Efficacy of Dynamic Chest Radiography for Chronic Thromboembolic Pulmonary Hypertension.

Background While current guidelines require lung ventilation-perfusion (V/Q) scanning as the first step to diagnose chronic pulmonary embolism in pulmonary hypertension (PH), its use may be limited by low availability and/or exposure to ionizing radiation. Purpose To compare the performance of dynamic chest radiography (DCR) and lung V/Q scanning for detection of chronic thromboembolic PH (CTEPH). Materials and Methods Patients with PH who underwent DCR and V/Q scanning in the supine position from December 2019 to July 2021 were retrospectively screened. The diagnosis of CTEPH was confirmed with right heart catheterization and invasive pulmonary angiography. Observer tests were conducted to evaluate the diagnostic accuracy of DCR and V/Q scanning. The lungs were divided into six areas (upper, middle, and lower for both) in the anteroposterior image, and the number of lung areas with thromboembolic perfusion defects was scored. Diagnostic performance was compared between DCR and V/Q scanning using the area under the receiver operating characteristic curve. Agreement between the interpretation of DCR and that of V/Q scanning was assessed using the Cohen kappa coefficient and percent agreement. Results A total of 50 patients with PH were analyzed: 29 with CTEPH (mean age, 64 years ± 15 [SD]; 19 women) and 21 without CTEPH (mean age, 61 years ± 22; 14 women). The sensitivity, specificity, and accuracy of DCR were 97%, 86%, and 92%, respectively, and those of V/Q scanning were 100%, 86%, and 94%, respectively. Areas under the receiver operating characteristic curve for DCR and V/Q scanning were 0.92 (95% CI: 0.79, 0.97) and 0.93 (95% CI: 0.78, 0.98). Agreement between the consensus interpretation of DCR and that of V/Q scanning was substantial (κ = 0.79 [95% CI: 0.61, 0.96], percent agreement = 0.9 [95% CI: 0.79, 0.95]). Conclusion Dynamic chest radiography had similar efficacy to ventilation-perfusion scanning in the detection of chronic thromboembolic pulmonary hypertension. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Wandtke and Koproth-Joslin in this issue.

Near-infrared photoimmunotherapy through bone.

Near-infrared photoimmunotherapy (NIR-PIT) is a molecularly targeted cancer phototherapy that is based on injecting a conjugate of a silicon-phthalocyanine derivative, IRdye 700DX (IR700), and a monoclonal antibody that targets an expressed antigen on the cancer cell surface. Subsequent local exposure to NIR light results in the rapid and highly selective immunogenic cell death of targeted cancer cells. Because many cancers grow in bones through which light does not penetrate well, the goal of this study was to determine if NIR-PIT can effectively treat cancers in bone. A bovine rib was used as a bone sample. Because the sample's NIR light transmittance was shown to be approximately 4.52% in preliminary tests, it was hypothesized that a maximum radiation dosage of 128 and 1500 J/cm2 would be sufficient to induce cell death in in vitro target cells and in vivo mouse tumor models, respectively. Cell viability was measured through bioluminescence studies comparing relative luciferase activity, as well as a cytotoxicity assay. In the in vitro model, tumor cell viability was significantly decreased after 64 and 128 J/cm2 NIR light irradiation through the bone. An in vivo mouse tumor model also showed that 1500 J/cm2 NIR light irradiation through the bone significantly reduced tumor viability at both 24 and 48 hours posttreatment compared to the control group (P = .026 and .040 respectively). Therefore, despite limitations in light transmission, NIR-PIT nevertheless is capable of effectively treating cancers within bone.

The Effect of Antibody Fragments on CD25 Targeted Regulatory T Cell Near-Infrared Photoimmunotherapy.

