Publications by authors named "Kasper Aanaes"

31 Publications

Impact of human papillomavirus in sinonasal cancer-a systematic review.

Acta Oncol 2021 Sep 28;60(9):1175-1191. Epub 2021 Jul 28.

Department of Otorhinolaryngology, Head and Neck Surgery, and Audiology, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Human papillomavirus (HPV) is an established prognostic marker in oropharyngeal squamous cell carcinoma. Currently, the role of HPV in sinonasal carcinoma is being explored.

Objectives: This systematic review addresses the role of HPV in sinonasal cancer, establishing the occurrence of HPV-positive cancers and the influence of HPV-positivity on prognosis in sinonasal cancer as well as the utility of the putative surrogate marker of HPV (p16) in sinonasal cancer.

Material And Methods: Studies were identified with searches of Medline PubMed and Embase OVID (4 May 2020). Articles on original research concerning sinonasal cancer and HPV in humans written in English were included. Case reports with less than five cases were excluded.

Results: Initially, 545 articles were identified; 190 duplicate articles were removed leaving 355 articles for title/abstract screening. Title/abstract screening excluded 243 articles, leaving 112 studies assessed for eligibility. After full-text screening, 57 studies were included. All articles investigated the significance of HPV in sinonasal carcinomas. HPV was reported in approximately 30% of sinonasal squamous cell carcinoma (SNSCC), where it was associated with a better prognosis. In sinonasal cancer, p16 is associated with diagnostic pitfalls and a putative utility of p16 in SNSCC has yet to be established. HPV was not frequently reported in other types of sinonasal carcinomas, besides the recently described subtype, HPV-dependent Multiphenotypic Sinonasal Carcinoma. In other types of sinonasal carcinoma, HPV is not frequently found.

Conclusion: Approximately 30% of SNSCC are HPV-positive. HPV-positivity in SNSCC is associated with improved survival. HPV occurs only rarely in other sinonasal cancers. There is currently not sufficient evidence for p16 as a surrogate marker of HPV in SNSCC.
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http://dx.doi.org/10.1080/0284186X.2021.1950922DOI Listing
September 2021

[Life-threatening oedema triggered by inhalation of nitrous oxide].

Ugeskr Laeger 2021 05;183(19)

In this case report we describe a life-threatening oedema in a 20-year-old woman triggered by inhalation of nitrous oxide. On admission, flexible rhinolaryngoscopy revealed a rapidly progressing oedema of the epiglottis and arytenoid region. The patient was immediately intubated and transferred to the intensive care unit. Due to progression of the oedema a surgical tracheostomy was performed. On day six the canula was removed, and the patient could be discharged in good condition.
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May 2021

Incidence and survival of head and neck cancer in the Faroe Islands.

Int J Circumpolar Health 2021 12;80(1):1894697

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

The Faroese people constitute a geographically isolated population, and research on cancer in this population is sparse. Thus, this study aimed to calculate the age-standardised incidence rate (ASIR) and 5-year survival rates in head and neck cancers (HNC) in the Faroese population from 1985 to 2017. All patients registered with HNC in the Faroese Cancer Registry (FCR) from 1985 to 2017 were included. The ASIR per 100,000 (World Standard Population) and 5-year survival rates were calculated. We also calculated the distribution of tobacco, alcohol consumption, cancer stages and various timelines.  202 patients were included in the study (62% men). The ASIR for all HNC was 10.0/100,000 persons-years and was higher among men than women. Women's survival rate was significantly higher than men's (p = 0.026). The results imply that oropharyngeal cancer (OPC) had the best survival rate and was diagnosed at a significantly earlier stage. This retrospective nation-wide study showed that ASIRs and 5-year survival rates for Faroese HNC patients in general resembled the ones reported for Danish HNC patients. Timelines for Faroese HNC patients were shorter compared with Greenlandic HNC patients, but longer compared with the Danish fast track programme limits.
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http://dx.doi.org/10.1080/22423982.2021.1894697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971248PMC
December 2021

COVID-19 infection rate among tertiary referral center otorhinolaryngology healthcare workers.

Eur Arch Otorhinolaryngol 2021 Aug 5;278(8):3091-3098. Epub 2021 Feb 5.

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.

Importance: Otorhinolaryngology is considered one of the medical specialties with a high risk for exposure to corona disease 2019 (COVID-19). Uncontrolled transmission in a hospital department poses a risk to both healthcare workers (HCWs) and patients.

Objective: To monitor SARS-CoV-2 incidence, transmission, and antibody development among HCWs to identify high risk procedures, pathways, and work areas within the department.

Methods: Prospective cohort study of HCWs using repetitive oro- and nasopharygeal swab samples, antibody tests, and self-reported symptoms questionnaires at a tertiary referral center in Copenhagen, Denmark.

Results: 347/361 (96%) HCWs participated. Seven (1.9%) were positive on swab tests and none had symptoms. Fifteen (4.2%) developed antibodies. Only one case of potential transmission between HCWs was identified. Infection rates were low and no procedures or areas within the department were identified as exposing HCWs to a higher risk.

Conclusions And Relevance: Adherence to the surveillance program was high. The low incidence among HCW during the first wave of the COVID-19 pandemic may reflect local transmission and infection control precautions, as well as a low infectious burden in the Danish society.
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http://dx.doi.org/10.1007/s00405-021-06615-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862982PMC
August 2021

The impact and prevalence of SARS-CoV-2 in patients with head and neck cancer and acute upper airway infection in a tertiary otorhinolaryngology referral center in Denmark.

Eur Arch Otorhinolaryngol 2021 Sep 3;278(9):3409-3415. Epub 2021 Jan 3.

