Nasal biomarker profiles in acute and chronic rhinosinusitis

BACKGROUND: Clinical manifestations of rhinosinusitis include acute rhinosinusitis, chronic rhinosinusitis (CRS) with nasal polyps and CRS without polyps. OBJECTIVE: Possible mechanisms defining these three forms of rhinosinusitis should be investigated assessing biomarker profiles in nasal secretions. METHODS: Fifteen cytokines, three cellular activation markers and total IgE were determined in nasal secretions of seven patients with acute rhinosinusitis, 12 patients with CRS without polyps, 13 patients with CRS with polyps and six healthy controls. Principal component analysis was used to extract relevant factors. RESULTS: Irrespective of the clinical manifestation, all biomarkers assessed were increased in patients with rhinosinusitis when compared with controls (P<0.001). Principal component analysis allowed the extraction of three factors explaining 83% of data variance. The general inflammatory activation was mainly reflected by the first factor. The second factor differentiated acute from CRS. This factor correlated with IL-12, which is involved in pathogen-related immune activation by antigen-presenting cells. It was also positively correlated with IL-4, IL-10 and IL-13, which play an important role in the resolution of infections. The third factor differentiated CRS with polyps from CRS without polyps (P=0.001). It represented IL-5 and nasal IgE (nIgE), whereas eosinophil cationic protein and tryptase were not specific for CRS with polyps. CONCLUSION: In mucosal infection, numerous inflammatory mediators are activated. Simple correlations of few biomarkers with a specific disease process bear the risk of overestimating a possibly unspecific effect. To assess biomarker profiles, more complex analytic tools may be more appropriate to delineate mechanisms underlying mucosal disease. Using principal component analysis, it was found that high nIgE and IL-5 levels are specific for CRS with nasal polyps.     

The IFN-γ–p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.     

Differentiation of chronic sinus diseases by measurement of inflammatory mediators

Background:  Chronic rhinosinusitis (CRS) clinically is a heterogeneous group of sinus diseases, which may cover different disease entities, or may represent a disease continuum. Studying inflammatory cells and mediators in clearly defined disease subgroups may lead to a better differentiation of chronic sinus diseases.
Methods:  Sinonasal mucosal tissue from 10 nasal polyp (NP) patients, 13 cystic fibrosis patients (CF-NP), eight CRS subjects without polyps, and nine control patients were stained for CD3, CD25, CD68, CD20, myeloperoxidase (MPO), CD138 and tissue homogenates were assayed for eotaxin, interleukin (IL)-1 β , IL-2sR α , IL-5, interferon (IFN)- γ , IL-8, transforming growth factor (TGF)- β 1, tumor necrosis factor- α , and MPO by enzyme-linked immunosorbent assay or UNICAP system.
Results:  Nasal polyp and CF-NP showed increased numbers and activation of T cells, while only NP displayed an increase in plasma cells. Nasal polyp had significantly higher levels of eosinophilic markers [eosinophils, eotaxin, and eosinophil cationic protein (ECP)] compared with CRS, controls and CF-NP. Chronic rhinosinusitis was characterized by a Th1 polarization with high levels of IFN- γ and TGF- β , while NP showed a Th2 polarization with high IL-5 and immunoglobulin (Ig) E concentrations. Nasal polyp and CF-NP were discriminated by edema from CRS and controls, with CF-NP displaying a very prominent neutrophilic inflammation.
Conclusion:  Based on cellular and mediator profiles, we suggest that CRS, NP, and CF-NP are distinct disease entities within the group of chronic sinus diseases.     