Regulatory T (Treg) cells play a major role in immune suppression permitting tumors to evade immune surveillance. Depletion of intratumoral Treg cells can result in tumor regression. However, systemic depletion of Tregs may also induce autoimmune adverse events. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cell-specific cancer therapy that locally kills specific cells in the tumor. Antibody-photoabsorber (IRDye700DX) conjugates (APC) are injected and bind to the tumor, and subsequent administration of NIR light to the tumor results in rapid cell death only in targeted cells. CD25-targeted NIR-PIT has been shown to induce spatially selective depletion of tumor-associated Treg cells. In this study, we compared the efficacy of an antibody fragment, anti-CD25-F(ab')2, and a full antibody, anti-CD25-IgG, as agents for NIR-PIT. Tumor-bearing mice were divided into four groups: (1) no treatment; (2) anti-CD25-IgG-IR700 i.v. only; (3) anti-CD25-F(ab')2-IR700 i.v. with NIR light exposure; and (4) anti-CD25-IgG-IR700 i.v. with NIR light exposure. Although both CD25-targeted NIR-PITs resulted in significant tumor growth inhibition, the anti-CD25-F(ab')2-IR700 based NIR-PIT was superior to the anti-CD25-IgG-IR700 NIR-PIT. The anti-CD25-F(ab')2-IR700 demonstrated faster clearance from the body than the anti-CD25-IgG-IR700. Sustained circulation of anti-CD25-IgG-IR700 may block IL-2 binding on the activated effector T-cells decreasing immune response. In conclusion, anti-CD25-F(ab')2 based NIR-PIT was more effective in reducing tumor growth than anti-CD25-IgG based NIR-PIT. Absence of the Fc portion of the APC leads to faster clearance and therefore promotes a superior activated T cell response in tumors.

Activatable Near-Infrared Fluorescence Imaging Using PEGylated Bacteriochlorin-Based Chlorin and BODIPY-Dyads as Probes for Detecting Cancer.

Near infrared (NIR) fluorescent probes are attractive tools for biomedical in vivo imaging due to the relatively deeper tissue penetration and lower background autofluorescence. Activatable probes are turned on only after binding to their target, further improving target to background ratios. However, the number of available activatable NIR probes is limited. In this study, we introduce two types of activatable NIR fluorophores derived from bacteriochlorin: chlorin-bacteriochlorin energy-transfer dyads and boron-dipyrromethene (BODIPY)-bacteriochlorin energy-transfer dyads. These fluorophores are characterized by multiple narrow excitation bands with relatively strong emission in the NIR. Targeted bacteriochlorin-based antibody or peptide probes have been previously limited by aggregation after conjugation. Polyethylene glycol (PEG) chains were added to improve the hydrophilicity without altering pharmacokinetics of the targeting moieties. These PEGylated bacteriochlorin-based activatable fluorophores have potential as targeted activatable, multicolor NIR fluorescent probes for in vivo applications.

Near infrared photoimmunotherapy using a fiber optic diffuser for treating peritoneal gastric cancer dissemination.

BACKGROUND: Peritoneal dissemination (PD) of abdominal malignancies is a common form of metastasis and its presence signals a poor prognosis. New treatment is required for patients with PD. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). In this study, we investigate in vitro and in vivo efficacy of trastuzumab (tra)-IR700DX NIR-PIT on a human epidermal growth factor receptor type 2 (HER2)-positive gastric cancer cell line. METHODS: NIR-PIT effects were investigated in vitro and in vivo. Disseminated peritoneal implants mice were separated into 5 groups: (1) no treatment; (2) tra-IR700 i.v. only; (3) NIR light only; (4) NIR-PIT; (5) repeated NIR-PIT. The peritoneal cavity was irradiated with NIR light using a fiber optic diffuser delivered through the catheter. RESULTS: Specific binding and cell-specific killing was observed after NIR-PIT in vitro. In the in vivo study, fluorescence endoscopy showed high tumor accumulation of tra-IR700 within tumors. Significantly prolonged survival was achieved in the three treatment groups (tra-IR700 i.v. only, NIR-PIT, and repeated NIR-PIT groups) compared with control and NIR light only group (p < 0.05 for tra-IR700 i.v. only, p < 0.01 for NIR-PIT, and p < 0.0001 for repeated NIR-PIT). Moreover, most prolonged survival was shown for the repeated NIR-PIT group (p < 0.0001 vs tra-IR700 i.v. only, p < 0.01 vs NIR-PIT). CONCLUSION: NIR-PIT using a fiber optic diffuser to deliver light is a promising candidate for the treatment of disseminated peritoneal metastases and could be readily translated to humans.