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Purpose: To determine the prevalence of SARS-CoV-2 at a Danish tertiary referral otorhinolaryngology clinic during the first wave of the COVID-19 pandemic among patients with suspected acute upper airway infection (UAI) and patients operated for head and neck cancer (HNC), respectively. To monitor changes in the number of patient encounters for acute UAI and the number of referrals for the workup of HNC.

Trial Registration: NCT-04356560 (Clinicaltrials.gov).

Methods: Prospective enrolled case series of all patients with suspected acute UAI (n = 88) and of patients undergoing surgery for HNC (n = 96), respectively, from March 23rd to May 5th, 2020, at a public tertiary referral otorhinolaryngology clinic in Denmark. SARS-CoV-2 was diagnosed with nasopharyngeal and oropharyngeal swabbing. Patients with suspected acute UAI had symptoms and definitive diagnoses registered in a database. Trends in the number of referrals and patient encounters were retrieved from an electronic patient journal system and analyzed retrospectively.

Results: Eighty-eight patients with acute UAI were enrolled including 55 men and 34 women, median age of 31 years (range: 10 months to 82 years). One patient (1.1%) tested positive. Among 96 patients operated for HNC, zero tested positive. The number of referrals for HNC workup, and patient encounters for peritonsillar abscesses, decreased markedly in the first 3 weeks.

Conclusion: The prevalence of SARS-CoV-2 during the first 6 weeks of the first wave was minimal among patients with acute UAI and zero among patients operated for HNC. The decrease in referrals for the workup of HNC may increase time to treatment initiation and patient morbidity.
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http://dx.doi.org/10.1007/s00405-020-06514-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778690PMC
September 2021

Autologous fibrin sealant co-delivered with antibiotics is a robust method for topical antibiotic treatment after sinus surgery.

Acta Otolaryngol 2021 Feb 6;141(2):181-186. Epub 2020 Nov 6.

Department of Clinical Microbiology, Copenhagen University Hospital, Rigshospitalet, Denmark.

Background: Most patients with cystic fibrosis have the risk of pathogenic bacteria being exchanged between their sinuses and lungs.

Aims: A method for topical application of antibiotics where the antibiotics persist for a long period of time is needed.

Material And Methods: Ten patients with cystic fibrosis and bacterial sinusitis were included. Autologous platelet rich fibrin was mixed with an antibiotic solution and sprayed onto the mucosa at the end of an endoscopic sinus surgery; Colistin, a Ciprofloxacin-Colistin combination or Tobramycin was used. The antibiotic concentration was measured in the sinonasal mucus four, seven and 13 days after surgery.

Results: Nine patients had in their nose/sinuses at the time of surgery; in eight of these was not detected by culture at the final visit. In the majority of the ten included patients the antibiotics were continuously released for more than 7 days. No severe side effects were seen.

Conclusions: Autologous platelet rich fibrin co-delivered with antibiotics is a feasible method for topical antibiotic treatment in supplementary to sinus surgery.

Significance: We expect that this treatment is successful for eradication of sinonasal bacterial infections in immunosuppressed patients suffering from recalcitrant sinus infections. The efficacy should be evaluated in randomized controlled trials.
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http://dx.doi.org/10.1080/00016489.2020.1841909DOI Listing
February 2021

Chronic rhinosinusitis in COPD: A prevalent but unrecognized comorbidity impacting health related quality of life.

Respir Med 2020 09 12;171:106092. Epub 2020 Aug 12.

Department of Otorhinolaryngology - Head and Neck Surgery and Audiology, Copenhagen University Hospital, Rigshospitalet, Denmark.

Introduction: Unified airway disease where upper respiratory tract inflammation including chronic rhinosinusitis (CRS) affects lower airway disease is known from asthma, bronchiectasis, cystic fibrosis and primary ciliary dyskinesia but little is known about CRS and health related quality of life in COPD. We investigate firstly, the prevalence of CRS in COPD. Secondly the impact of CRS on HRQoL. Thirdly, risk factors for CRS in COPD.

Methods: cross-sectional study of CRS in 222 COPD patients from 2017 to 2019 according to EPOS2012/2020 and GOLD2019 criteria. Patients completed the COPD assessment test (CAT), Medical Research Council dyspnea scale and Sinonasal outcome test 22 (SNOT22) and questions on CRS symptoms. They then had a physical examination including flexible nasal endoscopy, CT-sinus scan and HRCT-thorax.

Results: 22.5% of COPD patients had CRS and 82% of these were undiagnosed prior to the study. HRQoL (CAT, SNOT22 and the SNOT22-nasal symptom subscore) was significantly worse in COPD patients with CRS compared with those without CRS and healthy controls. Multiple logistic regression analysis suggests that the most likely candidate for having CRS was a male COPD patient who actively smoked, took inhaled steroids, had a high CAT and SNOT22_nasal symptom subscore.

Discussion: the largest clinical study of CRS in COPD and the only study diagnosing CRS according to EPOS and GOLD. This study supports unified airway disease in COPD. The SNOT22_nasal symptoms subscore is recommended as a standard questionnaire for COPD patients and patients at risk should be referred to an otorhinolaryngologist.
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http://dx.doi.org/10.1016/j.rmed.2020.106092DOI Listing
September 2020

Developing a national e-learning course in otorhinolaryngology: the Danish experience.

Eur Arch Otorhinolaryngol 2020 Jun 13;277(6):1829-1836. Epub 2020 Mar 13.

Department of Otorhinolaryngology, Head and Neck Surgery, Rigshospitalet, Copenhagen, Denmark.

Purpose: E-learning provides a flexible and effective approach to learning and is increasingly used in otorhinolaryngology (ORL). We developed a national theoretical e-learning course for ORL trainees and describe our experiences with implementation as well as piloting the e-learning course.

