Headache and Facial Pain/Pressure in the Chronic Rhinosinusitis Population: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the severity and prevalence of headache and facial pain/pressurere in the chronic rhinosinusitis (CRS) population. DATA SOURCES: CINAHL, PubMed, Scopus. REVIEW METHODS: The literature was searched from inception through June 2023 for English language articles documenting "headache" or "facial pain/pressure" and "chronic rhinosinusitis." Data collected included Lund-MacKay computed tomography score, Lund-Kennedy endoscopy score, sinonasal outcome test, and visual analog scale. Meta-analyses were performed on continuous measures (mean), proportions (%), and regression. RESULTS: A total of 69 studies were included with 8643 CRS patients and 703 control patients. The CRS group had a mean age of 44.1 (range: 16-82; 95% confidence interval [CI]: 40.3-48) and 86.1% [95% CI: 76.4-93.5] with nasal polyposis. The control group had a mean age of 39.2 (range: 17-88; 95% CI: 28.7-49.8). All CRS subgroups had significantly more severe headache and facial pain/pressure when compared to the control (P < .0001). Patients without polyps had significantly more severe facial pain/pressure and headache when compared to patients with polyps (P < .0001). Facial pain/pressure is a moderate problem or worse in 29.8% of polypoid patients versus 56.4% of nonpolypoid patients; Δ26.6% [95% CI: 0.7-50; P = .045]. CONCLUSIONS: Across all outcome metrics, CRS patients experience significantly more severe headache and facial pain/pressure when compared to a control population. Nonpolypoid patients experience significantly more severe facial pain/pressure and headache when compared to polypoid patients. The majority of nonpolypoid patients experience facial pain/pressure that is moderate in severity or worse.

Surgical management of headache and facial pain/pressure in chronic rhinosinusitis: A systematic review and meta-analysis.

BACKGROUND: Headache and facial pain are common symptoms of chronic rhinosinusitis (CRS). However, given the numerous etiologies that can cause these symptoms, the impact of sinus surgery is not well characterized. METHODS: A systematic review was performed by searching the literature from inception through June 6, 2023. English-language articles reporting outcomes for facial pain/pressure or headache following endoscopic sinus surgery were selected for inclusion. Meta-analyses were performed using random and fixed effect models on continuous measures (mean), mean difference (Δ), and proportions (%). RESULTS: A total of 26 articles reporting on 2839 patients were selected for inclusion. The mean patient age was 44.0 ± 3.9 (range 16.0-84.0), with an average symptom duration of 5.3 ± 2.8 years. Among these patients, 56.5% (95% confidence interval [CI]: 52.3-60.6) were male and 77.0% (95% CI: 56.6-92.3) had nasal polyposis (NP). Patients with and without NP reported substantial reductions in both 22-item sino-nasal outcome test facial pain/pressure (with NP: -1.4 [95% CI: -1.6 to -1.2; relative reduction 59.1%]; without NP: -1.5 [95% CI: -1.9 to -1.1; relative reduction 60.9%]) and visual analogue scale (VAS) headache (with NP: -2.5 [95% CI: -2.8 to -2.1; relative reduction 67.2%]; without NP: -2.8 [95% CI: -4.7 to -1.0; relative reduction 42.7%]). Symptom reductions were greater in the without NP versus with NP group; VAS facial pain/pressure: Δ0.4 (95% CI: 0.2-0.6; p = 0.0006) and VAS headache: Δ0.4 (95% CI: 0.1-0.7; p = 0.02). CONCLUSIONS: Our findings suggest that CRS patients, regardless of polyp status, benefit from significant reductions in facial pain/pressure and headache following surgical therapy.

Medical Management of Headache and Facial Pain in CRS: A Systematic Review and Meta-Analysis.

