Contrast-enhanced ultrasound imaging for monitoring the efficacy of near-infrared photoimmunotherapy.

BACKGROUND: Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy combining NIR-light irradiation with an antibody and IR700DX, a light-sensitive substance, to destroy tumours. However, homogeneous irradiation is difficult because the light varies depending on the distance and tissue environment. Therefore, markers that indicate sufficient irradiation are necessary. Nanoparticles sized 10∼200 nm show enhanced permeation and retention within tumours, which is further enhanced via NIR-PIT (super enhanced permeability and retention, SUPR). We aimed to monitor the effectiveness of NIR-PIT by measuring SUPR. METHODS: A xenograft mouse tumour model was established by inoculating human cancer cells in both buttocks of Balb/C-nu/nu mice, and NIR-PIT was performed on only one side. To evaluate SUPR, fluorescent signal examination was performed using QD800-fluorescent nanoparticles and NIR-fluorescent poly (d,l-lactide-co-glycolic acid) (NIR-PLGA) microparticles. Harmonic signals were evaluated using micro-bubbles of the contrast agent Sonazoid and contrast-enhanced ultrasound (CEUS) imaging. The correlation between SUPR immediately after treatment and NIR-PIT effectiveness on the day after treatment was evaluated. FINDINGS: QD800 fluorescent signals persisted only in the treated tumours, and the intensity of remaining signals showed high positive correlation with the therapeutic effect. NIR-PLGA fluorescent signals and Sonazoid-derived harmonic signals remained for a longer time in the treated tumours than in the controls, and the kE value of the two-compartment model correlated with NIR-PIT effectiveness. INTERPRETATION: SUPR measurement using Sonazoid and CEUS imaging could be easily adapted for clinical use as a therapeutic image-based biomarker for monitoring and confirming of NIR-PIT efficacy. FUNDING: This research was supported by ARIM JAPAN of MEXT, the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217) (JSPS), CREST (JPMJCR19H2, JST), and FOREST-Souhatsu (JST). Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; The Japan Health Foundation; and Princess Takamatsu Cancer Research Fund. Funders only provided financial support and had no role in the study design, data collection, data analysis, interpretation, and writing of the report.

Near-Infrared Photoimmunotherapy for Thoracic Cancers: A Translational Perspective.

The conventional treatment of thoracic tumors includes surgery, anticancer drugs, radiation, and cancer immunotherapy. Light therapy for thoracic tumors has long been used as an alternative; conventional light therapy also called photodynamic therapy (PDT) has been used mainly for early-stage lung cancer. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a completely different concept from conventional PDT, has been developed and approved in Japan for the treatment of recurrent and previously treated head and neck cancer because of its specificity and effectiveness. NIR-PIT can apply to any target by changing to different antigens. In recent years, it has become clear that various specific and promising targets are highly expressed in thoracic tumors. In combination with these various specific targets, NIR-PIT is expected to be an ideal therapeutic approach for thoracic tumors. Additionally, techniques are being developed to further develop NIR-PIT for clinical practice. In this review, NIR-PIT is introduced, and its potential therapeutic applications for thoracic cancers are described.

Spatiotemporal depletion of tumor-associated immune checkpoint PD-L1 with near-infrared photoimmunotherapy promotes antitumor immunity.

BACKGROUND: Near-infrared photoimmunotherapy (NIR-PIT) is a new modality for treating cancer, which uses antibody-photoabsorber (IRDye700DX) conjugates that specifically bind to target tumor cells. This conjugate is then photoactivated by NIR light, inducing rapid necrotic cell death. NIR-PIT needs a highly expressed targeting antigen on the cells because of its reliance on antibodies. However, using antibodies limits this useful technology to only those patients whose tumors express high levels of a specific antigen. Thus, to propose an alternative strategy, we modified this phototechnology to augment the anticancer immune system by targeting the almost low-expressed immune checkpoint molecules on tumor cells. METHODS: We used programmed death-ligand 1 (PD-L1), an immune checkpoint molecule, as the target for NIR-PIT. Although the expression of PD-L1 on tumor cells is usually low, PD-L1 is almost expressed on tumor cells. Intratumoral depletion with PD-L1-targeted NIR-PIT was tested in mouse syngeneic tumor models. RESULTS: Although PD-L1-targeted NIR-PIT showed limited effect on tumor cells in vitro, the therapy induced sufficient antitumor effects in vivo, which were thought to be mediated by the 'photoimmuno' effect and antitumor immunity augmentation. Moreover, PD-L1-targeted NIR-PIT induced antitumor effect on non-NIR light-irradiated tumors. CONCLUSIONS: Local PD-L1-targeted NIR-PIT enhanced the antitumor immune reaction through a direct photonecrotic effect, thereby providing an alternative approach to targeted cancer immunotherapy and expanding the scope of cancer therapeutics.

Hurdles for the wide implementation of photoimmunotherapy.

Near infrared photoimmunotherapy (NIR-PIT) is a molecularly targeted treatment for cancers achieved by injecting a conjugate of IRDye700DX® (IR700), a water-soluble silicon phthalocyanine derivative in the near infrared, and a monoclonal antibody that targets cancer cell antigens. NIR-PIT is a highly specific treatment with few side effects that results in rapid immunogenic cell death. Despite it being a very effective and innovative therapy, there are a few challenges preventing full implementation in clinical practice. These include the limits of near infrared light penetration, selection of targets, concerns about tumor lysis syndrome and drug costs. However, NIR-PIT has been approved by the regulatory authorities in Japan, allowing for exploration of how to mitigate challenges while maximizing the benefits of this treatment modality.