Treatment of chronic rhinosinusitis with intranasal amphotericin B: a randomized, placebo-controlled, double-blind pilot trial

BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. Its etiology is unknown, and there is a paucity of effective medical treatments. OBJECTIVE: We tested the hypothesis that intranasal antifungal treatment improves the objective computed tomography (CT) findings (inflammatory mucosal thickening), nasal endoscopy stages, and symptoms of CRS. METHODS: A randomized, placebo-controlled, double-blind, single-center trial used amphotericin B to treat 30 randomly selected patients with CRS. Patients were instructed to instill 20 mL amphotericin B (250 mug/mL) or placebo to each nostril twice daily for 6 months. The primary outcome was a quantitative reduction in inflammatory mucosal thickening on CT scans of a standardized coronal cut. Secondary outcome measures were endoscopic scores, patient symptom scores, and levels of intranasal inflammatory mediators. RESULTS: Twenty-four patients completed the 6 months of treatment. Patients receiving amphotericin B achieved a relative reduction in the percentage of mucosal thickening on CT scans (n = 10; -8.8%) compared with placebo (n = 14; +2.5%; P = .030). Likewise, the changes in the endoscopic scores improved in the amphotericin B group compared with placebo ( P = .038). Between-group comparisons of the changes in the intranasal mucus levels of eosinophil-derived neurotoxin showed a reduction in the amphotericin B group and an increase in the placebo group ( P = .046); levels of IL-5 showed similar tendencies ( P = .082). CONCLUSION: Intranasal amphotericin B reduced inflammatory mucosal thickening on both CT scan and nasal endoscopy and decreased the levels of intranasal markers for eosinophilic inflammation in patients with CRS.     

Relationship of TLR2, TLR4 and tissue remodeling in chronic rhinosinusitis

In order to explore the role of innate immunity in the remodeling of CRS (chronic rhinosinusitis), we investigated the correlation between TLR2, TLR4 and remodeling involved cytokines and histopathological features. Immunohistochemical staining was applied to detect the expression of TLR2, TLR4 and TGF-β1. Masson staining was used for observing the collagen deposition. The other histopathologic features of remodeling were observed by hemotoxylin and eosin (HE) staining. Nasal epithelial cell culture was used to elucidate the effect of TLR2, TLR4 agonists and inhibitors on the expression of TGF-β1 and MMP-9. The association study showed that the significantly higher expression of TLR2, TLR4, TGF-β1 and collagen appeared in CRSsNP (chronic rhinosinusitis without nasal polyps) patients compared with CRSwNP (chronic rhinosinusitis with nasal polyps) patients. In CRSsNP, patients with a severe epithelial damage (score 3) had a significantly higher expression of TLR2 than patients with mild epithelial damage (score ≤ 2) (P < 0.05). Moreover the expression of TLR2 correlated negatively with squamous hyperplasia in CRSsNP, and positively with gland hyperplasia in CRSwNP. The expression of TLR2 and TLR4 was closely related to neutrophil infiltration in CRSsNP (P < 0.01). TGF-β1 was downregulated by TLR2 agonist in CRSwNP and upregulated by TLR4 agonist in CRSsNP (P < 0.05). MMP-9 was upregulated by TLR4 agonist in CRSwNP (P < 0.05). TLR2 and TLR4 had close relationship with TGF-β1 and the histologic features of remodeling, especially collagen deposition and neutrophil infiltration in CRSsNP. The innate immunity could influence the histologic characteristics and involved cytokines through TLR2 and TLR4 in the remodeling of CRS.     

Features of airway remodeling and eosinophilic inflammation in chronic rhinosinusitis: is the histopathology similar to asthma?

