Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.

Surgical Treatment and Outcomes for Sinonasal and Skull Base Phosphaturic Mesenchymal Tumors.

OBJECTIVE: To describe our clinical experience with surgical treatments for sinonasal phosphaturic mesenchymal tumors diagnosed at our institution. STUDY DESIGN: Retrospective case series. SETTING: Affiliated Sixth People's Hospital, Shanghai Jiao Tong University. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of 10 patients diagnosed with phosphaturic mesenchymal tumors associated with tumor-induced osteomalacia between December 2014 and October 2019. RESULTS: There were 4 men and 6 women with a disease course of 1 to 19 years. All patients exhibited hypophosphatemia and tumor-induced osteomalacia. The tumor was located in the sinonasal region, frontal bone, and temporal bone in 8 patients, 1 patient, and 1 patient, respectively. Technetium-99m octreotide scintigraphy was used for tumor localization in 4 cases. Six patients underwent endoscopic resection; the remaining 4 underwent unilateral transorbital anterior and posterior ethmoid artery ligation + endoscopic resection, endoscopic resection + skull base repair, internal carotid artery stenting + transcatheter arterial embolization + temporal bone tumor excision + adipose tissue plugging, and endoscopic resection + transfrontal craniotomy (n = 1 each). Two patients had a history of incomplete endoscopic resection. All patients achieved clinical remission and normalized biochemical indices after surgery. Only 1 patient developed recurrence and died of a brain hernia. CONCLUSIONS: A diagnosis of sinonasal phosphaturic mesenchymal tumors should be based on a combination of clinical, imaging, and pathological findings. Technetium-99m octreotide scintigraphy helps in locating the tumor. Complete surgical excision guarantees clinical remission, and preoperative transcatheter arterial embolization or feeding artery ligation may reduce intraoperative bleeding in cases of highly vascularized tumors.

Pro-inflammatory role of transient receptor potential canonical channel 6 in the pathogenesis of chronic rhinosinusitis with nasal polyps.

BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) has not been fully elucidated. This study sought to explore the role and mechanism of transient receptor potential canonical channel 6 (TRPC6) in the pathogenesis of CRSwNP. METHODS: Immunohistochemistry (IHC) was employed to evaluate TRPC6 immunolabeling. Real-time polymerase chain reaction (PCR) was conducted to assay TRPC6, stromal interaction molecule 1 (STIM1), and calcium release-activated calcium channel protein 1 (Orai1) messenger RNA (mRNA) levels in 70 patients with CRSwNP, including eosinophilic CRSwNP (ECRSwNP) or non-eosinophilic CRSwNP (nECRSwNP), and 28 control subjects. The concentrations of inflammatory mediators, including interleukin (IL)-1ß, IL-5, and IL-25, were assayed by enzyme-linked immunosorbent assay (ELISA). In experiments on human nasal epithelial cell (HNEC) culture and stimulation, the mean fluorescence intensity (MFI) of intracellular Ca2+ was assayed by flow cytometry. Western blotting, real-time PCR, and ELISA were also conducted to assess the effects and mechanisms of TRPC6 activator 1-oleoyl-2-acetyl-glycerol (OAG) and TRPC6 inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) on HNECs. RESULTS: Upregulation of TRPC6, STIM1, and Orai1 levels was found in CRSwNP patients, particularly in those with ECRSwNP. TRPC6-positive cells correlated positively with the numbers of eosinophils and neutrophils, respectively. Moreover, TRPC6 mRNA was positively correlated with STIM1 and Orai1 mRNA levels. The concentrations of inflammatory mediators, including IL-1ß, IL-5, and IL-25, were elevated in CRSwNP, especially in ECRSwNP. In cultured HNECs, TRPC6, STIM1, Orai1, Ca2+ MFI levels, and inflammatory mediators were upregulated by lipopolysaccharide (LPS) and OAG but were inhibited by SKF-96365. CONCLUSION: TRPC6 plays a pro-inflammatory role in the pathogenesis of CRSwNP via regulating Ca2+ flow.

The effect of bilirubin on the excitability of mitral cells in the olfactory bulb of the rat.