Methods: E-learning course content was developed as structured multiple choice quizzes for the European core curriculum textbook. An open-source learning management system was adapted for a self-paced e-learning course. We piloted the e-learning course as a non-mandatory option for the 15 residents participating in the Danish 4-day national training course in rhinology in February 2019. A post-course survey was sent out to the participants and used in the evaluation along with activity data from the learning management system.

Results: Fourteen out of 15 trainees participated in the e-learning course. Nine participants completed > 95% of the course. The activity data demonstrated that participants with the highest completion rate typically began well in advance of the course (> 2 months). Overall the e-learning course was rated positively in relation to learning and as preparation for the national training course. Participants responded that the level of the e-learning course was higher than and also at times in slight incongruity with the content of the national curriculum. Participants would like protected study time for e-learning activities in their residency program. All participants responded that they would use e-learning in relation to future national training courses.

Conclusions: Developing a national e-learning course is feasible and is well-received by trainees as well as other educational stakeholders.
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http://dx.doi.org/10.1007/s00405-020-05889-wDOI Listing
June 2020

Antibody response against Pseudomonas aeruginosa and its relationship with immune mediators in the upper and lower airways of cystic fibrosis patients.

Pediatr Pulmonol 2020 04 5;55(4):959-967. Epub 2020 Feb 5.

Department of Pediatric Pulmonology/Cystic Fibrosis Center, Brandenburg Medical School (MHB) University, Klinikum Westbrandenburg, Brandenburg an der Havel, Germany.

Background: The upper airways (UAW) are a niche and a reservoir of Pseudomonas aeruginosa strains that cause chronic infection of the lower airways (LAW) in cystic fibrosis (CF). Here, we assessed the role of anti-P. aeruginosa immunoglobulin A (IgA) and IgG antibodies in upper and lower airway infections in cystic fibrosis patients.

Methods: Nasal lavage fluid and induced sputum samples of 40 CF patients were microbiologically cultured. We searched for correlations between anti-P. aeruginosa IgA and IgG levels, measured by enzyme-linked immunosorbent assay (optical density), and unspecific immune mediators in both specimens.

Results: Anti-P. aeruginosa IgA (median optical density: 0.953 vs 0.298) and IgG (0.120 vs 0.059) were significantly higher in nasal lavage than in sputum, but not significantly different between patients with and without chronic P. aeruginosa infection in UAW. Matrix metallopeptidase-9 (MMP-9) in nasal lavage and neutrophil elastase (NE) in sputum were predictors of IgA in nasal lavage and IgA in sputum, respectively. IgA was a predictor of myeloperoxidase (MPO) in nasal lavage. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was a predictor of IgG in sputum. IgG, TIMP-1, and NE in sputum were predictors of IgG in nasal lavage.

Conclusion: The anti-P. aeruginosa IgA response was more prominent in CF patients' UAW, indicating a lower degree of inflammatory responses. Proteases may play a role in the anti-P. aeruginosa humoral response in the upper and LAW, and anti-P. aeruginosa IgG may be involved in the crosstalk between upper and lower airways in cystic fibrosis patients.
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http://dx.doi.org/10.1002/ppul.24671DOI Listing
April 2020

Primary ciliary dyskinesia patients have the same clone in sinuses and lungs.

Eur Respir J 2020 01 16;55(1). Epub 2020 Jan 16.

Dept of Otorhinolaryngology - Head and Neck Surgery and Audiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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http://dx.doi.org/10.1183/13993003.01472-2019DOI Listing
January 2020

Acquired complement C1 esterase inhibitor deficiency in a patient with a rare variant with unknown significance.

BMJ Case Rep 2019 Sep 4;12(9). Epub 2019 Sep 4.

OPEN, Clinical Institute, University of Southern Denmark, Odense, Denmark.

Angioedema (AE) is caused by a wide range of diseases and pharmaceuticals; it can become life-threatening when located to the airways. Patients with deficiency or malfunction of complement C1 esterase inhibitor (hereditary or acquired) experience recurrent AE due to an accumulation of the vasoactive mediator bradykinin (BK). Complement C1 inhibitor normally decreases BK production, so a reduced function hereof causes increased levels. The diagnosis of hereditary or acquired AE can be difficult due to similarities to allergic reactions (swelling, abdominal pain, rash). We describe a 35-year-old man presenting with upper-airway AE progressing rapidly and promptly required cricothyroidotomy. Complement and autoantibody screening together with sequencing of were performed and gave the diagnosis of acquired complement C1 esterase inhibitor deficiency. The patient is unusual to have this disease before the age of 40 years. No associated comorbidities were found. It is important to know that antiallergic medication is not effective in BK-mediated AE.
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http://dx.doi.org/10.1136/bcr-2019-231122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731889PMC
September 2019

Can secretory immunoglobulin A in saliva predict a change in lung infection status in patients with cystic fibrosis? A prospective pilot study.

Health Sci Rep 2018 Aug 12;1(8):e52. Epub 2018 Jul 12.

Department of Clinical Microbiology Rigshospitalet Denmark.

Background: Chronic lung infection with is the main cause of mortality in patients with cystic fibrosis (CF). Sinus colonization with P. aeruginosa often precedes intermittent lung colonization, and intermittent colonization precedes chronic infection.When P. aeruginosa colonizes the sinuses, elevated immunoglobulin A (IgA) levels specific against P. aeruginosa can be detected in saliva. Therefore, we hypothesized that increasing levels of IgA in saliva can be detected before P. aeruginosa lung colonization.

Methods: Forty-nine CF patients free from lung colonization with P. aeruginosa or other Gram-negative bacteria (GNB) were included in this prospective study. Saliva and serum samples were collected and examined for IgA antibodies against P. aeruginosa with at least 6-month intervals between sequential samples.