Endoscopic near infrared photoimmunotherapy using a fiber optic diffuser for peritoneal dissemination of gastric cancer.

Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC) which is activated by near infrared light. Here, we describe the efficacy of endoscopic NIR-PIT using the APC trastuzumab-IR700DX (tra-IR700) in the setting of human epidermal growth factor 2 positive (HER2 + ) gastric carcinoma with peritoneal disseminations. In this in vivo study, fluorescence endoscopy showed high tumor accumulation of tra-IR700 within disseminated peritoneal implants. Mice with disseminated peritoneal gastric cancer were separated into 4 groups: (i) control (no treatment); (ii) tra-IR700 i.v. only; (iii) NIR light only; and (iv) endoscopic NIR-PIT. NIR light irradiation was carried out through a fiber optic diffuser under endoscopic guidance. In vivo bioluminescence images showed significantly greater therapeutic effect in the endoscopic NIR-PIT group than that in the control groups (P < .01 vs other control groups). Histological analysis showed diffuse cancer cell death in NIR-PIT-treated tumors. In conclusion, NIR-PIT with NIR light delivered via an endoscopic fiber optic diffuser is a promising method for the treatment of peritoneal dissemination of gastric cancer. Moreover, this technique could be readily used in other types of cancers with peritoneal dissemination provided that suitable antibodies could be found.

Near Infrared Photoimmunotherapy with Combined Exposure of External and Interstitial Light Sources.

Near infrared photoimmunotherapy (NIR-PIT) is a new target-cell-specific cancer treatment that induces highly selective necrotic/immunogenic cell death after systemic administration of a photoabsorber antibody conjugate and subsequent NIR light exposure. However, the depth of NIR light penetration in tissue (approximately 2 cm) with external light sources limits the therapeutic effects of NIR-PIT. Interstitial light exposure using cylindrical diffusing optical fibers can overcome this limitation. The purpose in this study was to compare three NIR light delivery methods for treating tumors with NIR-PIT using a NIR laser system at an identical light energy; external exposure alone, interstitial exposure alone, and the combination. Panitumumab conjugated with the photoabsorber IRDye-700DX (pan-IR700) was intravenously administered to mice with A431-luc xenografts which are epithelial growth factor receptor (EGFR) positive. One and 2 days later, NIR light was administered to the tumors using one of three methods. Interstitial exposure alone and in combination with external sources showed the greatest decrease in bioluminescence signal intensity. Additionally, the combination of external and interstitial NIR light exposure showed significantly greater tumor size reduction and prolonged survival after NIR-PIT compared to external exposure alone. This result suggested that the combination of external and interstitial NIR light exposure was more effective than externally applied light alone. Although external exposure is the least invasive means of delivering light, the combination of external and interstitial exposures produces superior therapeutic efficacy in tumors greater than 2 cm in depth from the tissue surface.

