Shinya Takaishi

Objective: Dupilumab is effective in treating patients with intractable chronic rhinosinusitis with nasal polyps (CRSwNP); however, the factors influencing its efficacy remain unclear. Systemic corticosteroids (SCS) are occasionally administered to patients receiving dupilumab; however, concomitant use can obscure the efficacy of dupilumab. The present study aimed to investigate the factors associated with the efficacy of dupilumab, while minimizing the influence of SCS. Study Design: Retrospective longitudinal study. Setting: A single academic hospital. Methods: We retrospectively evaluated medical records of 193 patients who started dupilumab for CRSwNP at our institution between March 2020 and July 2023. Patients who were prescribed SCS even once during a specific period were excluded. Finally, 50 patients were enrolled. We assessed correlations between pre‐treatment parameters (age, time since last sinus surgery, blood eosinophil count, blood eosinophil proportion, and serum total immunoglobulin E) and endpoints (changes in nasal polyp score, nasal congestion score, and Lund‐Mackay computed tomography score [LMK‐CTS] from baseline). Additionally, the endpoints were compared between subgroups (male vs female, presence vs absence of asthma, presence vs absence of nonsteroidal anti‐inflammatory drug‐exacerbated respiratory disease, and three groups classified according to the blood eosinophil proportion). Results: Statistically, neither significant differences between the subgroups nor significant correlations between the parameters and the endpoints were observed, except for a correlation between the blood eosinophil proportion and the changes in LMK‐CTS ( r = 0.47, P = .037 [n = 21]). Conclusion: Although a higher baseline peripheral blood eosinophil percentage may be associated with smaller changes in LMK‐CTS, our findings need further investigation.

Background: To repair orbital medial wall fractures, otorhinolaryngologists often use the silicone sheet technique by inserting an inverted U-shaped silicone sheet into the middle meatus after the removal of fractured bones, and packing gauze inside the silicone sheet for several days to fix the shape of the medial wall. However, this method does not sufficiently reduce the orbital content. Objective: To describe the surgical procedure to repair medial wall fractures using nasal septal cartilage as the reconstructive material. Methods: First, endoscopic septoplasty is performed. Although the correction of the septal deviation is performed to secure the operative field, the nasal septal cartilage, except the L-strut is resected simultaneously. After septoplasty, the fractured bones of the lamina papyracea are removed from the herniated orbital contents, and then the orbital contents can be reduced without resistance by pushing laterally. Subsequently, the cartilage is inserted beneath the fracture edges of the orbital medial wall with great care to avoid entrapping the orbital soft tissue and extraocular muscles. Results: The cartilage can be placed appropriately along the medial wall of the orbit. Conclusion: This technique enables to repair most cases of orbital medial wall fractures using the endoscopic endonasal approach alone without alloplastic implants.

Background To repair a blow-out fracture, the endonasal approach is indicated when the center of the fracture occurs in the orbital floor medial to the infraorbital nerve, or when the orbital tissue is herniated inwards; additionally, the combined endonasal and transmaxillary approach is indicated for fractures of the anterior and lateral parts of the orbital floor. Method and conclusion The use of endoscopic modified medial maxillectomy and special instruments enabled the surgeon to repair an outwardly herniated blow-out fracture by the endonasal approach alone, despite the center of the fracture being in the orbital floor lateral to the infraorbital nerve.

Summary: Transgenic rice seeds that contain genetically modified Cry j 1 and Cry j 2, the two major allergens of Cryptomeria japonica (Japanese cedar; JC), have been developed as immunotherapeutic candidates for JC pollinosis. Because the transgenic rice (TG‐rice) seeds express allergens containing whole amino acid sequences of Cry j 1 and Cry j 2 in the endosperm tissue (edible part of rice grain), they can potentially target all Cry j 1‐ and Cry j 2‐specific T‐cells. However, it was unknown whether antigenicity of Cry j 1 and Cry j 2 could be completely preserved in TG‐rice seeds. We verified the antigenicity of TG‐rice seeds to T‐cells through the analysis of the proliferative responses of T‐cells in Cry j 1‐ or Cry j 2‐immunized mice or T‐cell lines to TG‐rice seed extract. First, four mouse strains were immunized with Cry j 1 or Cry j 2. T‐cells in the immunized mice proliferated on treatment with TG‐rice seed extract, but not non‐transgenic wild‐type rice (WT‐rice) seed extract. Furthermore, T‐cell lines were established from the spleen cells of the immunized mice. Each T‐cell line resulted in a proliferative response to TG‐rice seed extract, but not to WT‐rice seed extract, suggesting that TG‐rice seeds certainly express T‐cell epitopes corresponding to T‐cell lines. Considering the modified amino acid sequences of Cry j 1 and Cry j 2 in TG‐rice seeds, the expression of specific T‐cell epitopes suggested that TG‐rice seeds express all possible T‐cell epitope repertoires of Cry j 1 and Cry j 2.

Japanese cedar (JC) pollinosis is a serious type I allergic disease in Japan. Although subcutaneous immunotherapy and sublingual immunotherapy have been applied to treat JC pollinosis, high doses of allergens may cause IgE-mediated allergic reactions. The transgenic rice seeds that contain genetically modified Cry j 1 and Cry j 2, the two major allergens of JC pollen, have been developed as candidates for oral immunotherapy. Although the antigens in the transgenic rice seeds (Tg-rice seeds) were engineered such that they decrease binding ability with IgE and they are of insufficient length to cross-link IgE on the surface of mast cells or basophils, the safety of Tg-rice seeds for patients with JC pollinosis was unclear. To verify the safety of Tg-rice seeds in terms of allergies, we investigated the percentage of activated basophils induced by Tg-rice seed extract in the basophil activation test. Blood samples from 29 patients with JC pollinosis were collected. Tg-rice seed extract, non-transgenic wild-type rice seed extract, and Cry j 1 and Cry j 2 were mixed with the blood with reagents. The percentage of activated basophils was assessed by CD203c expression, a basophil activation marker. The percentage of activated basophils after the stimulation with Tg-rice seed extract was 4.5 ± 1.6% (mean ± SD) compared with 62.9 ± 20.2% after Cry j 1- and Cry j 2-stimulation (difference 58.4%, P < 0.001, 95% confidence interval 51.0–65.9%). The results will contribute to the safety of Tg-rice seeds in terms of allergies.

Interleukin-31 (IL-31) is a recently identified cytokine produced by Th2 cells that is involved in the development of atopic dermatitis-induced skin inflammation and pruritus. Its receptor, IL-31RA, is expressed by a number of cell types, including epithelial cells, eosinophils, and activated monocytes and macrophages. To date, however, the regulation of Th2 responses by distinct cell types and tissues expressing IL-31RA has not been well studied. In this study, Cry j 2, one of the major allergens of Japanese cedar pollen, was administered to IL-31RA-deficient or wild-type (WT) mice via nasal or intraperitoneal injection for induction of specific Th2 responses. After nasal administration of Cry j 2, IL-31RA-deficient mice showed lower Cry j 2-specific CD4+ T cell proliferation, Th2 cytokine (IL-5 and IL-13) production, and Th2-mediated (IgE, IgG1, and IgG2b) antibody responses than WT mice. In contrast, IL-31RA-deficient mice administered Cry j 2 intraperitoneally showed stronger Th2 immune responses than WT mice. These results indicate that IL-31R signaling positively regulates Th2 responses induced by nasal administration of Cry j 2, but negatively regulates these responses when Cry j 2 is administered intraperitoneally. Collectively, these data indicate that the induction of antigen-specific Th2 immune responses might depend on tissue-specific cell types expressing IL-31RA.