Results: A total of 110 measurements of IgA in saliva were included. During a median of 8.5-month follow-up, 25 patients changed their lung infection status. We were able to construct a statistical model that for a given value of IgA in saliva, could predict the probability of a change in lung infection status within the next 8.5 months (median):  = 1 / (1 + exp(-(-0.9582 + 1.6518*IgA)). The model includes a prediction band where 95% of new measurements are predicted to fall within. The model, however, failed to reach statistical significance ( = 0.056 1-tailed), probably because of lack of power.

Conclusion: The saliva IgA model may predict a worsening in lung infection status presumably acting as a surrogate marker of P. aeruginosa bacterial sinusitis. The model may identify patients at risk of subsequent lung colonization and, thus, be a helpful clinical tool, but it should be tested in studies with larger sample sizes to evaluate its utility.
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http://dx.doi.org/10.1002/hsr2.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266372PMC
August 2018

Sinus bacteriology in patients with cystic fibrosis or primary ciliary dyskinesia: A systematic review.

Am J Rhinol Allergy 2017 Sep;31(5):293-298

Department of Otorhinolaryngology- Head and Neck Surgery and Audiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: A correlation exists between the microbial flora of the upper and lower airways in patients with cystic fibrosis (CF) or with primary ciliary dyskinesia (PCD). The sinuses can function as a bacterial reservoir where gram-negative bacteria adapt to the airways and repeatedly are aspirated to and colonize the lungs according to the theory of the united (unified) airways. Whereas the pattern of bacterial flora in the lower airways has been extensively studied, the upper airways have drawn limited attention.

Objective: Our aim was to review the literature that reported bacterial flora in the sinuses and nasal cavities of patients with CF or PCD.

Methods: A number of medical literature data bases were systematically searched between January 1960 and July 2016. We applied the following inclusion criteria: a minimum of one case of PCD (or Kartagener syndrome) or CF, and microbiology analyses from the nose or paranasal sinuses.

Results: We included 46 studies (1823 patients) from 16 countries. Staphylococcus aureus was found in 30% of the noses and sinuses of patients with CF. Other common bacteria found included Pseudomonas aeruginosa, coagulase negative staphylococci, and Haemophilus influenzae. In PCD, H. influenzae was the most common bacteria (28%), followed by Streptococcus pneumoniae and P. aeruginosa. If studies that included nonsurgical swab and blowing samples were excluded, then P. aeruginosa was the most common bacterium in patients with CF (34%) and in patients with PCD (50%), followed by S. aureus and H. influenza.

Conclusion: S. aureus, P. aeruginosa, coagulase negative staphylococci, and H. influenzae dominated in the upper airways of patients with CF. In patients with PCD, H. influenzae, S. pneumoniae, and P. aeruginosa dominated. When studies that included swab and blowing samples were excluded, P. aeruginosa was the most common bacterium in both groups. Direct comparisons among the studies were restricted due to very heterogeneous methods, and a better standardization of procedures and outcomes is needed.
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http://dx.doi.org/10.2500/ajra.2017.31.4461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590177PMC
September 2017

Diagnosis of biofilm infections in cystic fibrosis patients.

APMIS 2017 Apr;125(4):339-343

Costerton Biofilm Center, Institute for Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

Chronic Pseudomonas aeruginosa biofilm lung infection in cystic fibrosis patients is the best described biofilm infection in medicine. The initial focus can be the paranasal sinuses and then follows repeated colonization and infection of the lungs by aspiration. The matrix of the biofilms is dominated by alginate and the pathogenesis of tissue damage is immune complex-mediated chronic inflammation dominated by polymorphonuclear leukocytes and their products (DNA, oxygen radicals and proteases). The P. aeruginosa biofilm infection can be diagnosed by microscopy of lung tissue, sputum and mucus from the paranasal sinuses, where aggregates of the bacteria are found surrounded by the abundant alginate matrix. Specific PNA-FISH probes can be used to identify P. aeruginosa and other pathogens in situ in the biofilms. Growth of mucoid colonies from the locations mentioned above is also diagnostic for biofilm infection. Rise of specific anti-P. aeruginosa antibodies is likewise diagnostic, IgG in serum in case of lung infection, sIgA in saliva or nasal secretions in case of paranasal sinus infection. Similar approaches have been developed to diagnose chronic biofilm infections in cystic fibrosis caused by other pathogens e.g., Stenotrophomonas, Burkholderia multivorans, Achromobacter xylosoxidans and Mycobacterium abscessus complex.
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http://dx.doi.org/10.1111/apm.12689DOI Listing
April 2017

Sinus surgery can improve quality of life, lung infections, and lung function in patients with primary ciliary dyskinesia.

Int Forum Allergy Rhinol 2017 03 23;7(3):240-247. Epub 2016 Nov 23.

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen, Denmark.

Background: Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary ciliary dyskinesia (PCD). From the sinuses, Pseudomonas aeruginosa can infect the lungs.

Methods: We studied the effect of endoscopic sinus surgery (ESS) on symptoms of CRS and lower airway infections in PCD patients in a prospective single-arm intervention study of ESS with adjuvant therapy using nasal irrigation with saline, topical nasal steroids, and 2 weeks of systemic antibiotics. Additional treatment with local colistin for 6 months was instigated when P. aeruginosa was cultured at ESS.

Results: Twenty-four PCD patients underwent ESS to search for an infectious focus (n = 10), due to severe symptoms of CRS (n = 8), or both (n = 6). Bacteria were cultured from sinus samples in 21 patients (88%), and simultaneous sinus and lung colonization with identical pathogens were observed in 13 patients (62%). Four patients with preoperative P. aeruginosa lung colonization (25%) had no regrowth during follow-up; 2 of these had P. aeruginosa sinusitis. Sinonasal symptoms were improved 12 months after ESS and we observed a trend toward better lung function after ESS.