Olfactory dysfunction is a common clinical phenomenon observed in various liver diseases. Previous studies have shown a correlation between smell disorders and bilirubin levels in patients with hepatic diseases. Bilirubin is a well-known neurotoxin; however, its effect on neurons in the main olfactory bulb (MOB), the first relay in the olfactory system, has not been examined. We investigated the effect of bilirubin (>3 µM) on mitral cells (MCs), the principal output neurons of the MOB. Bilirubin increased the frequency of spontaneous firing and the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). TTX completely blocked sEPSCs in almost all of the cells tested. Bilirubin activity was partially blocked by N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid (AMPA) receptor antagonists. Furthermore, we found that bilirubin increased the frequency of intrinsic firing independent of synaptic transmission in MCs. Our findings suggest that bilirubin enhances glutamatergic transmission and strengthens intrinsic firing independent of synaptic transmission, all of which cause hyperexcitability in MCs. Our findings provide the basis for further investigation into the mechanisms underlying olfactory dysfunction that are often observed in patients with severe liver disease.

Taurine attenuates bilirubin-induced neurotoxicity in the auditory system in neonatal guinea pigs.

OBJECTIVES: Previous work showed that taurine protects neurons against unconjugated bilirubin (UCB)-induced neurotoxicity by maintaining intracellular calcium homeostasis, membrane integrity, and mitochondrial function, thereby preventing apoptosis from occurring, in primary neuron cultures. In this study, we investigated whether taurine could protect the auditory system against the neurotoxicity associated with hyperbilirubinemia in an in vivo model. METHODS: Hyperbilirubinemia was established in neonatal guinea pigs by intraperitoneal injection of UCB. Hearing function was observed in electrocochleograms (ECochGs) and auditory brainstem responses (ABRs) recorded before and 1, 8, 24, and 72 h after UCB injection. For morphological evaluations, animals were sacrificed at 8h post-injection, and the afferent terminals beneath the inner hair cells (IHCs), spiral ganglion neurons (SGNs), and their fibers were examined. RESULTS: It was found that UCB injection significantly increased latencies and inter-wave intervals, and thresholds of ABR and compound action potentials, and caused marked damage to type I SGNs, their axons, and terminals to cochlear IHCs. When baby guinea pigs were pretreated with taurine for 5 consecutive days and then injected with bilirubin, electrophysiological abnormalities and morphological damage were attenuated significantly in both the peripheral and central auditory system. CONCLUSIONS: From these observations, it was concluded that taurine limited bilirubin-induced neural damage in the auditory system. These findings may contribute to the development of taurine as a broad-spectrum agent for preventing and/or treating hearing loss in neonatal jaundice.

Primary maxillomandibular advancement with concomitant revised uvulopalatopharyngoplasty with uvula preservation for severe obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: This study aimed to evaluate the efficacy and safety of primary maxillomandibular advancement (MMA) with concomitant adjunctive revised uvulopalatopharyngoplasty with uvula preservation (H-UPPP) in selected patients with severe obstructive sleep apnea-hypopnea syndrome (OSASH). METHODS: Eleven consecutive male patients with velo-orohypopharyngeal and hypopharyngeal narrowing underwent MMA with concomitant H-UPPP for severe OSAHS. All patients underwent a physical examination, Epworth Sleepiness Scale evaluation, cephalometry, nocturnal polysomnogram, and velopharyngeal insufficiency questionnaire survey before and at 6 to 12 months after surgery. RESULTS: On the basis of the success criteria, defined as an apnea-hypopnea index less than 20 and a decrease greater than 50%, the success rate was 91%. The apnea-hypopnea index decreased from 67.44 (13.30) to 9.41 (7.20) events per hour (P < 0.001) and the lowest oxygen saturation increased from 63.0% (10.70%) to 88.55% (4.59%) (P < 0.001) after surgery. All patients showed a significant decrease in mandibular plane to hyoid bone and increase in PAS after surgery. One patient reported regurgitation of liquids when drinking hastily after surgery. Two patients reported regurgitation as occasional occurrences. Half a year later, 2 patients reported complete resolution of the symptoms. One patient still complained of rare regurgitation of liquids when drinking quickly. Five patients had paresthesia of the lower lip; in 4 patients, the paresthesia had resolved by 12 months after surgery. One patient still complained of paresthesia of the lower lip after 2 years of follow-up. No major complication (eg, upper airway obstruction) occurred. CONCLUSIONS: Primary MMA with concomitant adjunctive H-UPPP is effective in selected patients with severe OSAHS without major complications.

