Impact of semen microbiota on the composition of seminal plasma.

Several studies have found associations between specific bacterial genera and semen parameters. Bacteria are known to influence the composition of their niche and, consequently, could affect the composition of the seminal plasma. This study integrated microbiota profiling and metabolomics to explore the influence of seminal bacteria on semen metabolite composition in infertile couples, revealing associations between specific bacterial genera and metabolite profiles. Amino acids and acylcarnitines were the predominant metabolite groups identified in seminal plasma. Different microbiota profiles did not result in globally diverse metabolite compositions in seminal plasma. Nevertheless, levels of specific metabolites increased in the presence of a dysbiotic microbiota. Urocanate was significantly increased in abnormal semen samples (adjusted P-value < 0.001) and enriched in samples dominated by Prevotella spp. (P-value < 0.05), which was previously linked to a negative impact on semen. Therefore, varying microbiota profiles can influence the abundance of certain metabolites, potentially having an immunomodulatory effect, as seen with urocanate.IMPORTANCEMale infertility is often considered idiopathic since the specific cause of infertility often remains unidentified. Recently, variations in the seminal microbiota composition have been associated with normal and abnormal semen parameters and may, therefore, influence male infertility. Bacteria are known to alter the metabolite composition of their ecological niches, and thus, seminal bacteria might affect the composition of the seminal fluid, crucial in the fertilization process. Our research indicates that distinct seminal microbiota profiles are not associated with widespread changes in the metabolite composition of the seminal fluid. Instead, the presence of particular metabolites with immunomodulatory functions, such as urocanate, could shed light on the interplay between seminal microbiota and variations in semen parameters.

Nasal polyp epithelial atypia and exposure to nickel and copper.

BACKGROUND: Possible factors for cell atypia in nasal mucosa include noxious chemicals: ammonia, formaldehyde and heavy metals. AIMS: Case presentation of a nasal polyp with epithelial dysplasia in a worker exposed to nickel and copper salt dust. CASE REPORT: A 27-year-old man complained of impaired nasal breathing and mild right-sided epistaxis. He was exposed to copper and nickel salt dust for 6 years. Clinical examination showed a polypoid lesion arising from the right middle turbinate. Histopathological examination of the excised lesion showed high-grade epithelial dysplasia. Duration of exposure and concentration of heavy metals in serum suggest the biological plausibility of exposure to these factors and development of epithelial dysplasia in the nasal mucosa. CONCLUSIONS: Epithelial dysplasia may occasionally be noted in inflammatory nasal polyps, especially in workers exposed to heavy metals.

Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.

Background: Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period. Methods: Patients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States). Results: Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score ≥3]; 61.1% Ki67 expression low (<14% positive cells); using immunohistochemistry (IHC) surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0.0-23.8) for all, 7.2 years (0.0-23.2), for M0, 2.6 years (0.0-12.7) for M1 patients. A significant improvement over time was observed in age-corrected BC mortality. BC-specific-mortality was higher for men younger than 50 years. Better overall (OS) and recurrence-free survival (RFS) were observed for highly ER+ (P = 0.001), highly PR+ (P = 0.002), highly AR+ disease (P = 0.019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions: Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

Serum cytokine profile of laryngeal squamous cell carcinoma patients.

OBJECTIVES: This study aimed to evaluate serum cytokine concentrations in healthy individuals and laryngeal squamous cell carcinoma patients. METHODS: A total of 59 laryngeal squamous cell carcinoma patients and 44 healthy controls were included. Multiplex analysis of interleukins 2, 4, 5, 6, 10, 12, 13 and 17 and interferon-gamma with respect to the presence of laryngeal carcinoma, tumour-node-metastasis T stage, nodal involvement and larynx subsite was performed. RESULTS: Statistical analysis revealed no difference in serum cytokine levels between patients and healthy controls. The serum interleukin-12 concentration was significantly higher in patients with early (T1-2) than in those with late (T3-4) stage disease and without nodal involvement (p < 0.05). Serum interleukin-10 levels were significantly higher in T3-4 stage than in T1-2 stage patients (p < 0.05). Additionally, serum interleukin 10, 12 and 13 concentrations (p < 0.05) and interleukin-6 concentration (p < 0.01) were significantly higher in patients with T1-2 stage supraglottic vs glottic tumours. CONCLUSION: Serum cytokines level cannot be used as laryngeal squamous cell carcinoma markers. Progression from T1-2 to T3-4 stage is followed by decreased serum interleukin-12 levels and increased interleukin-10 levels. Nodal involvement is associated with lower serum interleukin-12 levels. In patients with early stage tumours, serum interleukin 6, 10, 12 and 13 concentrations are significantly higher in those with supraglottic vs glottic tumours.

Middle turbinate chondro-osseous respiratory epithelial adenomatoid hamartoma.