Conclusion: We demonstrated an improvement in CRS-related symptoms after ESS and adjuvant therapy. In selected PCD patients, the suggested regimen may postpone chronic lung infection with P. aeruginosa and stabilize lung function.
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http://dx.doi.org/10.1002/alr.21873DOI Listing
March 2017

[Vallecula cyst that could be mistaken for epiglottitis].

Ugeskr Laeger 2016 02;178(6):V66984

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February 2016

Simultaneous sinus and lung infections in patients with primary ciliary dyskinesia.

Acta Otolaryngol 2015 Jan 5;135(1):58-63. Epub 2014 Nov 5.

Department of Otolaryngology - Head and Neck Surgery and Audiology.

Conclusion: The sinuses should be considered as a bacterial reservoir and a target for surgery and antibiotic treatment in patients with primary ciliary dyskinesia (PCD). The observed decrease in serum precipitating antibodies (precipitins) against Pseudomonas aeruginosa may indicate a beneficial effect of combined endoscopic sinus surgery (ESS) and concomitant medical treatment.

Objectives: The purpose of this research, which is the first study addressing bacteriology in the sinuses of patients with PCD, was to examine the association between sinus and lung infections.

Methods: We reviewed findings of bacterial pathogens from the sinuses obtained during ESS and the lung infection status in eight PCD patients over a 6 year period. Precipitins against P. aeruginosa were used as a marker of severity of chronic infection and effect of treatment.

Results: Preoperatively, seven of the eight patients (88%) exhibited intermittent or chronic pulmonary infection with P. aeruginosa. Sinus cultures were obtained during ESS in seven patients. The sinuses were colonized with P. aeruginosa in four of seven patients (57%). Bacterial sinusitis was found in five of seven patients (71%) and the same bacterium was found in the sinuses and lungs in all cases. Decreasing precipitins against P. aeruginosa were observed postoperatively in three of four evaluable patients.
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http://dx.doi.org/10.3109/00016489.2014.962185DOI Listing
January 2015

Sinus biofilms in patients with cystic fibrosis: is adjusted eradication therapy needed?

Eur Arch Otorhinolaryngol 2015 Sep 9;272(9):2291-7. Epub 2014 Oct 9.

Department of Otorhinolaryngology, Head & Neck Surgery and Audiology, Rigshospitalet and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark,

The paranasal sinuses can be a focus for colonisation of the cystic fibrosis (CF) lungs with pathogens. In the sinuses, bacteria can adapt to the lung environment and enhance their antibiotic resistance, with biofilm formation thought to be the most important adaptive mechanism, causing recalcitrant disease. The presence of biofilms in CF sinuses is sparsely described. In this descriptive cross-sectional study, the sinus mucosa from 16 CF patients were analysed by fluorescence in situ hybridization using specific peptide nucleic acid (PNA-FISH) probes for Pseudomonas aeruginosa and Staphylococcus aureus to demonstrate the presence of biofilms. Small clusters of biofilm were visualised lining the sinus mucosa of CF patients. Biofilms were found in 10 out of 18 cases; 7 with intermittent lung colonisation, 2 chronically infected, and one lung transplanted patient. Finding P. aeruginosa biofilms in intermittently lung-colonised patients encourage us to intensify the attempt to eradicate pathogenic bacteria from the CF sinuses in an early stage using combined antibiotic therapy in the prolonged exposure of the sinus-mucosal surface.
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http://dx.doi.org/10.1007/s00405-014-3322-xDOI Listing
September 2015

Environmental heterogeneity drives within-host diversification and evolution of Pseudomonas aeruginosa.

mBio 2014 Sep 16;5(5):e01592-14. Epub 2014 Sep 16.

Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark

Unlabelled: Microbial population polymorphisms are commonly observed in natural environments, including long-term infected hosts. However, the underlying processes promoting and stabilizing diversity are difficult to unravel and are not well understood. Here, we use chronic infection of cystic fibrosis airways by the opportunistic pathogen Pseudomonas aeruginosa as a system for investigating bacterial diversification processes during the course of infection. We analyze clonal bacterial isolates sampled during a 32-year period and map temporal and spatial variations in population diversity to different infection sites within the infected host. We show that the ancestral infecting strain diverged into distinct sublineages, each with their own functional and genomic signatures and rates of adaptation, immediately after initial colonization. The sublineages coexisted in the host for decades, suggesting rapid evolution of stable population polymorphisms. Critically, the observed generation and maintenance of population diversity was the result of partitioning of the sublineages into physically separated niches in the CF airway. The results reveal a complex within-host population structure not previously realized and provide evidence that the heterogeneity of the highly structured and complex host environment promotes the evolution and long-term stability of pathogen population diversity during infection.

Importance: Within-host pathogen evolution and diversification during the course of chronic infections is of importance in relation to therapeutic intervention strategies, yet our understanding of these processes is limited. Here, we investigate intraclonal population diversity in P. aeruginosa during chronic airway infections in cystic fibrosis patients. We show the evolution of a diverse population structure immediately after initial colonization, with divergence into multiple distinct sublineages that coexisted for decades and occupied distinct niches. Our results suggest that the spatial heterogeneity in CF airways plays a major role in relation to the generation and maintenance of population diversity and emphasize that a single isolate in sputum may not represent the entire pathogen population in the infected individual. A more complete understanding of the evolution of distinct clonal variants and their distribution in different niches could have positive implications for efficient therapy.
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http://dx.doi.org/10.1128/mBio.01592-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172072PMC
September 2014

An exploratory study of microbial diversity in sinus infections of cystic fibrosis patients by molecular methods.

J Cyst Fibros 2014 Dec 11;13(6):645-52. Epub 2014 Mar 11.

