS: To compare the cGAMP-injected B16F10 model with the B16F10 model, experiments were performed as described in our previous manuscript. [18F]FDG-PET was measured before treatment and 7 days after the start of treatment. In this study, [18F]FDG uptake in tumors in the cGAMP/anti-PD-1 combination group was lower than that in the anti-PD-1 treatment group tumors on day 7, as shown by PET and ex vivo validation. Flow-cytometry was performed to assess immune cell populations and glucose metabolism. Anti-PD-1 and/or cGAMP treatment increased the infiltration level of immune cells into tumors. The cGAMP/anti-PD-1 combination group had significantly lower levels of GLUT1high cells/hexokinase IIhigh cells in CD45- cancer cells compared with tumors in the anti-PD-1 treated group. These results suggested that if immune responses in tumors are higher than a certain level, glucose uptake in cancer cells is reduced depending on that level. Such a change of glucose uptake might be caused by the difference in infiltration or activation level of immune cells between the anti-PD-1 treated group and the cGAMP/anti-PD-1 combination group. CONCLUSIONS: [18F]FDG uptake in cancer cells after anti-PD-1 treatment might be affected by the tumor immune microenvironment including immune cell infiltration, composition, and activation status.

Asian dust increases radiocesium retention ability of serpentine soils in Japan.

Radiocesium (RCs) is selectively adsorbed on interlayer sites of weathered micaceous minerals, which can reduce the mobility of RCs in soil. Therefore, soils developed from mica-deficient materials (e.g. serpentine soils) may have a higher risk of soil-to-plant transfer of RCs. Soils were collected from three serpentine soil profiles; Udepts in Oeyama, Japan, and Udepts and Udox in Kinabalu, Malaysia. Soil was sampled every 3 cm from 0 to 30 cm depth and sieved to isolate soil particles of ≤20 µm diameter for the assessment of radiocesium interception potential (RIP) after a series of pretreatments. One subset was treated with H2O2 to remove organic matter (OM). Another subset was further treated with hot sodium citrate to remove hydroxy-Al polymers (Al(OH)x). RIPuntreated was <0.4 mol kg-1 whereas mica-K content was <0.02% by weight for ≤20-µm soil particles from Udepts and Udox in Kinabalu, Malaysia, values as low as those of non-micaceous minerals (e.g. kaolinite and smectite). Neither OM nor Al(OH)x removal resulted in a large increase in RIP value for these soils. These results clearly indicated that serpentine soils in Malaysia have very few RCs selective adsorption sites due to the absence of micaceous minerals. In contrast, soil from Udepts in Oeyama, Japan showed average RIPuntreated of 5.6 mol kg-1 and mica-K content of 0.72% by weight for the ≤20-µm particles. Furthermore, the RIP value was significantly increased to an average of 22.5 mol kg-1 after removing both OM and Al(OH)x. These results strongly suggest that weathered micaceous minerals primarily control the ability to retain RCs. These micaceous minerals cannot originate from serpentine minerals, and are probably incorporated as an exotic material, such as Asian dust. This hypothesis is supported by the δ18O value of quartz isolated from the ≤20-µm soil particles from Oeyama, Japan (+16.13‰±0.11‰), very similar to that of Asian dust. In conclusion, serpentine soils in Japan may exhibit a reduced risk of soil-to-plant transfer of RCs due to the historical deposition of Asian dust.

The effectiveness of end-of-life care simulation in undergraduate nursing education: A randomized controlled trial.

BACKGROUND: Nursing students have limited opportunities to experience end-of-life care, so it is difficult for them to learn how to deliver it empirically. The use of simulations with standardized patients may be a way to provide realistic experience of end-of-life care for nursing students. OBJECTIVES: The aim of this study was to evaluate the effectiveness of end-of-life care simulations with standardized patients in improving the knowledge, skill performance and self-confidence of undergraduate nursing students. DESIGN: Randomized controlled study. SETTING: Japanese university nursing school. PARTICIPANTS: Thirty-eight students in the third year of the Bachelor's degree in nursing (simulation group = 20, control group = 18). METHODS: After randomization to a simulation or control group, participants in the simulation group participated in an end-of-life care simulation with standardized patients. The primary outcome of a change in the knowledge score was assessed using a knowledge questionnaire, skill performance by completing Objective Structured Clinical Evaluations, and self-confidence related to end-of-life care by self-reported questionnaires. RESULTS: The simulation group improved significantly in knowledge, skill performance in physical assessment and psychological care, and self-confidence related to end-of-life care. The results of the two-way analysis of variance showed a significant interaction between groups and time (p = 0.000). Analysis of the simple main effect showed a significant difference (p = 0.000) between groups after the end-of-life care simulation and a significant difference (p = 0.000) over time in the simulation group. There were large effects on knowledge improvement (η2 = 0.372), physical assessment (η2 = 0.619), psychological care skill performance (η2 = 0.588), and self-confidence in both physical assessment (η2 = 0.410) and psychological care (η2 = 0.722). CONCLUSIONS: End-of-life care simulation with standardized patients would be an effective strategy to train nursing students, who have limited opportunities to experience end-of-life care.

Anti PD-1 treatment increases [18F]FDG uptake by cancer cells in a mouse B16F10 melanoma model.

BACKGROUND: Programmed cell death 1 (PD-1) inhibitors act as immune checkpoint inhibitors and are more effective for improving survival time with less toxicity as compared with conventional chemotherapies. In anti PD-1 therapy, it is important to evaluate metabolism in the cancer microenvironment, as this helps to clarify the pathological conditions. Herein, we investigate the early effects of PD-1 therapy on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake in vivo, focusing on cell distribution and glycolysis in both cancer and immune cells. RESULTS: In a B16F10 melanoma model, [18F]FDG-positron emission tomography (PET) was performed before treatment and 7 days after the start of treatment. Values were calculated as the percentage-injected activity per gram of tissue (%IA/g). Flow-cytometry was then performed to assess immune cell populations and glucose metabolism. There was a negligible difference in [18F]FDG uptake between tumors in the treatment group and non-treatment group before the treatment. In contrast, mean [18F]FDG uptake in the treatment group tumors was significantly higher (8.06 ± 0.48 %IA/g; P = 0.0074) than that in the non-treatment group (4.02 ± 1.03 %IA/g) after anti PD-1 treatment. Assessment of tumor immune cell populations showed that treatment slightly enriched CD8+ T cells and CD4+ T cells; however, infiltration of immune cells was negligible, and thus, immune cells were not responsible for the increase in [18F]FDG uptake. On the other hand, anti PD-1 treatment significantly increased glucose transporter 1 (GLUT1) and hexokinase II expression in CD45- cancer cells, indicating that anti PD-1 treatment increased glucose metabolism in cancer cells. CONCLUSION: The present study shows that anti PD-1 therapy increases glucose metabolism in cancer cells.