Evaluation of Early Therapeutic Effects after Near-Infrared Photoimmunotherapy (NIR-PIT) Using Luciferase-Luciferin Photon-Counting and Fluorescence Imaging.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that induces highly selective immunogenic cell death. It is based on an antibody-photoabsorber conjugate (APC) that is activated by NIR light. The purpose of this study was to investigate the effects of NIR-PIT as measured by luciferase-luciferin photon-counting and fluorescence imaging. Six days after subcutaneous injection of A431-luc-GFP cells tumors formed in a xenograft mouse model. The EGFR-targeting antibody, panitumumab, was conjugated to the photoabsorber, IRDye-700DX (pan-IR700), and was intravenously administered to tumor-bearing mice. Serial luciferase-luciferin photon-counting images and both green fluorescent protein (GFP) and IR700 fluorescence images were obtained from the same mice before and after NIR-PIT treatment (0, 10, 20, 30 min (early phase), and 24, 48 h (late phase) after NIR light exposure). Optical signal intensities were compared for each modality. IR700 fluorescence and luciferase-luciferin photon-counting images showed decreased intensities in both the early and late phases after NIR-PIT (p < 0.01). On the other hand, GFP fluorescence images showed decreased intensities only in the late phase (p < 0.01). In the early phase, GFP fluorescence images showed smaller intensity reductions compared to IR700 fluorescence and luciferase-luciferin photon-counting (p < 0.01), while in the late phase, IR700 fluorescence showed smaller intensity reductions than luciferase-luciferin photon-counting and GFP fluorescence (p < 0.05), due to redistribution of pan-IR700 within the tumor bed. In conclusion, luciferase-luciferin photon-counting imaging is suitable to evaluate early phase NIR-PIT effects, while both luciferase-luciferin photon-counting and GFP reflected later phase effects.

Relationship between impaired cardiac sympathetic activity and spatial dyssynchrony in patients with non-ischemic heart failure: assessment by MIBG scintigraphy and tagged MRI.

BACKGROUND: Impairment of cardiac sympathetic activity has various detrimental effects on cardiac function. The purpose was to investigate the relationship between left ventricular (LV) dyssynchrony and cardiac sympathetic activity in non-ischemic heart failure (HF). METHODS: Twenty-seven patients with non-ischemic HF were enrolled. Cardiac sympathetic activity was assessed by heart-to-mediastinum ratio (H/M ratio) on (123)I-Metaiodobenzylguanidine scintigraphy. LV dyssynchrony was assessed by cross-correlation analysis of time curves of myocardial circumferential strains delivered from cine-tagging MR images. Temporal dyssynchrony was defined as contraction delay between septal and lateral segments >110 milliseconds. Spatial dyssynchrony was defined as the negative value of the maximum correlation for the two strain time curves. RESULTS: H/M ratio was significantly lower for patients with spatial dyssynchrony compared to patients without (1.8 ± 0.3 vs 2.1 ± 0.3, P < .05). There was no difference between patients with and without temporal dyssynchrony (2.0 ± 0.2 vs 2.0 ± 0.3). The incidence of spatial dyssynchrony was significantly higher in patients with H/M ratio <2.0 than those whose ratios were ≥2.0 (75% vs 20%, P = .001). There was no difference in the incidence of temporal dyssynchrony between the two groups (17% vs 20%). CONCLUSION: Impairment of cardiac sympathetic activity was found to be associated with spatial dyssynchrony in patients with non-ischemic HF.

Differentiating primary CNS lymphoma from glioblastoma multiforme: assessment using arterial spin labeling, diffusion-weighted imaging, and ¹8F-fluorodeoxyglucose positron emission tomography.