Short hydration with 20 mEq of magnesium supplementation for lung cancer patients receiving cisplatin-based chemotherapy: a prospective study.

BACKGROUND: Intravenous administration of magnesium with a short hydration regimen is recommended for patients receiving high-dose cisplatin to protect against cisplatin-induced nephrotoxicity. However, the optimal dose of magnesium supplementation has not been clarified. The aim of this trial was to investigate the safety and efficacy of a short hydration regimen with 20 mEq of magnesium supplementation for lung cancer patients receiving cisplatin-based chemotherapy. METHODS: The key eligibility criteria included cytologically or histologically diagnosed lung cancer, candidacy for cisplatin-based (≥ 60 mg/m2) chemotherapy or chemoradiotherapy, no prior chemotherapy, aged 20-75 years, and adequate renal function. Cisplatin was administered with pre-hydration with 20 mEq of magnesium sulfate. Mannitol was administered just before cisplatin infusion to enforce diuresis. The primary endpoint was the proportion of patients who underwent cisplatin-based chemotherapy with a short hydration regimen with 20 mEq of magnesium supplementation without a grade 2 or higher elevation in creatinine. RESULTS: Forty patients with a median age of 66 years (range 35-74) were prospectively enrolled. Median baseline creatinine was 0.71 mg/dL. Median dose of cisplatin in the first cycle was 80 mg/m2. In the first cycle, no patients developed grade 2 creatinine toxicity. During the treatment period, one patient developed grade 2 creatinine elevation; thus, the proportion of patients without a grade 2 or higher elevation in creatinine was 97.5% (95% confidence interval 86.8-99.9). CONCLUSION: A short hydration regimen with 20 mEq of magnesium supplementation is safe and feasible for patients with lung cancer receiving cisplatin-based chemotherapy.

Prevalence of potential candidates for electric-acoustic stimulation implant in a hearing-impaired population.

OBJECTIVE: To estimate the prevalence of potential electric-acoustic stimulation (EAS) implant candidates in a hearing-impaired population through a review of auditory examinations. METHODS: In total, 7356 patients underwent audiometric examination in our department between 2011 and 2014. The prevalence of patients meeting the audiometric criteria for EAS and standard cochlear implant (CI) was assessed. RESULTS: The percentage of EAS implant candidates meeting the pure-tone audiometric criteria was 0.71% (n=34) among the hearing-impaired individuals (n=4758) examined in our department, whereas 2.52% (n=120) met the criteria for standard CI. Among the 34 EAS implant candidates, 2 individuals (5.83%) received EAS implant surgery after approval of the EAS device in Japan. CONCLUSIONS: There was a lower prevalence of EAS implant candidates than standard CI candidates. Nevertheless, healthcare professionals should carefully examine the audiograms of patients with high frequency hearing loss with regard to meeting the indication criteria for EAS implant. This will enable patients to gain access to adequate information relating to further examinations and treatment options.

Aqueous fraction of Sauropus androgynus might be responsible for bronchiolitis obliterans.

BACKGROUND AND OBJECTIVE: Bronchiolitis obliterans (BO) has been reported to develop following ingestion of Sauropus androgynus (SA), a leafy shrub distributed in Southeast Asia. Little is known about direct effects of SA on airway resident cells or haematopoietic cells in vitro. Identification of the SA component responsible for the development of BO would be an important key to elucidate its mechanism. We sought to elucidate the direct effects of SA on airway resident cells or haematopoietic cells and identify the SA element responsible for the pathogenesis of BO. METHODS: SA dry powder was partitioned into fractions by solvent extraction. Human and murine monocytic cells, epithelial cells and endothelial cells were cultured with SA solution or fractions eluted from SA. We also investigated the effect of SA in vivo using a murine BO syndrome (BOS) model. RESULTS: The aqueous fraction of SA induced significant increases of inflammatory cytokine and chemokine production from monocytic lineage cells. This fraction also induced significant apoptosis of endothelial cells and enhanced intraluminal obstructive fibrosis in allogeneic trachea allograft in the murine BOS model. We found individual differences in tumour necrosis factor α (TNF-α) production from monocytes of healthy controls stimulated by this aqueous fraction of SA, whereas it induced high-level TNF-α production from monocytes of patients with SA-induced BO. CONCLUSIONS: These results suggest that an aqueous fraction of SA may be responsible for the pathogenesis of BO.

Thalamic arteriovenous malformation with an unusual draining system--case report.

A 52-year-old man suddenly experienced headache and vomiting. Computed tomography demonstrated a small area of hemorrhage in the right cerebellar hemisphere. Angiography revealed a thalamic arteriovenous malformation (AVM) fed by the bilateral medial posterior choroidal arteries and left marginal tentorial artery, and drained into the confluence via the cerebellar veins without flow into the supratentorial venous system. The draining veins included two varices, one of which, in the right cerebellar hemisphere, was thought to be the source of bleeding. The AVM nidus was removed via the right occipital transtentorial approach. A portion of a drainer adhered to the surface of the great vein of Galen but without opening into the galenic system and all drainers from this thalamic AVM flowed into the infratentorial cerebellar venous system.