BACKGROUND: Asthma and chronic rhinosinusitis (CRS) coexist clinically in >50% of patients with CRS. Although epithelial damage and basement membrane thickening are well-known features of airway remodeling in asthma, they have not been described in CRS. OBJECTIVE: In this study, we tested the hypothesis that histopathologic features of asthma, namely, the chronic eosinophilic inflammation, epithelial damage, and basement membrane thickening of the airway mucosa, are also present in sinonasal specimens from patients with CRS. METHODS: We examined histologic specimens from 22 randomly selected patients with refractory CRS undergoing endoscopic sinus surgery and 4 healthy control subjects. The shedding of the epithelium and basement membrane thickening were evaluated by 3 independent observers' scores of hematoxylin-and-eosin staining. Eosinophilic inflammation was monitored with immunohistochemistry for eosinophil major basic protein. A novel, computerized method objectively analyzed confocal microscopic images of major basic protein immunofluorescence to determine areas with the least and most inflammation per specimen. RESULTS: Specimens from all patients with CRS (22/22) revealed epithelial damage (shedding) and basement membrane thickening. Strikingly heterogeneous eosinophilic inflammation, which did not differ between allergic and nonallergic patients, was detected in all patients with CRS and was absent in all healthy control subjects. CONCLUSION: The histopathologic findings of asthma, namely, heterogeneous eosinophilic inflammation and features of airway remodeling, are also present in CRS. These findings, coupled with the common clinical coexistence of both diseases, suggest that the same pathologic disease process is manifest as CRS in the sinonasal tissue and as asthma in the lower airway.     

Epithelial–Mesenchymal Transition in Chronic Rhinosinusitis: Differences Revealed Between Epithelial Cells from Nasal Polyps and Inferior Turbinates

The pathogenesis of chronic rhinosinusitis (CRS) remains unclear to date. The tissue remodeling in nasal polyps may be the result of inflammatory mediators and may involve epithelial–mesenchymal transition (EMT) and EMT-associated features such as cell motility in nasal epithelial cells (NECs). We determined whether NEC in nasal polyps of CRS already display features of EMT in vivo or respond with EMT to growth factor stimulation in vitro. Nasal polyp tissues expressed both epithelial and mesenchymal markers. Primary NEC from inferior turbinates and nasal polyps responded to the EMT-inducing agents transforming growth factor (TGF)-β1 and epidermal growth factor (EGF) with different expression patterns of EMT markers (E-cadherin, N-cadherin, Snail, Slug, Twist), however, only NEC from nasal polyps were susceptible to TGF-β1 and EGF-dependent cell migration. Our data suggest that a partial EMT is associated with the pathogenesis of nasal polyps in CRS patients. Furthermore, we show for the first time that epithelial cells from both nasal polyps and inferior turbinates were able to undergo an EMT-like process following exposure to TGF-β1 or EGF in vitro but that only NEC from nasal polyps responded with enhanced cell motility. Our data suggest that NEC from CRS patients have undergo partial EMT and that this process may be involved in the pathogenesis of CRS.

     

Allergic fungal sinusitis: an immunohistologic analysis

BACKGROUND: Allergic fungal sinusitis is a noninvasive form of fungal sinusitis that has recently been delineated as a distinct clinicopathologic entity. It is increasingly recognized as a cause of chronic sinusitis, with the primary causative agents being members of the Dematiaceae fungus family. Although its immunopathogenesis has not been elucidated, the eosinophil is a prominent inflammatory cell on histologic examination. OBJECTIVE: We sought to characterize the involvement of eosinophils in sinus tissue and accompanying mucin from patients with allergic fungal sinusitis. As a comparison, neutrophil and mast cell involvement was also evaluated in the same group of patients. METHODS: Tissue specimens from 8 patients with allergic fungal sinusitis, along with 8 nasal polyp specimens from patients without allergic fungal sinusitis, were stained by using indirect immunofluorescence for eosinophil granule major basic protein (MBP). Neutrophil elastase and mast cell tryptase staining was also performed on the same allergic fungal sinusitis and nasal polyp tissues. RESULTS: MBP was diffusely localized within the mucin, showing intense staining at the periphery and variable staining of degenerated cell clusters throughout. Extracellular MBP in the mucin was strikingly greater than intact eosinophil staining. Diffuse extracellular neutrophil elastase was also present in the mucin. Mucinous areas showed no tryptase localization. Adjacent nonmucinous areas of respiratory mucosa showed predominantly cellular staining with eosinophil MBP, neutrophil elastase, and mast cell tryptase. MBP staining of nasal polyps showed a predominantly cellular pattern with focal areas of extracellular deposition. CONCLUSIONS: Given the known toxicities of eosinophil granule MBP and neutrophil elastase, their extracellular presence supports the contribution of these proteins in the pathogenesis of allergic fungal sinusitis and further indicates that eosinophil and neutrophil activation occurs in the disease.     

