OBJECTIVES: Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial. This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression. METHODS: Patients with bipolar Ⅱ depression were enrolled in this prospective, two-center, randomized, 12-week pilot trial. The main indicator for assessing treatment effectiveness was a Montgomery-Asberg Depression Rating Scale (MADRS) of ≥50%. All eligible patients initially received four weeks of lurasidone monotherapy. Patients who responded well continued to receive this kind of monotherapy. However, no-response patients were randomly assigned to either valproate or vortioxetine treatment for eight weeks. By comprehensively comparing the results of MADRS over a period of 4‍‒‍12 weeks, a systematic analysis was conducted to determine whether vortioxetine could be used as an adjuvant drug for treating bipolar depression. RESULTS: Thirty-seven patients responded to lurasidone monotherapy, and 60 patients were randomly assigned to the valproate or vortioxetine group for eight weeks. After two weeks of combined valproate or vortioxetine treatment, the MADRS score in the vortioxetine group was significantly lower than that in the valproate group. There was no difference in the MADRS scores between the two groups at 8 and 12 weeks. The incidence of side effects did not significantly differ between the valproate and vortioxetine groups. Importantly, three patients in the vortioxetine group appeared to switch to mania or hypomania. CONCLUSIONS This study suggested that lurasidone combination with vortioxetine might have potential benefits to bipolar II depression in the early stage, while disease progression should be monitored closely for the risk of switching to mania.
Humans ; Bipolar Disorder/drug therapy* ; Vortioxetine/therapeutic use* ; Male ; Female ; Middle Aged ; Adult ; Valproic Acid/administration & dosage* ; Lurasidone Hydrochloride/administration & dosage* ; Prospective Studies ; Treatment Outcome ; Pilot Projects ; Drug Therapy, Combination ; Sulfides/therapeutic use* ; Antidepressive Agents/therapeutic use*

Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade (ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified; some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration (FDA) for clinical treatment. However, limited responses and immune-related adverse events (irAEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoplasms/drug therapy* ; Immunotherapy/methods* ; Animals

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive, extensive, and irreversible heterotopic ossification (HO) of soft tissues throughout the body, leading to severe disabilities. FOP is caused primarily by mutations in activin A receptor type 1 (ACVR1), also known as activin-like kinase 2 (ALK2), which encodes a receptor belonging to the bone morphogenetic protein (BMP) type I family. However, the continuous and complex process of HO in FOP is not yet fully understood, which has impeded the development of therapeutic drugs. Despite surgical removal of HO, which often results in recurrence and expansion of ossification, there is currently no definitive drug treatment available to completely prevent, halt, or reverse the progression of HO in FOP. Currently, researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates, including saracatinib, palovarotene, and rapamycin. This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs, with the goal of providing insights for further research and the development of new treatment methods.
Myositis Ossificans/genetics* ; Humans ; Activin Receptors, Type I/genetics* ; Ossification, Heterotopic ; Mutation ; Sirolimus/therapeutic use* ; Quinolones/therapeutic use* ; Benzodioxoles/therapeutic use* ; Animals ; Quinazolines/therapeutic use*

Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Intravascular large B-cell lymphoma (IVLBCL), a rare subtype of non-Hodgkin lymphoma, is classified as an independent subtype of extranodal diffuse large B-cell lymphoma (DLBCL) in the 2008 World Health Organization (WHO) Classification (Turner et al., 2010). The 5th edition of the World Health Organization (WHO 2022) classification of hematolymphoid tumors retains this subtype (Alaggio et al., 2022). IVLBCL, which is characterized by neoplastic lymphocyte proliferation within the lumen of small blood vessels, tends to invade organs, such as the nervous system, skin, bone marrow (BM), and lung (D'Angelo et al., 2019; Satoh et al., 2019; Vásquez et al., 2019; Fukami et al., 2020).
Humans ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Vascular Neoplasms/therapy*

Immunomodulatory cancer therapy is witnessing the rise of viral immunotherapy. The oncolytic influenza A virus, although promising in preclinical investigations, remains to be implemented in clinical practice. Recent progress in genetic engineering, coupled with experiential insights, offers opportunities to enhance the therapeutic efficacy of the influenza A virus. This review explores the use of the influenza virus, its attenuated forms, and associated vaccines in cancer immunotherapy, highlighting their respective advantages and challenges. We further elucidate methods for engineering influenza viruses and innovative approaches to augment them with cytokines or immune checkpoint inhibitors, aiming to maximize their clinical impact. Our goal is to provide insights essential for refining influenza A virus-based viral tumor immunotherapies.
Humans ; Neoplasms/immunology* ; Immunotherapy/trends* ; Influenza A virus/immunology* ; Oncolytic Virotherapy/trends* ; Animals ; Cancer Vaccines/therapeutic use* ; Oncolytic Viruses ; Genetic Engineering ; Immune Checkpoint Inhibitors/therapeutic use*

