Interfractional target changes in brain metastases during 13-fraction stereotactic radiotherapy

[Background] The risk for radiation necrosis is lower in fractionated stereotactic radiotherapy (SRT) than in conventional radiotherapy, and 13-fraction SRT is our method of choice for the treatment of brain metastases ≥ around 2 cm or patients who are expected to have a good prognosis. As 13-fraction SRT lasts for at least 17 days, adaptive radiotherapy based on contrast-enhanced mid-treatment magnetic resonance imaging (MRI) is often necessary for patients undergoing 13-fraction SRT. In this study, we retrospectively analyzed interfractional target changes in patients with brain metastases treated with 13-fraction SRT. [Methods] Our analyses included data from 23 patients and 27 metastatic brain lesions treated with 13-fraction SRT with dynamic conformal arc therapy. The peripheral dose prescribed to the planning target volume (PTV) was 39–44.2 Gy in 13-fractions. The gross tumor volume (GTV) of the initial SRT plan (initial GTV), initial PTV, and modified GTV based on the mid-treatment MRI scan (mid-treatment GTV) were assessed. [Results] The median initial GTV was 3.8 cm3 and the median time from SRT initiation to the mid-treatment MRI scan was 6 days. Compared to the initial GTV, the mid-treatment GTV increased by more than 20% in five lesions and decreased by more than 20% in five lesions. Interfractional GTV volume changes of more than 20% were not significantly associated with primary disease or the presence of cystic components/necrosis. The mid-treatment GTV did not overlap perfectly with the initial PTV in more than half of the lesions. [Conclusions] Compared to the initial GTV, the mid-treatment GTV changed by more than 20% in almost one-third of lesions treated with 13-fraction SRT. As SRT usually generates a steep dose gradient as well as increasing the maximum dose of PTV compared to conventional radiotherapy, assessment of the volume and locational target changes and adaptive radiotherapy should be considered as the number of fractions increases

TONS504-PHOTODYNAMIC THERAPY INDUCES CYTOTOXIC EFFECTS IN EMT6 CELLS

In the present study, TONS504 (C51H58N8O5I2; molecular weight, 1,116.9), a novel cationic hydrophilic photosensitizer, was synthesized from protoporphyrin IX dimethyl ester through a five‑step process according to a patented method for use in photodynamic therapy (PDT). The subcellular localization of TONS504 and the cytotoxic effects of TONS504‑mediated PDT in the mouse mammary tumor EMT6 cell line were investigated. TONS504 was localized primarily in the lysosomes and partially in the mitochondria. The cytotoxic effects of TONS504‑mediated PDT in the mouse mammary tumor EMT6 cell line were investigated using a WST8 assay and an Oxidative Stress kit. The cell viability values following treatment with 10 µg/ml TONS504 at light energies of 0, 1, 5 and 10 J/cm2 were 92.5, 101.8, 27.7 and 1.8%, respectively. The percentages of reactive oxygen species (ROS)(+) cells following the same treatment were 8.6, 8.5, 29.2 and 70.1%, respectively, whereas the percentages of apoptotic cells were 7.1, 5.6, 24.8 and 48.7%, respectively. The percentages of ROS(+) and apoptotic cells in the group subjected to TONS504‑mediated PDT increased in a manner dependent on the TONS504 concentration and light energy. Further studies are required to evaluate the in vivo pharmacokinetics, tissue distribution and photodynamic effects of TONS504

Artesunate Enhances the Cytotoxicity of 5-Aminolevulinic Acid-Based Sonodynamic Therapy against Mouse Mammary Tumor Cells In Vitro

Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound (US) and a sonosensitizer agent. 5-Aminolevulinic acid (5-ALA) has been used as a sonodynamic sensitizer for cancer treatment. However, studies have shown that 5-ALA-based SDT has limited efficacy against malignant tumors. In this study, we examined whether artesunate (ART) could enhance the cytotoxicity of 5-ALA-based SDT against mouse mammary tumor (EMT-6) cells in vitro. In the ART, ART + US, ART + 5-ALA, and ART + 5-ALA + US groups, the cell survival rate correlated with ART concentration, and decreased with increasing concentrations of ART. Morphologically, many apoptotic and necrotic cells were observed in the ART + 5-ALA + US group. The percentage of reactive oxygen species-positive cells in the ART + 5-ALA + US group was also significantly higher than that in the 5-ALA group (p = 0.0228), and the cell death induced by ART + 5-ALA + US could be inhibited by the antioxidant N-acetylcysteine. These results show that ART offers great potential in enhancing the efficacy of 5-ALA-based SDT for the treatment of cancer. However, these results are only based on in vitro studies, and further in vivo studies are required

Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation

Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis

A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII)

BACKGROUND: The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved. METHODS: This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71-75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020. DISCUSSION: If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma. TRIAL REGISTRATION: Registry number: jRCTs031200099 . Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020

Development of non-steroidal anti-inflammatory drug intolerance over a 3 year period