OBJECTIVE: Chondroosseous respiratory epithelial adenomatoid hamaroma (COREAH) is an extremely rare, developmental malformation. COREAH is characterized by a spectrum of chondro-osseous metaplasia that arise from the mesenchymal stroma, and it includes dilated submucosal glands lined with respiratory epithelium. This case report aimed to describe a COREAH that originated in the nasal cavity. CASE REPORT: A 68-year-old woman presented with unilateral nasal obstruction. Endonasal and radiological findings suggested a diagnosis of an unilateral inflammatory polyp. However, after excision of the mass with endoscopic guidance, a histological examination supported a final diagnosis of a nasal COREAH. CONCLUSION: To our knowledge, this was the first description of a COREAH that originated from the middle turbinate and presented as a choanal polyp. The role of the pathologist is essential for a correct diagnosis.

Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells.

Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma.

Effects of Preoperative Clarithromycin Administration in Patients with Nasal Polyposis.

OBJECTIVE: In recent years, various investigators have shown considerable interest in the use of macrolide antibiotics for treatment of chronic rhinosinusitis and nasal polyposis. The aim of this study was to evaluate the clinical effects of preoperative long-term, low-dose clarithromycin administration in patients with nasal polyposis. METHODS: Eighty nasal polyp patients (42 non-atopic and 38 atopic) were included in this prospective, non-placebo controlled investigation and randomized equally to either the combined clarithromycin-surgical or surgical group. Forty patients received 500 mg of clarithromycin daily for eight weeks, and, after evaluation, they were treated by functional endoscopic sinus surgery (FESS). The other 40 patients were treated only surgically. The nasal symptom scores and endoscopic scores after macrolide treatment/surgical treatment, and after six and 12 months of follow-up were evaluated. RESULTS: After clarithromycin therapy, we found improvement in symptom scores in 25/40, and improvement in endoscopic scores in 19/40 patients. We found no significant difference in nasal symptom score between allergic and non-allergic patients regarding the outcome to macrolide (p = 0.352) or surgical treatment (p = 0.396). When we compared differences between endoscopic scores at the time points of 12 months and six months postoperatively (ESt12 minus ESt6), we found statistically lower differences in the clarithromycin-surgery group than in the surgery group (p = 0.006). CONCLUSION: Preoperative clarithromycin administration postponed nasal polyp relapse after FESS. Allergies have no influence on the clinical efficacy of clarithromycin therapy and on the efficacy of FESS.

Influence of allergy on clinical, immunological and histological characteristics of nasal polyposis.

OBJECTIVES: Although polyps seem to be a manifestation of the chronic inflammation of nasal/paranasal sinuses mucosa in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. The aim of this prospective study was to compare the clinical characteristics of nasal polyposis in non-allergic and allergic patients, to compare the cytokine levels in nasal secretions in atopic and non-atopic nasal polyp patients and to correlate these levels with eosinophil counts in nasal polyp tissue specimens. METHODS: This study included thirty patients with nasal polyposis (13 atopic and 17 non-atopic) requiring surgical treatment. Nasal secretion samples were collected from the nasal cavities of all 30 subjects a few days before the surgical treatment. The levels of tumour necrosis factor-alpha (TNF-alpha), tumour necrosis factor-beta (TNF-beta), interleukin (IL)-1beta, IL-2, IL-12, interferon-gamma (IFN-gamma), IL-4, IL-5, IL-6, IL-10, and IL-8 were measured using the flow cytometric method. Each of the 30 patients was staged clinically according to nasal symptom score, endoscopic score and Lund-Mackay computed tomography (CT) score. All these patients had undergone sinus surgery. Eosinophils were counted in hematoxylin- and eosin-stained sections of all nasal polyp samples. RESULTS: Our results showed that allergy does not modify the symptoms, or the endoscopic and CT findings, of nasal polyposis. We found significantly higher concentrations of IL-4 (p < 0.01), IL-5 (p < 0.05), IL-6 (p < 0.05) and TNF-beta (p < 0.05) in nasal secretions of allergic nasal polyp patients than in non-allergic ones. Eosinophil counts were significantly higher in tissues of atopic patients' polyps than in non-atopic subjects (p < 0.01). No correlation was observed between cytokine levels and eosinophil counts. CONCLUSION: Non-atopic and atopic patients' polyps have different immunological patterns. Our results showed that the presence of Th2 cytokines was a more significant feature in allergic patients with nasal polyposis than in non-allergic patients.

Effect of long-term, low-dose clarithromycin on T helper 2 cytokines, eosinophilic cationic protein and the 'regulated on activation, normal T cell expressed and secreted' chemokine in the nasal secretions of patients with nasal polyposis.

BACKGROUND: Little is known about the effects of macrolides on the cytokines and chemokines that modulate the function of eosinophils in nasal polyposis. METHODS: Twenty-two non-allergic and 18 allergic patients with nasal polyps were administered clarithromycin 500 mg/day (single oral dose) for eight weeks. We measured the nasal secretion levels of the T helper 2 (also known as Th2) cytokines interleukin 4, 5 and 6, the 'regulated on activation, normal T cell expressed and secreted' (also known as RANTES) chemokine, and the eosinophilic cationic protein, before and after treatment. RESULTS: After clarithromycin treatment, we found reduced levels of the 'regulated on activation, normal T cell expressed and secreted' chemokine in samples from both non-allergic and allergic patients (p < 0.05). Clarithromycin treatment decreased the levels of eosinophilic cationic protein only in non-allergic patients (p < 0.05), and decreased the level of interleukin 6 only in allergic patients (p < 0.05). Decreased levels of the 'regulated on activation, normal T cell expressed and secreted' chemokine were associated with a reduction in polyp size both in non-allergic and allergic patients. CONCLUSION: Clarithromycin has a strong anti-inflammatory effect in nasal polyposis, but has different immunomodulatory effects in allergic and non-allergic nasal polyposis patients.