Department of Biotechnology, Chemistry, and Environmental Engineering, Aalborg University, Sohngaardholmsvej 49, DK-9000 Aalborg, Denmark; Life Science Division, Danish Technological Institute, Kongsvang Allé 29, DK-8000 Aarhus C, Denmark. Electronic address:

Background: For the first time microorganisms in CF sinuses are investigated by molecular methods in response to an absence of anaerobes in CF sinus samples during a two-year period at the Copenhagen CF center.

Methods: Endoscopic sinus surgery was performed in 19 CF patients. DNA from intact bacterial cells was investigated by 16S rRNA gene analysis and quantitative PCR. Results were compared to culture-dependent routine diagnosis.

Results: Molecular methods showed a large microbial diversity, which included undetected anaerobes that may play a pathogenic role. Importantly, the culture methods did not always detect known CF pathogens. Quantitative PCR showed generally a higher abundance of classic CF pathogens e.g. Pseudomonas aeruginosa and Staphylococcus aureus compared with the anaerobe Propionibacterium acnes.

Conclusions: The results indicate that the culture methods in some cases may not be suitable as stand-alone method for this patient group, as diversity may be underestimated and important species undetected.
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http://dx.doi.org/10.1016/j.jcf.2014.02.008DOI Listing
December 2014

Bacterial sinusitis can be a focus for initial lung colonisation and chronic lung infection in patients with cystic fibrosis.

Authors:
Kasper Aanæs

J Cyst Fibros 2013 Sep;12 Suppl 2:S1-20

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

A major purpose of treating patients with cystic fibrosis (CF) is to prevent or delay chronic lung infections with CF-pathogenic Gram-negative bacteria. In the intermittent stage, bacteria can usually be eradicated from the lungs with antibiotics, but following eradication, the next lung colonisations often occur with bacteria of identical genotype. This may be due to re-colonisation from the patient's paranasal sinuses. In our study, we found that approximately two-thirds of CF patients having sinus surgery (FESS) had growth of CF-lung-pathogenic Gram-negative bacteria in their sinuses (Pseudomonas aeruginosa, Achromobacter xylosoxidans, Burkholderia cepacia complex). The environment in the sinuses is in many ways similar to that of the lower respiratory tract, e.g. low oxygen concentration in secretions. Sinus bacteria are more difficult to eradicate than in the lungs, thus, having good conditions for adapting to the environment in the lungs. In the presence of bacteria, the environment of the sinuses differs from that of the lower respiratory tract by having a higher immunoglobulin A (IgA): IgG ratio, and reduced inflammation. We found a significant correlation between the concentration of IgA against P. aeruginosa (standard antigen and alginate) in nasal secretions and saliva and CF patients' infection status (not lung colonised, intermittently colonised or chronically lung-infected with P. aeruginosa). This supports the hypothesis that infections often originate in the sinuses and can be a focus for initial lung colonisation or for maintaining lung infections in CF patients. We are confident that anti-P. aeruginosa IgA can be used as an early supplementary tool to diagnose P. aeruginosa colonisation; P. aeruginosa being the microorganism causing most morbidity and mortality in CF patients. This is important since urgent treatment reduces morbidity when CF patients are early colonised with P. aeruginosa, however, there is a lack of diagnostic tools for detecting the early colonisation in the lungs and in the sinuses. We initiated a treatment strategy for CF patients to prevent sino-nasal bacteria being seeded into the lower airways: we recommended extensive functional endoscopic FESS with creation of sufficient drainage from all involved sinuses with subsequent i.v. antibiotics and at least 6 months of twice daily nasal irrigation with saline and antibiotics. By this strategy, sinus bacteria could be eradicated in a large proportion of patients. Essentially, growth of CF-pathogenic bacteria from the lower respiratory tract was decreased following the treatment. Furthermore, a number of patients have been free from CF-pathogenic bacteria for more than one year after FESS, and thus re-classified as "not lung colonised". We also corroborated that CF patients obtain an improved quality of life and reduction in their symptoms of chronic rhinosinusitis after FESS. It is primarily intermittently lung colonised CF patients with CF-pathogenic bacteria in their sinuses that seem to benefit from the treatment strategy. This is in accordance with the fact that we did not see a significant increase in lung function and only a small decrease in specific antibodies after FESS; a high systemic immune and inflammatory response and a decreasing lung function is generally not present in patients who primarily have sinus CF-pathogenic bacteria. It is important that guidelines are created for how CF patients with CF-pathogenic bacteria in the sinuses are to be treated, including criteria for who may likely benefit from FESS, and who may be treated exclusively with conservative therapy, e.g. saline and antibiotic irrigations.
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http://dx.doi.org/10.1016/S1569-1993(13)00150-1DOI Listing
September 2013

P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs.

J Cyst Fibros 2013 Dec 9;12(6):729-36. Epub 2013 Mar 9.

Department of International Health, Immunology and Microbiology, Unit of Bacteriology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Pseudomonas aeruginosa cells are present as biofilms in the paranasal sinuses and the lungs of chronically infected cystic fibrosis (CF) patients. Since different inflammatory responses and selective antibiotic pressures are acting in the sinuses compared with the lungs, we compared the adaptive profiles of mucoid and non-mucoid isolates from the two locations.

Methods: We studied the genetic basis of phenotypic diversification and gene expression profiles in sequential lung and sinus P. aeruginosa isolates from four chronically infected CF patients, including pre- and post-lung transplantation isolates.

Results: The same phenotypes caused by similar mutations and similar gene expression profiles were found in mucoid and non-mucoid isolates from the paranasal sinuses and from the lungs before and after transplantation.