The clinicopathologic spectrum of benign mass lesions of the vocal fold due to vocal abuse

Benign masses of the vocal fold related to phonotrauma are clinically classified into polyps, nodules, Reinke's edema, and cysts. Despite the apparent distinctiveness of the clinical nomenclature, low inter- and intraobserver diagnostic agreement has been reported. Excepting cysts, which are epithelial lined, histologic examination of the remaining lesions has shown a variety of overlapping features insufficiently specific for the clinical diagnoses. This study reviews the clinicopathologic characteristics among these benign lesions of the vocal fold. A total of 78 nonneoplastic lesions of the vocal fold were reviewed by 2 pathologists for the presence of epithelial hyperplasia, basement membrane thickening, edema, vascular proliferation, and extracellular "amyloid-like" fibrin. In 46 cases with prebiopsy stroboscopic images, 2 otolaryngologists classified each lesion as polyp, nodule, Reinke's edema, cyst, or other. They agreed in 43% (n = 20, 13 polyps, 5 nodules, 1 Reinke's edema, 1 other) and disagreed in 57% (n = 26). There was no histologic feature that reliably distinguished among the lesions. In addition, reactive stromal cell atypia was present in 14 cases. Cysts were distinctive, as all were epithelial lined. The clinicopathologic classification of benign laryngeal lesions is neither clinically reproducible nor histologically unique. Treatment will continue to be individualized based on clinical judgment.     

Aging Reduces the Expression of Lung CINC and MCP-1 mRNA in a P. aeruginosa Rat Model of Infection

We investigated dynamic changes of inflammatory cell infiltration and expression of cytokine-induced neutrophil chemoattractant (CINC) and monocyte chemoattractant protein-1 (MCP-1) mRNA in aged rats with Pseudomonas aeruginosa pulmonary infection. Disease manifestation and lung tissue pathology (lesion dispersion, inflammatory reactions, tissue edema and bleeding) were more severe in aged rats than young rats. At various time points, lung tissue polymorphonuclear neutrophil and mononuclear macrophage numbers were lower in the aged group than the young group (P < 0.05), and at 24 h there was no difference in mononuclear macrophage numbers. After inoculation with P. aeruginosa, CINC and MCP-1 mRNA expression increased in both groups, but the peak lagged in old rats compared with young. Thus, aging can reduce the expression of CINC and MCP-1 mRNA in lung tissues, and reduce the infiltration of neutrophils and monocyte–macrophages induced by CINC and MCP-1. This might lead to increased risk of pneumonia in elderly patients.     

Basement membrane thickening and clinical features of children with asthma

BACKGROUND: Asthma is a chronic inflammatory disease, characterized by airway inflammation, bronchial hyper-responsiveness, and airway obstruction. Although asthma induces partially reversible airway obstruction, obstruction can sometimes become irreversible. This may be a consequence of airway remodeling, which includes a number of structural changes, such as epithelial detachment, basement membrane (BM) thickening, smooth muscle hypertrophy, and new vessel formation. This study evaluated children with asthma for the presence of BM thickening. METHODS: Eighteen children with asthma and 24 control subjects underwent flexible bronchoscopy with endobronchial biopsy. Light microscopy was used to measure BM thickness in paraffin-embedded biopsy sections. The association between BM thickening and age, sex, duration of asthma, asthma severity, FEV(1), FEV(1)/FVC, FEF(25-75%), methacholine PC(20), eosinophil count, and presence of atopy was examined. RESULTS: Basement membrane thickness was greater in subjects with asthma (8.3 +/- 1.4 microM) than in control subjects (6.8 +/- 1.3 microM, P = 0.0008). Multiple regression analysis revealed that sex, FEV(1)/FVC, total IgE, and atopy (IgE for Dermatophagoides pteronyssinus >0.34 kUA/l) were significant predictive factors for BM thickness. There was no significant association between BM thickness and age, duration of asthma, FEV(1), FEF(25-75%), methacholine PC(20), eosinophil count, or asthma severity. CONCLUSIONS: Basement membrane thickening has been known to be present in children with asthma. In addition, we report an association between BM thickness and sex, FEV(1)/FVC, total IgE, and the presence of IgE specific to D. pteronyssinus.     