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as certain forms of non-melanoma skin cancer (NMSC) or keratinocyte carcinoma, are the most common forms of malignant neoplasms worldwide (Sharp et al., 2024). BCC and cSCC have been identified as two major components of NMSC, comprising one-third of all malignancies (Burton et al., 2016). Generally speaking, patients with NMSC tend to have relatively favorable survival outcomes, while different histopathological subtypes of NMSC exhibit distinct biological behaviors (Stătescu et al., 2023). Keratinocyte carcinoma, although not considered as deadly as melanoma, tends to metastasize if left untreated (Civantos et al., 2023; Nanz et al., 2024). cSCC can evolve locally, then aggressively metastasize, invade, and even lead to fatal consequences in a subset of patients (Winge et al., 2023). A solid, pigmented, smooth plaque or a hyperkeratotic papule with or without central ulceration and hemorrhage appears to be characteristic of cSCC (Thompson et al., 2016; Zhou et al., 2023). Of note, a rare type of intraepidermal cSCC in situ often appears as a velvety, demarcated, slightly raised erythematous plaque on the genitalia of men (Yamaguchi et al., 2016). Accounting for approximately 16.0% of scalp tumors and with a rising incidence, cSCC is now the second most common NMSC in humans (Verdaguer-Faja et al., 2024). According to the latest statistics, up to 2%‒5% of cSCCs in situ may gradually progress into invasive cSCCs in the final step (Rentroia-Pacheco et al., 2023). Several risk factors for the carcinogenesis and development of cSCC have been identified, including age, accumulative exposure to ultraviolet light radiation A and B, human papillomavirus infection, arsenic ingestion, chronic scarring, xeroderma pigmentosa, a relevant history of ionizing radiation, androgenetic alopecia in males, and immunosuppression therapy (Martinez and Otley, 2001; Welsch et al., 2012; Mortaja and Demehri, 2023).
Humans ; Aminolevulinic Acid/therapeutic use* ; Skin Neoplasms/pathology* ; Photochemotherapy/methods* ; Female ; Carcinoma, Squamous Cell/pathology* ; Middle Aged ; Photosensitizing Agents/therapeutic use* ; Carcinoma, Basal Cell/drug therapy*

Objective:The objective of this study is to analyze the detection rate, the pathogenic fungus distribution, risk factors and drug sensitivity of fungal infection of external auditory canal in patients diagnosed with chronic otitis media. Methods:The data of a total of 419 patients with chronic suppurative otitis media or middle ear cholesteatoma who were admitted from January 2019 to February 2023 were retrospectively analyzed. Results:A total of 419 patients were included, and 71 patients（16.9%） were positive for fungal culture. The disease mostly occurred in subjects aged 51-60 years old, and patients over 60 years old（47 cases, 66.2%）. From the fungal culture of external auditory canal secretions, 48 cases（11.4%） of Aspergillus and 14 cases（3.3%） of Candida were identified. The prevalence of fungal cultures in patients with chronic suppurative otitis media（20.8%） was significantly higher than that in patients with middle ear cholectestoma（4.9%）. The detection rate of Fungal was significantly increased after topical treatment with antibiotic ear drops（47.0% vs 13.6%）. Most of the isolated fungal strains are wild-type, and they are the sensitivity to voriconazole and fluconazole was the highest（97.2%）. For patients with positive fungal culture, iodoform gauze with triamcinolone acetonide and econazole cream was used to fill the external auditory canal during surgery. There was no significant difference in the tympanic membrane healing rate between patients with positive fungal culture and patients with negative fungal culture at 3 weeks after surgery（98.6% vs 97.7%）. Conclusion:Fungal infections of external auditory canal in patients with chronic otitis media tend to occur in older patients, which is more common in patients with chronic suppurative otitis media. Long-term topical treatment with antibiotic ear drops is an independent risk factor for fungal infection of external auditory canal in patients with chronic otitis media. The isolated fungal strains were highly sensitive to antifungal drugs. Therefore, it is advisable to refrain from employing topical antibiotic treatment for elderly patients with chronic suppurative otitis media/middle ear cholesteatoma, abuse of local antibiotic therapy should be avoided, and Fungal-related pathogenic examinations should be actively performed and anti-fungal drugs should be added if necessary.
Humans ; Middle Aged ; Female ; Male ; Risk Factors ; Retrospective Studies ; Chronic Disease ; Otitis Media, Suppurative/microbiology* ; Ear Canal/microbiology* ; Antifungal Agents/therapeutic use* ; Adult ; Mycoses/epidemiology* ; Aspergillus/isolation & purification* ; Candida/isolation & purification* ; Otitis Media/complications* ; Aged ; Cholesteatoma, Middle Ear/microbiology*