Conclusion: Bilateral exchange of P. aeruginosa isolates between the paranasal sinuses and the lungs occurs in chronically infected patients and extensive sinus surgery before the lung transplantation might prevent infection of the new lung.
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http://dx.doi.org/10.1016/j.jcf.2013.02.004DOI Listing
December 2013

National long-lasting effect of endonasal endoscopic sphenopalatine artery clipping for epistaxis.

Acta Otolaryngol 2013 Jul 11;133(7):744-8. Epub 2013 Mar 11.

Department of Otolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Conclusion: We consider sphenopalatine artery ligation to be a safe and effective treatment of posterior epistaxis as the long-term need for revision surgery and the complication rates are low. Surgery should be considered earlier in the treatment of posterior epistaxis.

Objectives: Posterior epistaxis is common and surgical endoscopic ligation of the sphenopalatine arteries is indicated in severe cases. Knowledge about long-term effects and complications is sparse.

Methods: Within 2001-2006, 78 patients underwent endonasal endoscopic-guided surgery for posterior epistaxis in one of the eight ENT clinics in Denmark treating these patients. In 2011, 45 patients were still alive and eligible for the study. Patients were contacted by telephone and invited to complete an interview questionnaire on late adverse affects and recurrence.

Results: In all, 42 of 45 patients participated in the mean follow-up. The mean follow-up was 6.7 years: 90% of patients (n = 38) obtained an effect of the treatment during follow-up; 78% (n = 33) had no recurrent epistaxis, 12% (n = 5) had recurrent epistaxis but only needed non-surgical specialized treatment; 10% (n = 4) required revision surgery due to recurrent epistaxis within the 6.7 mean years of follow-up; and 26% of the patients had minor postoperative complications, permanent nasal crusting being most persistent and frequent.
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http://dx.doi.org/10.3109/00016489.2013.773596DOI Listing
July 2013

The effect of sinus surgery with intensive follow-up on pathogenic sinus bacteria in patients with cystic fibrosis.

Am J Rhinol Allergy 2013 Jan;27(1):e1-4

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Most patients with cystic fibrosis (CF) have chronic rhinosinusitis; their sinuses are often colonized with bacteria that can initiate and maintain deleterious pulmonary infections. Theoretically, eradication of the sinus bacteria should reduce the frequency of lung infections and thereby reduce pulmonary morbidity. This article addressed whether bacteria in CF sinuses are eligible for eradication by sinus surgery and postoperative treatment.

Methods: A prospective study including 58 CF patients, who had extensive sinus surgery and growth of Pseudomonas aeruginosa, Achromobacter xylosoxidans, and/or Burkholderia multivorans in their sinuses, was initiated. All patients followed a systematic postoperative treatment program of nasal irrigations with saline and colistimethate sodium and systematic endoscopic cleansing. All patients had follow-up examinations including sinus cultures; each side of the nose was cultured separately.

Results: At the 6-month follow-up visit, 49 patients were cultured; 66 of 98 maxillary-ethmoidal complexes (67%) showed no growth of pathogenic bacteria. Some patients were not free from CF pathogenic bacteria at all cultures; however, 20 (41%) patients had no bilateral regrowth (p < 0.01) and 4 patients had no unilateral regrowth at any time during 6 months of follow-up. The eradication of CF pathogens was accomplished in patients from all three lung infection groups: intermittently colonized, chronically infected, and lung transplanted. The patient with the longest follow-up had no bacterial growth for 3 years.

Conclusion: Extensive sinus surgery combined with intensive follow-up can eradicate pathogenic bacteria from CF sinuses.
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http://dx.doi.org/10.2500/ajra.2013.27.3829DOI Listing
January 2013

Secretory IgA as a diagnostic tool for Pseudomonas aeruginosa respiratory colonization.

J Cyst Fibros 2013 Jan 20;12(1):81-7. Epub 2012 Jul 20.

Department of Otolaryngology - Head & Neck Surgery and Audiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Copenhagen, Denmark.

Background: Pseudomonas aeruginosa sinusitis may be the focus for intermittent lung colonization in patients with cystic fibrosis (CF). The sinusitis may induce elevated IgA levels in nasal secretion and saliva against P. aeruginosa.

Methods: 120 CF patients chronically infected, intermittently colonized or without P. aeruginosa in the lungs participated in this cross-sectional study. IgA and IgG against P. aeruginosa sonicate and alginate were measured in nasal secretions, saliva, and in serum by ELISA.

Results: The intermittently colonized patients had significantly higher IgA levels in nasal secretions and saliva than those without P. aeruginosa in the lungs, indicating that P. aeruginosa sinusitis may precede intermittent colonization and chronic infection of the lungs.

Conclusions: Specific IgA against P. aeruginosa in nasal secretions and saliva can contribute to differentiation between patients chronically infected, intermittently colonized, and without P. aeruginosa in the lungs. The diagnostic value of the IgA ELISA awaits a prospective study.
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http://dx.doi.org/10.1016/j.jcf.2012.07.001DOI Listing
January 2013

Colonisation and infection of the paranasal sinuses in cystic fibrosis patients is accompanied by a reduced PMN response.

J Cyst Fibros 2012 Dec 15;11(6):525-31. Epub 2012 May 15.

Department of Clinical Microbiology, afsnit 9301, Rigshospitalet, Juliane Maries Vej 22, DK-2100 Copenhagen Ø, Denmark.

Background: We studied whether the sinuses might be foci for Pseudomonas aeruginosa lung infection.

Methods: Endoscopic Sinus Surgery was performed in 78 CF patients; PFGE was used for bacterial genotyping. Material from sinuses and lungs were Gram-stained to detect biofilms. Immunoglobulins were measured in serum and saliva.