Morphological characteristics of inflammatory polyps of the large intestine in children

Inflammatory polyps of 32 children were studied morphologically. Inflammatory polyps comprised more than 20% of all removed polyps in 1983-2002. They were second among common polyps in children after juvenile polyps. Typical location of inflammatory polyps was the rectum. Characteristic morphological features of inflammatory polyps in children are predomination of the inflammatory component represented by granulation tissue. In contrast to juvenile polyps granulation tissue in inflammatory polyps does not contain glands but may contain foreign bodies and giant cells. About one third of the inflammatory polyps in children in this study was associated with mucosal prolapse syndrome evidenced by proliferation of smooth muscle cells and fibrous tissue in the stroma of polyp glandular component.     

Differential pathology of nasal polyps in cystic fibrosis and atopy.

Nineteen nasal polyps from 13 patients were examined histologically. Nine polyps from seven cystic fibrosis (CF) patients could be positively identified by a triad of observations: delicate, barely visible basement membrane of surface epithelium without submucosal hyalinization, lack of extensive infiltration of eosinophils (Giemsa stains), and a preponderance of acid mucin in glands and cysts of the polyp and in its surface mucous blanket (Alcian Blue-periodic acid-Schiff stains). Two polyps from two patients with CF and atopy showed the characteristic findings of CF without modification. Eight polyps from four atopic patients without CF were identified by the reverse triad of changes: extensive thickening of the epithelial basement membrane and its extension into the submucosa as an irregular hyaline membrane, high stromal eosinophil count, and mainly neutral mucin in mucous glands, cysts, and mucous blanket. Hyperplastic mucous glands, mucous cysts of variable sizes, focal metaplasia of surface epithelium, and acid mucin in goblet cells were considered nonspecific lesions.     

Olfactory cleft mucus galectin-10 predicts olfactory loss in chronic rhinosinusitis

BackgroundEosinophils have been reported to be involved in the pathogenesis of olfactory fluctuation in chronic rhinosinusitis (CRS). Galectin-10 is more frequently associated with type 2 inflammation and potentially a sign of intense eosinophil activation.ObjectiveTo explore olfactory cleft mucus and olfactory mucosa galectin-10 level and its association with olfactory dysfunction (OD) in CRS.MethodsWe prospectively enrolled 50 patients with CRS and 15 healthy controls. Olfactory cleft mucus and superior turbinate biopsy specimens were collected to analyze galectin-10 levels and quantify tissue eosinophils. Psychophysical olfactory testing, olfactory cleft endoscopy scale, and olfactory cleft computed tomography scores were obtained. The predictability of galectin-10 levels for OD in patients with CRS was analyzed by multivariable logistic regression analysis.ResultsBoth olfactory cleft mucus and olfactory mucosa galectin-10 levels in patients with CRS with OD were significantly higher than those in patients with CRS without OD (all P < .001). Mucus galectin-10 levels were positively correlated with tissue eosinophils (r = 0.541, P = 0.002), olfactory cleft endoscopy scale (r = 0.498, P = 0.006), and olfactory cleft computed tomography scores (r = 0.432, P = 0.019) in patients with CRS. Mucus galectin-10 levels were negatively correlated threshold, discrimination, and identification (r = ?0.589,  P = 0.001), olfactory threshold (r = ?0.522, P = 0.003), olfactory discrimination (r = ?0.488, P = 0.007), and olfactory identification (r = ?0.466, P = 0.011) scores. After adjusting for patient demographics and comorbidities, mucus galectin-10 levels were significantly associated with OD in patients with CRS (odds ratio, 1.299; P = .008). Mucus galectin-10 levels greater than 8.975 ng/mL were the best predictor of OD in CRS.ConclusionOlfactory cleft mucus galectin-10 is highly associated with OD in CRS.     

