Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions.

Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.

Clinical and Pathological Features of Pit1/SF1 Multilineage Pituitary Neuroendocrine Tumor.

BACKGROUND AND OBJECTIVES: Lineage-based classification has critical clinical implications in pituitary neuroendocrine tumor (PitNET). As the most prevalent subtype of multilineage PitNET, PitNET originating from both pituitary-specific positive transcription factor 1 (Pit1) and steroidogenic factor-1 (SF1) lineages (Pit1/SF1-adenoma) is expected to exhibit rich and varied clinical behaviors. A comprehensive understanding of the clinical and pathological characteristics of Pit1/SF1-adenoma will provide mechanistic insight and influence the prognosis and treatment of PitNET. METHODS: A retrospective study was conducted by reviewing 57 cases of Pit1/SF1-adenoma between 2018 and 2022. We also included 88 cases of PitNET arising from Pit1 cell lineage (Pit1-adenoma) and 70 cases of PitNET arising from SF1 cell lineage (SF1-adenoma) as controls. Comprehensive data, including demographic, symptom, endocrinal, radiological, surgical, pathological, and prognostic information, were systematically collected. All specimens were immunostained for pituitary transcription factors (PTFs) and pituitary hormones. RESULTS: The detection rate was 8.0% for Pit1/SF1-adenoma within PitNET surgical specimens. Pit1/SF1-adenoma displayed a male predominance, with the mean diagnosis age falling between Pit1-adenoma and SF1-adenoma. The endocrine activity of Pit1/SF1-adenoma was lower than Pit1-adenoma but higher than SF1-adenoma. Pit1/SF1-adenoma had a higher incidence of cavernous sinus invasion (56.1%) than both Pit1-adenoma (38.6%, P = .039) and SF1-adenoma (27.1%, P = .001). Furthermore, Pit1/SF1-adenoma showed more postoperative complications than Pit1-adenoma (29.8% vs 8.0%, P = .001). Nonfunctional Pit1/SF1-adenoma had a higher radiological tumor recurrence rate than nonfunctional SF1-adenoma (34.8% vs 10.9%, P = .021). Notably, the immunostaining pattern was diverse in Pit1/SF1-adenoma, with various combinations of staining intensity for PTFs and 15 combinations for 6 pituitary hormones. Intriguingly, various PTFs combinations had no different impact on the outcome of Pit1/SF1-adenoma. CONCLUSION: Pit1/SF1-adenoma represents a unique pathological subtype of PitNET, characterized by distinctive clinical behaviors. Identifying Pit1/SF1-adenoma can facilitate more precise management of PitNET by the practical use of Pit1/SF1 immunostaining.

XFab-α4-1BB/CD40L fusion protein activates dendritic cells, improves expansion of antigen-specific T cells, and exhibits antitumour efficacy in multiple solid tumour models.

BACKGROUND: Additional immunotherapies are still warranted for non-responders to checkpoint inhibitors with refractory or relapsing cancers, especially for patients with "cold" tumours lacking significant immune infiltration at treatment onset. We developed XFab-α4-1BB/CD40L, a bispecific antibody targeting 4-1BB and CD40 for dendritic cell activation and priming of tumour-reactive T cells to inhibit tumours. METHODS: XFab-α4-1BB/CD40L was developed by engineering an anti-4-1BB Fab arm into a CD40L trimer based on XFab® platform. Characterisation of the bispecific antibody was performed by cell-based reporter assays, maturation of dendritic cell assays, and mixed lymphocyte reactions. The abilities of antigen-specific T-cell expansion and antitumour efficacy were assessed in syngeneic mouse tumour models. Toxicological and pharmacodynamic profiles were investigated in non-human primates. RESULTS: XFab-α4-1BB/CD40L demonstrated independent CD40 agonistic activity and conditional 4-1BB activity mediated by CD40 crosslinking, leading to dendritic cell maturation and T-cell proliferation in vitro. We confirmed the expansion of antigen-specific T cells in the vaccination model and potent tumour regression induced by the bispecific antibody alone or in combination with gemcitabine in vivo, concomitant with improved tumour-reactive T-cell infiltration. XFab-α4-1BB/CD40L showed no signs of liver toxicity at doses up to 51 mg/kg in a repeated-dose regimen in non-human primates. CONCLUSIONS: XFab-α4-1BB/CD40L is capable of enhancing antitumour immunity by modulating dendritic cell and T-cell functions via targeting 4-1BB agonism to areas of CD40 expression. The focused, potent, and safe immune response induced by the bispecific antibody supports further clinical investigations for the treatment of solid tumours.

Efficacy and Safety of Long-Pulsed 755-nm Alexandrite Laser for Keratosis Pilaris: A Split-Body Randomized Clinical Trial.

INTRODUCTION: Keratosis pilaris (KP) is a disfiguring disease and is resistant to treatment. Several treatment methods are available, but the efficacy is limited. This prospective, rater-blinded, split-body comparative study investigated the efficacy and safety of long-pulsed 755-nm alexandrite laser in the treatment of KP. METHODS: Twenty-two patients with KP of bilateral arms were enrolled in this study. All participants were randomized and treated with a long-pulsed 755-nm alexandrite laser on the left or right arm in four sessions held 3 weeks apart. The unified moisturizing lotion was applied on both left and right arms once a day. Physicians' assessment scores and patients' self-assessment scores were recorded, and skin imaging changes in dermoscopy, high-frequency ultrasound, and skin biopsy were obtained at baseline and 4 weeks after the fourth treatment. RESULTS: Of the 21 patients who completed the study, 15 were women and 6 were men. At 4 weeks after the fourth treatment, the laser side showed significantly lower total (2.0 versus 4.5), roughness (1.0 versus 2.0), and redness (1.0 versus 2.0) scores according to physicians' assessment (all P < 0.05). Furthermore, the laser side showed significantly lower total (2.0 versus 4.0), roughness (1.0 versus 2.0), and redness scores (1.0 versus 2.0) according to the patients' self-assessment (all P < 0.05). The proportions of patients who achieved dermoscopically and ultrasonographically showed excellent improvements in follicular plugs (57.1% versus 14.3%), perifollicular erythema (52.4% versus 9.5%), perifollicular hyperpigmentation (47.6% versus 14.3%), and the number of epidermal bulges (57.1% versus 19.1%) in the laser side was significantly higher than those who achieved such improvements in the control side (all P < 0.05). Histopathology showed that the follicular plugs and inflammatory cell infiltration were improved at the final visit. Three patients exhibited reversible postinflammatory hyperpigmentation. CONCLUSION: Long-pulsed 755-nm alexandrite laser treatment is effective and safe in treating both skin roughness and redness in KP. TRIAL REGISTRATION NUMBER: ChiCTR2100054489.