INTRODUCTION: Our purpose was to evaluate the diagnostic performance of arterial spin labeling (ASL) perfusion imaging, diffusion-weighted imaging (DWI), and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastoma multiformes (GBMs). METHODS: Fifty-six patients including 19 with PCNSL and 37 with GBM were retrospectively studied. From the ASL data, an absolute tumor blood flow (aTBF) and a relative tumor blood flow (rTBF) were obtained within the enhancing portion of each tumor. In addition, the minimum apparent diffusion coefficient (ADCmin) and the maximum standard uptake value (SUVmax) were obtained from DWI and FDG-PET data, respectively. Each of the four parameters was compared between PCNSLs and GBMs using Kruskal-Wallis test. The performance in discriminating between PCNSLs and GBMs was evaluated using the receiver-operating characteristics analysis. Area-under-the-curve (AUC) values were compared among the four parameters using a nonparametric method. RESULTS: The aTBF, rTBF, and ADCmin were significantly higher in GBMs (mean aTBF ± SD = 91.6 ± 56.0 mL/100 g/min, mean rTBF ± SD = 2.61 ± 1.61, mean ADCmin ± SD = 0.78 ± 0.19 × 10(-3) mm(2)/s) than in PCNSLs (mean aTBF ± SD = 37.3 ± 10.5 mL/100 g/min, mean rTBF ± SD = 1.24 ± 0.37, mean ADCmin ± SD = 0.61 ± 0.13 × 10(-3) mm(2)/s) (p < 0.005, respectively). In addition, SUVmax was significantly lower in GBMs (mean ± SD = 13.1 ± 6.34) than in PCNSLs (mean ± SD = 22.5 ± 7.83) (p < 0.005). The AUC for aTBF (0.888) was higher than those for rTBF (0.810), ADCmin (0.768), and SUVmax (0.848), although their difference was not statistically significant. CONCLUSION: ASL perfusion imaging is useful for differentiating PCNSLs from GBMs as well as DWI and FDG-PET.

Incremental diagnostic value of SPECT/CT with 131I scintigraphy after radioiodine therapy in patients with well-differentiated thyroid carcinoma.

PURPOSE: To retrospectively determine the incremental diagnostic value of adding single photon emission computed tomography/computed tomography (SPECT/CT) to whole-body scintigraphy with iodine 131 ((131)I) compared with scintigraphy alone after radioiodine therapy in patients with well-differentiated thyroid carcinoma. MATERIALS AND METHODS: This retrospective study was institutional review board approved; written informed consent was waived. The study included 147 patients (94 female, 53 male patients; mean age, 51 years) with well-differentiated thyroid carcinoma treated with radioiodine therapy between October 2009 and August 2010. Whole-body scintigraphy and SPECT/CT were performed on the same day in all patients receiving radioiodine therapy. Each radioactive focus at whole-body scintigraphy was classified as positive or equivocal with respect to thyroid bed, lymph node, and distant metastasis uptake. Differences between whole-body scintigraphy and SPECT/CT findings were assessed with the generalized McNemar test. RESULTS: At SPECT/CT, origin was clearly determined of all five "hot spots" in the thyroid bed (remnant thyroid tissue or metastatic lymph node) that were judged as equivocal at whole-body scintigraphy. Interpretation of 24 (22.2%) of 108 radioactive foci for lymph node metastases was changed with SPECT/CT (P < .0001). One of 85 foci that were thought to be positive findings at whole-body scintigraphy turned out to be a negative finding (false-positive finding), and 13 and seven of 20 equivocal foci at whole-body scintigraphy were positive and negative findings, respectively, after adding SPECT/CT findings. Three false-negative findings at whole-body scintigraphy were corrected with SPECT/CT. For the detection of distant metastasis, the interpretations of 21 (40%) of 52 foci were corrected with SPECT/CT (P < .0001). One of 32 foci thought to be a positive finding at whole-body scintigraphy was a negative finding, and 11 and nine of 20 equivocal foci at whole-body scintigraphy were positive and negative findings, respectively, after SPECT/CT. At a patient-based analysis, SPECT/CT findings helped change the clinical staging in nine (6.1%) of 147 patients and therapeutic planning in three (2.0%) of 147 patients. CONCLUSION: SPECT/CT improved detection and localization of (131)I accumulation in lymph node metastases and distant metastases, compared with whole-body scintigraphy.

Usefulness of semi-quantitative analysis in 123I metaiodobenzylguanidine SPECT/CT for the differentiation of pheochromocytoma and cortical adenoma.