Polymorphisms in thymic stromal lymphopoietin gene demonstrate a gender and nasal polyposis-dependent association with chronic rhinosinusitis

Background

Recent studies have suggested that thymic stromal lymphopoietin (TSLP), a key cytokine involved in the dendritic cell-mediated activation of Th2-mediated inflammatory responses, is significantly increased in nasal polyps from atopic individuals. Our objective was therefore to explore firstly any associations between single nucleotide polymorphisms (SNPs) in and around the TSLP gene and development of chronic rhinosinusitis (CRS; with (CRSwNP) or without (CRSsNP) nasal polyps and, and secondly the influence of nasal polyposis and gender.

Methods

A population-based case-control association analysis was performed in a Han Chinese cohort. DNA extracted from peripheral blood leukocytes from 638 subjects with CRS (306 CRSwNP and 332 CRSsNP) and 325 healthy controls was assessed for 11 SNPs in and around TSLP gene, selected from the Chinese HapMap genotyping dataset. Genetic association tests were performed using the Haploview and STATA software package.

Results

Single-locus analysis of CRS risk, showed no significant differences in allele or genotype frequencies between CRS subjects and controls. Stratified analyses of association between the selected SNPs and CRS adjusted for gender demonstrated that rs13156068 (CC genotype: P = 0.010, OR = 0.289) and rs764917 (CC genotype: P = 0.040, OR = 0.509) were significantly protective against CRS, whereas rs6886755 (GT genotype: P = 0.040, OR = 0.509) presented a risk among females. In contrast, rs764917 (CA genotype: P = 0.033, OR = 1.553) presented risk for CRS in males. Furthermore, SNPs rs252706 (AA genotype: P = 0.012, OR = 0.552) and rs764917 (CA genotype: P = 0.001, OR = 0.182) displayed protective roles among CRSwNP, but not CRSsNP, subjects.

Conclusions

This study suggests that SNPs in TSLP gene may exert a gender and/or nasal polyposis-dependent risk for development of CRS in Chinese subjects.     

Hormonal pathology of the endometrium.

The endometrial tissue is a sensitive target for steroid sex hormones and is able to modify its structural characteristics with promptness and versatility. This article discusses briefly endogenous hormonal effects (cyclic changes, luteal phase defect, unopposed estrogen effect) and describes the histologic patterns encountered in the most commonly used hormone therapies: oral contraceptives, ovulation stimulation, hormone replacement therapy, and antitumoral hormone therapy. Oral contraceptives exert a predominant progestational effect on the endometrium, inducing an arrest of glandular proliferation, pseudosecretion, and stromal edema followed by decidualized stroma with granulocytes and thin sinusoidal blood vessels. Prolonged use results in progressive endometrial atrophy. Ovulation induction therapy accelerates the maturation of the stroma and is often associated with a discrepancy between early secretory glands and an edematous or decidualized stroma with spiral arterioles. Hormone replacement therapy with estrogen alone may result in continuous endometrial proliferation, hyperplasia, and neoplasia. The use of both estrogen and progesterone elicits a wide range of histologic patterns, seen in various combinations: proliferative and secretory changes, often mixed in the same tissue sample; glandular hyperplasia (in polyps or diffuse) ranging from simple to complex atypical; stromal hyperplasia and/or decidual transformation; epithelial metaplasia (eosinophilic, ciliated, mucinous); and inactive and atrophic endometrium. Progesterone therapy for endometrial hyperplasia and neoplasia induces glandular secretory changes, decidual reaction, and spiral arterioles. Glandular proliferation is usually arrested, but neoplastic changes may persist and coexist with secretory changes. Lupron therapy produces a shrinking of uterine leiomyomas by accelerating their hyaline degeneration, similar to that in postmenopausal involution. It generally produces endometrial atrophy. Tamoxifen for breast carcinoma has an estrogen agonist effect on the uterus in approximately 20% of patients, who develop endometrial polyps, glandular hyperplasia, adenomyosis, and/or leiomyomata. Both endometrioid and nonendometrioid carcinomas are seen, often in polyps. Their causal relationship to tamoxifen therapy is debatable.     