Bilirubin induces auditory neuropathy in neonatal guinea pigs via auditory nerve fiber damage.

Bilirubin can cause temporary or permanent sensorineural deafness in newborn babies with hyperbilirubinemia. However, the underlying targets and physiological effects of bilirubin-induced damage in the peripheral auditory system are unclear. Using cochlear functional assays and electron microscopy imaging of the inner ear in neonatal guinea pigs, we show here that bilirubin exposure resulted in threshold elevation in both compound action potential (CAP) and auditory brainstem response (ABR), which was apparent at 1 hr and peaked 8 hr after drug administration. The threshold elevation was associated with delayed wave latencies and elongated interwave intervals in ABR and CAP. At 72 hr postinjection, these measures returned to control levels, except for the CAP amplitude. Cochlear microphonics remained unchanged during the experiment. Morphological abnormalities were consistent with the electrophysiological dysfunction, revealing fewer auditory nerve fibers (ANFs) in the basal turn, myelin sheath lesions of spiral ganglion neurons (SGNs) and ANFs, and loss of type 1 afferent endings beneath inner hair cells (IHCs) without loss of hair cells at 8 hr posttreatment. Similar to the electrophysiological findings, morphological changes were mostly reversed 10 days after treatment, except for the ANF reduction in the basal turn. These results suggest that hyperbilirubinemia in neonatal guinea pigs impaired auditory peripheral neuromechanisms that targeted mainly the IHC synapses and the myelin sheath of SGNs and their fibers. Our observations indicate a potential connection between hyperbilirubinemia and auditory neuropathy.

[An endoscopic approach to reconstruction of skull base defects using a vascular pedicled nasoseptal mucoperiosteal flap].

OBJECTIVE: To introduce a method and the clinical effects of repairing skull base defects and dural defects using vascular pedicled nasoseptal mucoperiosteal flaps through an endoscopic endonasal approach. METHODS: The clinical and follow-up data for 8 patients who underwent endoscopic endonasal reconstruction of skull base defects and cerebrospinal fluid rhinorrhea with a vascular pedicled nasoseptal mucoperiosteal flap between July 2008 and March 2010 were retrospectively reviewed. All patients were male. The age of these patients ranged from 28 to 60 years (average 41 years). The diagnosis for these patients included one hemangiopericytoma of the anterior skull base one olfactory neuroblastoma (type of Kadish C), one ethmoid sinus cancer, three local recurrent cancers of the nasopharynx after radiotherapy, one carcinoid of skull base and one traumatic cerebrospinal fluid rhinorrhea with recurrent intracranial infection. There were six anterior skull base defects and two middle cranial fossa defects. An endoscopic endonasal surgical approach was used for the repair. A pedicled flap using the nasal septal mucoperiosteum based on the posterior nasal artery was harvested from the ipsilateral side. The tissue flap was used to cover the dural defects. The margin was covered with gelatin sponge and fixed with fibrin glue. The nasal cavity was packed with iodoform gauze, a Foley catheter balloon and Merocel in this sequence to secure the flap in place. Nasal packing was removed 5 to 7 days postoperatively. RESULTS: Partial septal flap necrosis was found in one case, but the flaps in the other 7 cases survived. A postoperative cerebrospinal fluid leak occurred in one case 7 days after surgery. This was re-explored and successfully repaired with abdominal fat. All cases healed well, with no delayed cerebrospinal fluid leaks or intracranial infections during the 6 to 24 months follow-up period. CONCLUSION: The vascular pedicled nasoseptal mucoperiosteal flap is a reliable choice for endoscopic endonasal skull base reconstruction.

Predictors of surgical outcomes of uvulopalatopharyngoplasty for obstructive sleep apnea hypopnea syndrome.