We report the detailed clinical course of a 47-year-old woman with aspirin-induced asthma in which non-steroidal anti-inflammatory drug (NSAID) intolerance developed over a 3 year period. The patient had mild asthma and was admitted with a femoral fracture in August 1996. Although she was given NSAIDs, including rectal diclofenac and oral loxoprofen, there was no worsening of asthma. After discharge, she was followed as having NSAID-tolerant asthma. When she developed perennial rhinitis and anosmia subsequent to an upper respiratory tract infection, asthma control was well maintained. Later, she experienced three episodes of severe asthmatic attacks after intake of aspirin or ketoprofen. Thus, we investigated her NSAID tolerability in September 1999. Sodium tolmetin inhalation challenge demonstrated a positive reaction, leading to the diagnosis of aspirin-induced asthma. Open challenges with loxoprofen and diclofenac also provoked positive reactions. The present case illustrates the potential variability of aspirin-induced asthma. Aspirin or NSAIDs challenge tests should be performed when nasal symptoms, particularly anosmia, develop or worsen

Diffuse alveolar hemorrhage caused by exposure to organic dust

Diffuse alveolar hemorrhage, a life-threatening disease, can complicate various conditions. We herein describe, for the first time, a patient with diffuse alveolar hemorrhage caused by exposure to organic dust. A 49-year-old woman who worked as a cantaloupe farmer in a greenhouse was referred to our hospital for sudden onset of dyspnea 3 h after exposure to organic dust. A chest X-ray and computed tomography scan performed on admission showed diffuse ground-glass opacities in both lung fields. Suspecting hypersensitivity pneumonitis, fiberoptic bronchoscopy was performed. Mucopurulent sputum was present in the trachea and both bronchi, and bronchoalveolar lavage revealed a progressively bloody return, typical of diffuse alveolar hemorrhage. Based on the history and bronchoscopy findings, she was diagnosed with diffuse alveolar hemorrhage following exposure to organic dust and was treated with antibiotics and corticosteroids. Diffuse alveolar hemorrhage should be considered in the differential diagnosis of diffuse ground-glass opacities observed on radiographs in farmers following exposure to organic dust

Dosimetric comparison between dual-isocentric dynamic conformal arc therapy and mono-isocentric volumetric-modulated arc therapy for two large brain metastases

Mono-isocentric volumetric-modulated arc therapy (VMAT) can be used to treat multiple brain metastases. It remains unknown whether mono-isocentric VMAT can improve the dose distribution compared with dual-isocentric dynamic conformal arc therapy (DCAT), especially for two brain metastases. We compared the dose distribution between dual-isocentric DCAT and mono-isocentric VMAT for two large brain metastases, and analyzed the relationship between the distance between the two targets and the difference in dose distribution. A total of 19 patients, each with two large brain metastases, were enrolled. The dose prescribed for each planning target volume (PTV) was 28 Gy in five fractions (D99.8 = 100%). We created new indices derived from conformity indices suggested by the Radiation Therapy Oncology Group (RTOG; mRTOG-CI) and Paddick et al. (mIP-CI), using the dosimetric parameters of the sum of the two PTVs. The median PTV was 5.05 cm³ (range, 2.10–28.47). VMAT significantly improved mRTOG-CI and mIP-CI compared with DCAT. In all cases, VMAT was able to improve mRTOG-CI and mIP-CI compared with DCAT. Whereas the normal brain volume receiving 5 Gy was similar between the two modalities, the normal brain receiving 10, 12, 15, 20, 25 and 28 Gy (V₁₀-V₂₈) was significantly smaller in VMAT. The mean beam-on times were 213.3 s and 121.9 s in DCAT and VMAT, respectively (P < 0.001). Mono-isocentric VMAT improved the target conformity and reduced the beam-on time and V₁₀-V₂₈ of the normal brain for not only two close metastases but also two distant metastases. Mono-isocentric VMAT seems to be a promising treatment technique for two large brain metastases

Selective depletion of basophils ameliorates immunoglobulin E-mediated anaphylaxis

Basophils, which are the rarest granulocytes, play crucial roles in protective immunity against parasites and development of allergic disorders. Although immunoglobulin (Ig)E-dependent responses via receptor for IgE (FcεRI) in basophils have been extensively studied, little is known about cell surface molecules that are selectively expressed on this cell subset to utilize the elimination in vivo through treatment with monoclonal antibody (mAb). Since CD200 receptor 3 (CD200R3) was exclusively expressed on basophils and mast cells (MCs) using a microarray screening, we have generated anti-CD200R3 mAb recognizing CD200R3A. In this study we examined the expression pattern of CD200R3A on leukocytes, and the influence of the elimination of basophils by anti-CD200R3A mAb on allergic responses. Flow cytometric analysis showed that CD200R3A was primarily expressed on basophils and MCs, but not on other leukocytes. Administration with anti-CD200R3A mAb led to the prominent specific depletion of tissue-resident and circulating basophils, but not MCs. Furthermore, in vivo depletion of basophils ameliorated IgE-mediated systemic and local anaphylaxis. Taken together, these findings suggest that CD200R3A is reliable cell surface marker for basophils in vivo, and targeting this unique molecule with mAb for the elimination of basophils may serve as a novel therapeutic strategy in ameliorating the allergic diseases