Severe Cytokine Release Syndrome after Haploidentical Peripheral Blood Stem Cell Transplantation

Inflammatory cytokines released by activated lymphocytes and innate cells in the context of cellular therapy can cause fever, vasodilatation, and end-organ damage, collectively known as cytokine release syndrome (CRS). CRS can occur after allogeneic blood or marrow transplantation, but is especially prevalent after HLA-haploidentical (haplo) peripheral blood transplantation (PBT). We reviewed charts of all patients who underwent haplo-PBT between October 1, 2013, and September 1, 2017 and graded CRS in these patients. A total of 146 consecutive patients who underwent related haplo-PBT were analyzed. CRS occurred in 130 patients (89%), with most cases of mild severity (grade 0 to 2). Severe CRS (grade 3 to 5) occurred in 25 patients (17%). In this group with severe CRS, 13 patients had encephalopathy, 12 required hemodialysis, and 11 were intubated. Death from the immediate complications of CRS occurred in 6 patients (24% of the severe CRS group and 4% of the entire haplo-PBT cohort). The cumulative probability of nonrelapse mortality (NRM) was 38% at 6 months for the patients with severe CRS and 8% (121 of 146) in patients without severe CRS. In conclusion, CRS occurs in nearly 90% of haplo-PBTs. Older haplo-PBT recipients (odds ratio [OR], 2.4; 95% confidence interval [CI], .83 to 6.75; P = .11) and those with a history of radiation therapy (OR, 3.85; 95% CI, 1.32 to 11.24; P = .01) are at increased risk of developing severe CRS. Although most recipients of haplo-PBT develop CRS, <20% experience severe complications. The development of severe CRS is associated with a significantly increased risk of NRM.     

Severity of Cytokine Release Syndrome and Its Association with Infections after T Cell-Replete Haploidentical Related Donor Transplantation

An increased risk of infections has been described after T cell-replete haploidentical cell transplantation (haploHCT). Cytokine release syndrome (CRS) after haploHCT is a known phenomenon, but the impact of CRS severity on the risk of infections remains unexplored. We retrospectively evaluated 78 consecutive adult haploHCT recipients from 2012 to 2018 for the development of CRS (graded based on the criteria of Lee et al) and examined the incidence and mortality due to infections in correlation with CRS severity. In our study cohort, which was stratified into 3 groups by severity of CRS, 80% of the patients developed infections within 180 days of HCT. Significantly higher proportions of patients with CRS grade 2 (89%) and grade ≥3 (90%) than patients with CRS grade 0-1 (68%) had at least 1 infection in the first 100 days (P = .04). Bloodstream infections (BSIs) were seen more frequently in patients with CRS grade 2 and grade ≥3 in the first 6 months. Multivariable analysis for time to infection showed that CRS grade ≥3 was independently associated with an elevated risk of any infection compared with CRS grade 0-1 (hazard ratio [HR], 3.05; P = .007). CRS grade ≥3 was also associated with a higher hazard of viral (HR, 3.42; P = .04) and bacterial infections (HR, 2.83; P = .03) compared with CRS grade 0-1. After adjusting for time to neutrophil engraftment as a time-dependent covariate, CRS grade ≥3 still had a significant effect on viral infections (HR, 2.49; P = .03), but not on bacterial infections (HR, 1.32; P = .57). CRS grade was also a significant predictor for infection density (overall, bacterial, and viral). The incidence of infection-related mortality by day +100 was higher in patients with severe CRS. Severe CRS developing after post-transplantation cyclophosphamide-based haploHCT is independently associated with viral infections and an increased risk of bacterial infections, likely through delayed neutrophil engraftment.     