OBJECTIVE: 123I metaiodobenzylguanidine (MIBG) scintigraphy is a useful tool for the diagnosis of pheochromocytomas (PHEOs), but some PHEOs are difficult to differentiate from cortical adenoma (CA) or normal adrenal uptake by visual evaluation alone. A new semi-quantitative analysis using 123I MIBG SPECT/CT is thus expected. Herein, we introduce the tumor-to-liver count ratio (T/L) and the tumor-to-muscle count ratio (T/M). METHODS: We examined the cases of 21 patients with PHEOs (10 males, 11 females; age 24-80, median 61 years) and 23 patients with CA (15 males and 8 females, age 30-78, median 58 years). The visual scoring based on 123I MIBG planar images (planar score) and SPECT images (SPECT score) was used as the conventional evaluation. Using 123I MIBG SPECT/CT findings, we calculated the semi-quantitative values of the count ratio using the maximum or mean count of the tumor and the liver or muscle as the reference organ (T/Lmax, T/Lmean, T/Mmax and T/Mmean). Each evaluation of the PHEOs and CAs was compared, and the diagnosing performance was evaluated based on an ROC analysis. RESULTS: The area under curve (AUC) values were as follows: the planar score, 0.833; SPECT score, 0.813; T/Lmax, 0.986; T/Lmean, 0.975; T/Mmax, 0.955; and T/Mmean, 0.933. The AUC for T/Mmax was significantly higher than those of the planar score, and SPECT score by ROC analysis (p < 0.01 each). CONCLUSION: The semi-quantitative value of 123I MIBG SPECT/CT is more useful than the conventional visual evaluation for differentiating PHEOs from CAs.

Near infrared photoimmunotherapy for cancers: A translational perspective.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly-developed, highly-selective cancer treatment, which utilizes a monoclonal antibody conjugated to a photoabsorbing dye, IRDye700DX (IR700). The antibody conjugate is injected into the patient and accumulates in the tumour. Within 24 h of injection the tumour is exposed to NIR light which activates the conjugate and causes rapid, selective cancer cell death. A global phase III clinical trial of NIR-PIT in recurrent head and neck squamous cell cancer (HNSCC) patients is currently underway. Conditional clinical approval for NIR-PIT in recurrent HNSCC has been granted in Japan as of September 2020. Not only does NIR-PIT induce highly selective and immediate cancer cell killing, but it also stimulates highly active anti-tumour immunity. While monotherapy with NIR-PIT has proven effective it is likely that combinations with immune-checkpoint inhibitors or additional NIR-PIT targeting immune suppressive cells in the tumour microenvironment will further improve results. In this review, we discuss the translational aspects of NIR-PIT especially in HNSCC, and potential future applications.

Real-time IR700 Fluorescence Imaging During Near-infrared Photoimmunotherapy Using a Clinically-approved Camera for Indocyanine Green.

Background/Aim: Near-infrared photoimmuno-therapy (NIR-PIT) is a newly approved cancer phototherapy. We aim to confirm whether a clinically approved camera for indocyanine green (ICG) could monitor IR700 fluorescence in real time during exposure to therapeutic NIR light. Materials and Methods: An NIR camera, LIGHTVISION, designed to image ICG fluorescence, was used. A431-GFP/luc tumor-bearing mice were exposed to therapeutic NIR light and real-time fluorescence imaging (RT-FI) was obtained and measured with LIGHTVISION. Bioluminescence imaging (BLI) was performed to confirm cell death. Results: RT-FI during NIR-PIT revealed an initial rapid loss of fluorescence, followed by a plateau which occurred at a light dose of approximately 30 J/cm 2 . Correlation between BLI and IR700 fluorescence loss showed that loss of fluorescence was associated with increased cell death. Conclusion: The efficacy of NIR-PIT could be monitored non-invasively and in real-time using weak fluorescence at wavelengths much longer than the peak fluorescence of IR700. This technique can achieve precise light dosimetry that allows us to decide on the optimal exposure.