OBJECTIVES: To investigate predictors of surgical outcomes of uvulopalatopharyngoplasty (UPPP) for obstructive sleep apnea hypopnea syndrome (OSAHS). STUDY DESIGN: Case series with planned data collection. SETTING: A university medical center. SUBJECTS AND METHODS: Thirty-nine patients with OSAHS received Z-palatopharyngoplasty (ZPPP) or Han-uvulopalatopharyngoplasty (H-UPPP). All patients were evaluated within 3 months before surgery and at 6 to 12 months after surgery. Statistical analyses were conducted on preoperative parameters that could have affected surgical efficacy and outcome. Success was defined as an apnea-hypopnea index (AHI) fewer than 20 times per hour and a decrease of more than 50%. RESULTS: The success rate was 56.4% (22/39 patients). There were statistically significant differences in AHI, lowest oxygen saturation (L-Sao(2)), time with oxygen saturation less than 90% (CT90), percentage of time with oxygen saturation less than 90% (CT90%), microarousal index (MI), apolipoprotein E (ApoE), high-density lipoprotein (HDL), fasting blood glucose (FBG), and Friedman OSA stage between the treatment success and failure groups. Higher success rate was predicted by lower severity, as indicated by lower AHI, CT90, CT90%, and MI; higher L-Sao(2); and fewer glucose and lipid metabolism abnormalities, shown by lower ApoE and FBG and higher HDL. CONCLUSIONS: Disease severity, glucose and lipid metabolism, and Friedman OSA stage may be important predictors of surgical outcome of UPPP for OSAHS.

[Analysis of allergens characteristic in 4637 patients with allergic rhinitis].

OBJECTIVE: To determine the distribution of allergens in patients with allergic rhinitis during the past 5 years in Shanghai area, and provide clinical reference for management strategies with regional character. METHODS: Patients with symptoms of allergic rhinitis were given skin prick test (SPT) from June 2005 to May 2010. Among the patients, the distribution of all allergens was analyzed. The positive rate was compared with age, gender, season, and so on. RESULTS: Among 4637 individuals, the total positive rate of SPT was 62.84%. Dust mites were identified as the mostly responsible allergens. There was significant difference of variation with seasons (χ2=93.581, P<0.01), the highest rate was found in autumn and the lowest was found in spring. There was significant difference of the positive rate in different months (χ2=112.001, P<0.01), the most in October. There was a negative correlation between the positive rate and age (r=-0.792, P<0.01). The response intensity to dust mite allergy was decreased with age increased (P<0.01). CONCLUSIONS: Dust mites were identified as the most common allergens among patients with allergic rhinitis during the past 5 years in Shanghai area. The younger group had the tendency of higher positive rate and response intensity than the elder. The positive rates of dust mites varied with different seasons.

[Superior mediastinum exposure in the removal of the advanced cancers in the lower neck regions].

OBJECTIVE: In order to achieve the radical removal of advanced cancers involving the lower neck regions. METHODS: Upon the thorough evaluation of tumors with different imaging methods, several kinds of superior mediastinum exposure were carried out in a series of 18 patients with advanced neck cancer of various kinds. There were 10 cases of stomal recurrence, 2 cases of recurrent thyroid carcinomas, 2 cases of advanced carcinomas in the cervical trachea, and 4 cases of metastatic carcinomas in the supraclavicular region. According to the site and extension of tumor invasion, simple manubrium resection were performed in 10 cases, resection of the medial half of the clavicle was adopted in 4 cases and resection of the manubrium and the medial 1/3 of both clavicles were used in 4 cases. Pectoralis major myocutaneous flaps were raised to reconstruct the defects resulting from tumor ablations. RESULTS: Radical removal of tumors was achieved in 16 cases. Minor complications occurred in 3 cases including one case of intraoperative pneumothorax and 2 cases of postoperative pharyngeal fistula. One patient developed aneurysm in the right common carotid artery after radical neck dissection and wound infection. One patient died of eruption of the innominate artery due to the major vessel injury caused by the tracheostomy tube two months after the operation. Results from postoperative follow-up demonstrated that one-year, two-year and three-year postoperative survival rate was 72.2% (13/18), 22.2% (4/18) and 11.1% (2/18), respectively, in this series. CONCLUSION: Superior mediastinum exposure is a necessary and reliable surgical approach in the removal of advanced tumors involving the lower neck and superior mediastinum.