Objective: To explore the efficacy of vonoprazan fumarate in the treatment of laryngopharyngeal reflux disease（LPRD） evaluated by the Chinese version of the RSS-12 scale. Methods:A total of 100 LPRD patients treated in the otolaryngology-head and neck surgery outpatient clinic of our hospital were randomly divided into two groups（50 cases each）. The observation group was treated with vonoprazan fumarate（20 mg, once daily）, and the control group was treated with esomeprazole enteric-coated capsules（20 mg, twice daily） for 12 weeks. The selected observation indicators in this study included RSI, the Chinese version of RSS-12, and RFS scores before and after treatment. Results:Prior to treatment, there was no statistically significant difference in the Chinese version of RSS-12, RSI, and RFS between the two groups（P>0.05）. After 8 and 12 weeks of antacid treatment, both the Chinese version of RSS-12 and RSI significantly decreased in both group （P<0.05）. The changes in symptoms were particularly noticeable between 0-8 weeks of treatment according to the Chinese version of RSS-12 and RSI. After 12 weeks of treatment, the RFS scores significantly decreased compared to pretreatment levels （P<0.05）. After 12 weeks of antacid treatment, according to the Chinese version of RSS-12, 80% of patients in the observation group showed a good therapeutic response, compared to 64% in the control group; according to RSI, 90% of patients in the observation group showed a good therapeutic response, compared to 84% in the control group. There was no statistically significant difference in the treatment effect between the two groups after 12 weeks of treatment（P>0.05）. Conclusion:Vonoprazan fumarate can significantly improve the symptoms and signs of laryngopharyngeal reflux, and their treatment effect is not inferior to proton pump inhibitors. Compared with RSI, the Chinese version of RSS-12 can serve as a new screening tool for clinical diagnosis of LPRD in China.
Humans ; Sulfonamides/therapeutic use* ; Male ; Pyrroles/therapeutic use* ; Female ; Laryngopharyngeal Reflux/drug therapy* ; Treatment Outcome ; Middle Aged ; Esomeprazole/therapeutic use* ; Proton Pump Inhibitors/therapeutic use* ; Adult

Objective:Aural fullness（AF） is one of the common symptoms in ENT outpatient department, the incidence is about 1.4%. Some patients have an unknown etiology and are diagnosed as idiopathic ear congestion. In this paper, the therapeutic effect of gabapentin on some patients with idiopathic ear congestion was studied. Methods:Forty-eight cases of patients with ear distress as the main complaint between January 2024 and September 2024 were examined by questionnaire, specialist physical examination, pure tone audiometry and acoustic impedance. Among them, 19 cases were diagnosed with definite etiology, 29 cases were diagnosed with idiopathic ear congestion, and 7 cases were lost to follow-up in the idiopathic ear congestion group. Twenty-two patients were divided into the administration group（12 cases receiving regular gabapentin treatment for 3-6 weeks） and the control group（10 cases receiving no medication） based on whether they received gabapentin to explore the effect of ear congestion and possible related factors. Results:Among the 12 patients in the medication group, 2 cases of aural fullness disappeared completely, 9 cases had different degrees of relief, and 1 case had no relief Among the 10 patients in the control group, 2 patients' aural fullness disappeared, 1 patient consciously relieved, and the remaining 7 patients had no significant change in ear boredom. According to the Wong-baker Facial expression Scale, the score of ear tightness decreased from 2.83 before medication to 1.51 after medication in the medication group. The remission rate of ear congestion in the medication group was significantly higher than that in the control group（P=0.004）. Conclusion:Gabapentin can be used to treat idiopathic aural fullness, which can reduce the symptoms effectively. This suggests that the occurrence of idiopathic aural fullness may be related to neuralgia and central sensitization.
Humans ; Gabapentin/therapeutic use* ; Amines/therapeutic use* ; gamma-Aminobutyric Acid/therapeutic use* ; Female ; Male ; Cyclohexanecarboxylic Acids/therapeutic use* ; Ear Diseases/drug therapy* ; Middle Aged ; Adult ; Aged