123I metaiodobenzylguanidine (MIBG) uptake predicts early relapse of neuroblastoma using semi-quantitative SPECT/CT analysis.

OBJECTIVE: 123I metaiodobenzylguanidine (MIBG) scintigraphy is a useful tool for the diagnosis of neuroblastoma (NB). MIBG uptake is correlated with norepinephrine transporter expression; hence, it is expected that high-MIBG tumors would be more highly differentiated and have a better prognosis than those with lower expression. We have introduced a method of assessing MIBG accumulation semi-quantitatively using SPECT/CT fusion images. The purpose of this study was to evaluate the relationship of 123I MIBG uptake measured by semi-quantitative values of SPECT/CT and early relapse of NB. METHODS: We studied the cases of 11 patients (5 males and 6 females, age 5-65 months, median age 20 months) with histopathologically proven NB between April 2010 and March 2015. The early-relapse group was defined as patients who had relapsed within 3 years after the first 123I MIBG SPECT/CT exam. Other patients were classified as the delay-relapse group. Uptake of MIBG was evaluated using the count ratio of tumor and muscles. T/Mmax and T/Mmean were defined as follows: T/Mmax = max count of tumor/max count of muscle, T/Mmean = mean count of tumor/mean count of muscle. RESULTS: The average T/Mmean values of the early-relapse group and delay-relapse group were 2.65 ± 0.58 and 7.66 ± 2.68, respectively. The T/Mmean values of the early-relapse group were significantly lower than those of delay-relapse group (p < 0.05). The average T/Mmax of the early-relapse group and delay-relapse group were 8.86 ± 3.22 and 16.20 ± 1.97, respectively. There was no significant difference in T/Mmax values between the two groups. CONCLUSIONS: Low 123I MIBG uptake using semi-quantitative SPECT/CT analysis was correlated with early relapse of NB.

Finding of Remarkable Synergistic Effect on the Aroxyl-Radical-Scavenging Rates (ks) under the Coexistence of Vitamin E Homologues (or Vegetable Oils) and Ubiquinol-10: Proposal of A New Mechanism to Explain An Increase of ks Value.

Measurements of aroxyl (ArO · )-radical-scavenging rate constants (ksAOH) of antioxidants (AOHs) (i.e., α-, ß-, γ-, δ-Tocopherol (TocH) and ubiquinol-10 (UQ10H2)) were performed in ethanol/chloroform/H2O (50/50/1, v/v) solution, using stopped-flow spectrophotometry. ksAOH values were measured not only for each AOH, but also for the mixtures of two AOHs (i.e., TocH and UQ10H2). ksTocH values for α-, ß-, γ-, δ-TocH increased 1.21, 1.28, 1.55, and 1.19 times, respectively, under the coexistence of constant concentrations of UQ10H2. Similar measurements were performed for eight vegetable oils 1 - 8, containing different concentrations of α-, ß-, γ-, δ-tocopherol (TocH) and -tocotrienol (Toc-3H). ksOil values of all eight vegetable oils 1 - 8 also increased 1.24 - 1.54 times under the coexistence of constant concentrations of UQ10H2. A new mechanism to explain the notable increase of ksAOH values under the coexistence of two kinds of phenolic AOHs was proposed. UV-vis absorption of α-, ß-, γ-Toc · radicals, produced by reaction of α-, ß-, γ-TocHs (or vegetable oils 1 - 8) with ArO · , disappeared under the coexistence of TocHs (or oils) and UQ10H2, suggesting that the prooxidant reaction resulting from the presence of Toc · radicals is suppressed in the presence of UQ10H2.