Correlation between cytokine levels in nasal fluid and eosinophil counts in nasal polyp tissue in asthmatic and non-asthmatic patients

Background/ Aims: Concentrations of mediators in nasal secretions could reflect the inflammatory status of the nasal mucosa and evolution of sinus disease. So, the aim of our study was to evaluate local immune reaction by measuring crucial Th1, Th2 and inflammatory cytokines innasal fluid samples of patients with nasal polyps (NP), and to correlate them to clinical, radiological findings and to the degree of eosinophil infiltration of polyp tissue. Therefore, in our study we compared the cytokine levels in nasal fluid of asthmatic and non-asthmatic patients with nasal polyposis, the eosinophil counts in NP tissues of these patients, and we correlated cytokine levels with eosinophil counts in NP tissue specimens. Material and methods: Thirty patients with nasal polyposis (NP) (15 asthmatic and 15 non asthmatic) were included in this prospective study. Nasal secretion samples were collected from nasal cavities of all subjects. The levels of 11 cytokines (TNF- , TNF- , IL-1 , IL-2, IL-4,IL-5, IL-6, IL-8, IL-10, IL-12, and IFN- ) were measured using commercial flow cytometric kit. Eosinophils were counted in haematoxylin-and-eosin-stained NP sections. Results: The concentrations of Th2 cytokines IL-5, IL-6, IL-10, and Th1 cytokine IFN- were significantly higher in patients with NP and asthma compared with non-asthmatic subjects. A positive correlation was found between IL-6 and TNF- levels in nasal fluid and eosinophil counts in polyp tissue in non-asthmatic subjects. In asthmatic NP patients, we found positive correlation between level of IL-6 and eosinophil counts and negative correlation between IFN- level and number of eosinophils in NP tissue specimens. Conclusion: Our results showed that these patients with similar clinical findings had significantly different mediator profiles in their nasal secretions, implying clear differences in pathogenesis of their NP (AU)

Correlation between cytokine levels in nasal fluid and eosinophil counts in nasal polyp tissue in asthmatic and non-asthmatic patients.

BACKGROUND/AIMS: Concentrations of mediators in nasal secretions could reflect the inflammatory status of the nasal mucosa and evolution of sinus disease. So, the aim of our study was to evaluate local immune reaction by measuring crucial Th1, Th2 and inflammatory cytokines in nasal fluid samples of patients with nasal polyps (NP), and to correlate them to clinical, radiological findings and to the degree of eosinophil infiltration of polyp tissue. Therefore, in our study we compared the cytokine levels in nasal fluid of asthmatic and non-asthmatic patients with nasal polyposis, the eosinophil counts in NP tissues of these patients, and we correlated cytokine levels with eosinophil counts in NP tissue specimens. MATERIAL AND METHODS: Thirty patients with nasal polyposis (NP) (15 asthmatic and 15 non-asthmatic) were included in this prospective study. Nasal secretion samples were collected from nasal cavities of all subjects. The levels of 11 cytokines (TNF-α, TNF-ß, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IFN-γ) were measured using commercial flow cytometric kit. Eosinophils were counted in haematoxylin-and-eosin-stained NP sections. RESULTS: The concentrations of Th2 cytokines IL-5, IL-6, IL-10, and Th1 cytokine IFN-γ were significantly higher in patients with NP and asthma compared with non-asthmatic subjects. A positive correlation was found between IL-6 and TNF-α levels in nasal fluid and eosinophil counts in polyp tissue in non-asthmatic subjects. In asthmatic NP patients, we found positive correlation between level of IL-6 and eosinophil counts and negative correlation between IFN-γ level and number of eosinophils in NP tissue specimens. CONCLUSION: Our results showed that these patients with similar clinical findings had significantly different mediator profiles in their nasal secretions, implying clear differences in pathogenesis of their NP.

A case of an uncommon anatomic variation of the middle turbinate associated with headache.

Headache due to the pressure of nasal mucosa in the absence of inflammation of the nose and paranasal sinuses is a clinical entity that has gained wide acceptance. Concha bullosa is the most commonly observed anatomical variation of the lateral nasal wall. The case is presented of a 31-year-old female with a history of intermittent frontal headache and bilateral nasal obstruction in whom we found the concha bullosa containing another, smaller concha bullosa inside. This is the first report of a case in which both outer and inner concha bullosa were septated (with two air cells inside). After resecting the lateral portion of outer concha bullosa and removing the inner concha bullosa, the patient reported no further headaches. The differential diagnosis of the variations of the middle turbinate and the relationships between the anatomic variations and pathophysiology of contact point headaches are discussed herewith.