Results: When P. aeruginosa was cultured simultaneously from the sinuses and the lungs they were genetically identical in 38 of the 40 patients (95%). In the sinuses, P. aeruginosa formed biofilms with minimal cellular inflammation, probably because of a significantly higher local production of secretory IgA compared with IgG (p<0.001).

Conclusions: We have shown that P. aeruginosa form biofilm in the sinuses, which constitute an important bacterial reservoir for subsequent lung infection. The high amount of IgA in the upper airways probably protects P. aeruginosa from the inflammatory immune system, and they can proceed unnoticed into a permanent infectious focus that cannot be eradicated with antibiotics.
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http://dx.doi.org/10.1016/j.jcf.2012.04.011DOI Listing
December 2012

CT of the paranasal sinuses is not a valid indicator for sinus surgery in CF patients.

J Cyst Fibros 2012 Mar 20;11(2):93-9. Epub 2011 Oct 20.

Department of Otolaryngology-Head & Neck Surgery, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Background: No guidelines comprise when or to what extent sinus surgery should be done in patients with cystic fibrosis (CF) or how a CT scan of the paranasal sinuses should influence the decision. Symptoms of rhinosinusitis and/or eradication of pathogenic bacteria from the sinuses are reasons for sinus surgery.

Methods: In this observational cross sectional study, 55 CF cases had their preoperative CT scans scored according to the Lund Mackay- and the Nair-system. Correlations between the CT scans, symptoms, surgical findings and cultures obtained during sinus surgery were made.

Results: There was no significant correlation between the CT score and detection of pus, pathogenic bacteria or symptoms. Pus and pathogenic bacteria were found in several cases without sinus opacification on the CT scan. Non pathogenic and sterile cultures were also found in sinuses with opacification.

Conclusions: A CT scan is not a valid criterion for sinus surgery in CF patients.
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http://dx.doi.org/10.1016/j.jcf.2011.09.009DOI Listing
March 2012

Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection.

ISME J 2012 Jan 30;6(1):31-45. Epub 2011 Jun 30.

Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.

The opportunistic pathogen Pseudomonas aeruginosa is a frequent colonizer of the airways of patients suffering from cystic fibrosis (CF). Depending on early treatment regimens, the colonization will, with high probability, develop into chronic infections sooner or later, and it is important to establish under which conditions the switch to chronic infection takes place. In association with a recently established sinus surgery treatment program for CF patients at the Copenhagen CF Center, colonization of the paranasal sinuses with P. aeruginosa has been investigated, paralleled by sampling of sputum from the same patients. On the basis of genotyping and phenotypic characterization including transcription profiling, the diversity of the P. aeruginosa populations in the sinuses and the lower airways was investigated and compared. The observations made from several children show that the paranasal sinuses constitute an important niche for the colonizing bacteria in many patients. The paranasal sinuses often harbor distinct bacterial subpopulations, and in the early colonization phases there seems to be a migration from the sinuses to the lower airways, suggesting that independent adaptation and evolution take place in the sinuses. Importantly, before the onset of chronic lung infection, lineages with mutations conferring a large fitness benefit in CF airways such as mucA and lasR as well as small colony variants and antibiotic-resistant clones are part of the sinus populations. Thus, the paranasal sinuses potentially constitute a protected niche of adapted clones of P. aeruginosa, which can intermittently seed the lungs and pave the way for subsequent chronic lung infections.
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http://dx.doi.org/10.1038/ismej.2011.83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246239PMC
January 2012

Decreased mucosal oxygen tension in the maxillary sinuses in patients with cystic fibrosis.

J Cyst Fibros 2011 Mar 3;10(2):114-20. Epub 2011 Jan 3.

Department of Otolaryngology-Head & Neck Surgery, Rigshospitalet, Denmark. Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

Background: Pseudomonas aeruginosa in the sinuses plays a role in the lungs in cystic fibrosis (CF) patients, but little is known about the sinus environment where the bacteria adapt. Anoxic areas are found in the lower respiratory airways but it is unknown if the same conditions exist in the sinuses.

Methods: The oxygen tension (pO(2)) was measured, using a novel in vivo method, in the maxillary sinus in a group of 20 CF patients.

Results: The CF patients had a significant lower pO(2) on the mucosa but not in the sinus lumen as compared with a control group of non-CF patients. Anoxic conditions were found in 7/39 (18%) of the sinuses from where we cultured P. aeruginosa, Stenotrophomonas maltophilia and/or coagulase negative staphylococci.

Conclusion: These findings support our hypothesis that P. aeruginosa can adapt or acclimate to the environment in the lungs, during growth in anoxic parts of the paranasal sinuses.
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http://dx.doi.org/10.1016/j.jcf.2010.12.002DOI Listing
March 2011

Improved prognosis for localized malignant lymphomas of the head and neck.

Acta Otolaryngol 2010 May;130(5):626-31

Department of Otolaryngology-Head & Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Conclusion: In this study we found localized malignant lymphomas of the head and neck to be highly treatable and to have a significantly improved prognosis with recent treatment methods. The head and neck surgeon should keep in mind that the prognosis, especially for diffuse large B-cell lymphoma, has improved if the patient receives the optimal treatment.

Objectives: The purpose of this study was to ascertain the current prognosis of localized malignant lymphoma of the head and neck given recent advancements in treatment and diagnostic features, as well as adding histological subtypes to the literature according to the 2001 classification.

Methods: We present a retrospective study including a cohort of 100 consecutive patients who had localized malignant lymphoma within the head and neck region diagnosed at a single centre from 2000 to 2007.

Results: The histology was revised according to the WHO classification and showed 58% with diffuse large B-cell lymphoma. The estimated 5-year overall survival rate was 83%, which should be seen in contrast to survival rates of 40-70% 25 years ago.
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http://dx.doi.org/10.3109/00016480903311229DOI Listing
May 2010
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