Increased Immunogenicity of a Minimally Immunogenic Tumor after Cancer-Targeting Near Infrared Photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer treatment that employs an antibody photoabsorber conjugate (APC) composed of a targeting monoclonal antibody (mAb) conjugated with a photoactivatable phthalocyanine-derivative dye. Once injected and allowed to bind to a tumor, the APC is activated by local near-infrared light which kills cancer cells and induces a strong immune response in the tumor microenvironment by unmasking of new tumor antigens emerging from damaged tumor cells. Due to its ability to incite an immune reaction, even in poorly immunogenic tumors, NIR-PIT has the potential to enhance immunogenicity in tumors especially after immune checkpoint inhibition. In this study, we employ a poorly immunogenic MOC2-luc syngeneic tumor model and evaluate the efficacy of cancer-targeting CD44-targeted NIR-PIT. Increased infiltration of CD8+ T cells observed after NIR-PIT suggested an enhanced immune environment. Next, we evaluated tumor progression and survival after the combination of CD44-targeted NIR-PIT and short-term administration of an anti-PD1 immune checkpoint inhibitor (ICI) to further activate CD8+ T cells. Additionally, in mice in which the tumors were eradicated by this combination therapy, a re-challenge with fresh MOC2-luc cells demonstrated failure of tumor implantation implying acquired long-term immunity against the cancer cells. Combination therapy decreased tumor progression and prolonged survival significantly. Therefore, we concluded that NIR-PIT was able to convert a minimally immunogenic tumor unresponsive to anti-PD-1 ICI into a highly immunogenic tumor responsive to anti-PD-1 ICI, and this therapy was capable of inducing long-term immunity against the treated cancer.

Near-Infrared Photoimmunotherapy Combined with CTLA4 Checkpoint Blockade in Syngeneic Mouse Cancer Models.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that induces necrotic/immunogenic cell death. It employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by NIR light. Tumor-targeting NIR-PIT is also at least partly mediated by a profound immune response against the tumor. Cytotoxic T-lymphocyte antigen-4 (CTLA4) is widely recognized as a major immune checkpoint protein, which inhibits the immune response against tumors and is therefore, a target for systemic blockade. We investigated the effect of combining tumor-targeted NIR-PIT against the cell-surface antigen, CD44, which is known as a cancer stem cell marker, with a systemic CTLA4 immune checkpoint inhibitor in three syngeneic tumor models (MC38-luc, LL/2, and MOC1). CD44-targeted NIR-PIT combined with CTLA4 blockade showed greater tumor growth inhibition with longer survival compared with CTLA4 blockade alone in all tumor models. NIR-PIT and CTLA4 blockade produced more complete remission in MOC1 tumors (44%) than NIR-PIT and programmed cell death protein 1 (PD-1) blockade (8%), which was reported in our previous paper. However, the combination of NIR-PIT and CTLA4 blockade was less effective in MC38-luc tumors (11%) than the combination of NIR-PIT and PD-1 blockade (70%). Nonetheless, in many cases ineffective results with NIR-PIT and PD-1 blockade were reversed with NIR-PIT and CTLA4 blockade.

Interleukin-15 after Near-Infrared Photoimmunotherapy (NIR-PIT) Enhances T Cell Response against Syngeneic Mouse Tumors.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by 690 nm light. Cancer cell-targeted NIR-PIT induces rapid necrotic/immunogenic cell death (ICD) that induces antitumor host immunity including re-priming and proliferation of T cells. Interleukin-15 (IL-15) is a cytokine that activates natural killer (NK)-, B- and T-cells while having minimal effect on regulatory T cells (Tregs) that lack the IL-15 receptor. Here, we hypothesized that IL-15 administration with cancer cell-targeted NIR-PIT could further inhibit tumor growth by increasing antitumor host immunity. Three syngeneic mouse tumor models, MC38-luc, LL/2, and MOC1, underwent combined CD44-targeted NIR-PIT and short-term IL-15 administration with appropriate controls. Comparing with the single-agent therapy, the combination therapy of IL-15 after NIR-PIT inhibited tumor growth, prolonged survival, and increased tumor infiltrating CD8+ T cells more efficiently in tumor-bearing mice. IL-15 appears to enhance the therapeutic effect of cancer-targeted NIR-PIT.