Prognostic Inflammation Score in Surgical Patients with Colorectal Cancer

Several inflammatory markers have been investigated as prognostic parameters in a variety of cancer population with mostly favorable results. This study aimed to verify the significance of common inflammatory markers as prognostic variables and assess whether a selective combination of them as prognostic inflammation score (PIS) could further improve their prognostic values in surgical patients with colorectal cancer (CRC). A total of 265 patients who had undergone curative resection of CRC were reviewed retrospectively. Preoperative levels of inflammatory markers such as serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC), and neutrophil/lymphocyte ratio (NLR) were assessed by uni- and multivariate survival analysis with disease-free (DFS) and disease-specific survival (DSS). PIS was constructed with a selective combination of inflammatory markers which were independently significant. On univariate analysis, CRP, ESR, and NLR were significantly associated with DFS and DSS. On multivariate analysis, CRP and NLR were independently significant prognostic variables for DSS and DFS respectively (P=0.013, P=0.021). When PIS was constructed with combination of CRP and NLR, it was independently and significantly associated with both DFS and DSS (P=0.006, P=0.010). Furthermore, PIS was superior to CRP for DSS (HR=15.679 vs. HR=5.183), and NLR for DFS in terms of prognosticating power (HR=4.894 vs. HR=2.687). When PIS is constructed with combination of CRP and NLR, it is a potentially significant prognostic variable associated with poor survival regardless pathologic prognostic variables in patients with CRC after curative resection.     

Histologic features of surgically removed fallopian tubes

CONTEXT: The fallopian tube is a common specimen in a pathology laboratory. It may be examined either alone as a salpingectomy or tubal ligation specimen, or as part of a more complex specimen from a hysterectomy and/or oophorectomy operation. Although the common histologic findings in the fallopian tube have been described previously, to our knowledge no study has documented the frequency of histologic changes in fallopian tubes removed for all reasons or associations with clinical history. DESIGN: Hematoxylin-eosin-stained slides from 287 fallopian tube specimens were reviewed without knowledge of the clinical history. Three categories and associated subcategories of histologic findings were identified (listed in descending order of frequency): stromal and architectural alterations (fibrosis, intramuscular edema, cellular luminal contents, inclusion cysts, Walthard nests, pigmentosis tubae, Wolffian duct remnants, decidualized stroma, endosalpingiosis, and metastatic carcinoma), epithelial characteristics (cytologic atypia, vacuolization, metaplasia, and tufting), and inflammatory changes (intramuscular mast cells, plasma cells, neutrophils, and lymphoid follicles). Histologic findings were correlated with clinical history, surgery type, and age. RESULTS: Intramuscular edema was identified in 12.5% of specimens, most frequently in postpartum women. Plical fibrosis (35.5% of specimens), epithelial atypia (7.3%), epithelial vacuolization (6.6%), and epithelial tufting/stratification (3.5%) correlated with increased patient age. Inflammatory cells were relatively common; 69% of specimens contained intramuscular mast cells, 19.9% had stromal plasma cells, 10.5% had neutrophils, and 2.1% had lymphoid follicles. CONCLUSIONS: This study provides data that may be valuable for surgical pathologists involved in identifying and characterizing common histologic changes in surgically removed fallopian tubes.