OBJECTIVES: This study aims to characterize the effect of medical therapy on headache and facial pain/pressure among patients with chronic rhinosinusitis (CRS). DATA SOURCES: CINAHL, PubMed, and Scopus. METHODS: CINAHL, PubMed, and Scopus were searched from inception through April 10th, 2024, for English language articles reporting headache or facial pain/pressure outcomes in CRS patients. Inclusion was restricted to studies reporting results of the medical treatment of CRS in nonsurgical cohorts. Primary outcome measures included the sino-nasal outcome test (SNOT) and the visual analogue scale (VAS). Meta-analyses of continuous measures (mean), mean difference (Δ), and proportions (%) were conducted. RESULTS: The initial search yielded 2429 unique articles. After a full-text review of 272 articles, 17 studies reporting outcomes for 2269 patients were included in the meta-analysis. The mean patient age was 48.6 years (range 18.0-86.0; 95% CI: 46.5 to 50.6), among which 55.4% (95% CI: 51.5 to 59.4) were male and 82.9% (95% CI: 68.8 to 93.4) had nasal polyposis. SNOT facial pain/pressure scores improved by 1.1 points (95% CI: -1.7 to -0.5; relative reduction 40.4%) with non-biologic therapies and 1.0 point (95% CI: -1.4 to -0.6; relative reduction 54.6%) with biologic therapies. On an 11-point scale, VAS headaches scores improved by 1.8 units (95% CI: -3.3 to -0.3; 42.1% relative reduction) in CRSwNP patients and 1.0 unit (95% CI: -1.7 to -0.3; 54.0% relative reduction) in CRSsNP patients. CONCLUSIONS: Our findings suggest medical therapy significantly reduces facial pain and pressure in the CRS population. Laryngoscope, 2024.

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.

CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members.

Familial cylindromatosis is an autosomal dominant predisposition to tumours of skin appendages called cylindromas. Familial cylindromatosis is caused by mutations in a gene encoding the CYLD protein of previously unknown function. Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappaB. The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2) and, to a lesser extent, TRAF6. These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages.

Targeted mutagenesis of the Hira gene results in gastrulation defects and patterning abnormalities of mesoendodermal derivatives prior to early embryonic lethality.

The Hira gene encodes a nuclear WD40 domain protein homologous to the yeast transcriptional corepressors Hir1p and Hir2p. Using targeted mutagenesis we demonstrate that Hira is essential for murine embryogenesis. Analysis of inbred 129Sv embryos carrying the null mutation revealed an initial requirement during gastrulation, with many mutant embryos having a distorted primitive streak. Mutant embryos recovered at later stages have a range of malformations with axial and paraxial mesendoderm being particularly affected, a finding consistent with the disruption of gastrulation seen earlier in development. This phenotype could be partially rescued by a CD1 genetic background, although the homozygous mutation was always lethal by embryonic day 11, with death probably resulting from abnormal placentation and failure of cardiac morphogenesis.

CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.

CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells. Its antiproliferative effects are at least 300 times more potent than the prototypical aminopeptidase inhibitor, bestatin. However, the mechanism by which inhibition of these enzymes leads to proliferative changes is not understood. Gene expression microarrays were used to profile changes in mRNA expression levels in the human promyelocytic leukemia cell line HL-60 treated with CHR-2797. This analysis showed that CHR-2797 treatment induced a transcriptional response indicative of amino acid depletion, the amino acid deprivation response, which involves up-regulation of amino acid synthetic genes, transporters, and tRNA synthetases. These changes were confirmed in other leukemic cell lines sensitive to the antiproliferative effects of CHR-2797. Furthermore, CHR-2797 treatment inhibited phosphorylation of mTOR substrates and reduced protein synthesis in HL-60 cells, both also indicative of amino acid depletion. Treatment with CHR-2797 led to an increase in the concentration of intracellular small peptides, the substrates of aminopeptidases. It is suggested that aminopeptidase inhibitors, such as CHR-2797 and bestatin, deplete sensitive tumor cells of amino acids by blocking protein recycling, and this generates an antiproliferative effect. CHR-2797 is orally bioavailable and currently undergoing phase II clinical investigation in the treatment of myeloid leukemia.