An unusual finding of an anaplastic meningioma in NF2-related schwannomatosis.

NF2-related schwannomatosis (NF2) is a rare autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas and multiple meningiomas. This case report presents the extremely rare occurrence of an anaplastic meningioma in a 12-year-old male with previously undiagnosed NF2. The patient presented with a history of abdominal pain and episodic emesis, gait unsteadiness, right upper and lower extremity weakness, and facial weakness. He had sensorineural hearing loss and wore bilateral hearing aids. MR imaging revealed a sizable left frontoparietal, dural-based meningioma with heterogeneous enhancement with mass effect on the brain and midline shift. Multiple additional CNS lesions were noted including a homogenous lesion at the level of T5 indicative of compression of the spinal cord. The patient underwent a frontotemporoparietal craniotomy for the removal of his large dural-based meningioma, utilizing neuronavigation and transdural ultrasonography for precise en bloc resection of the mass. Histopathology revealed an anaplastic meningioma, WHO grade 3, characterized by brisk mitotic activity, small-cell changes, high Ki-67 proliferation rate, and significant loss of P16. We report an anaplastic meningioma associated with an underlying diagnosis of NF2 for which we describe clinical and histopathological features.

Candida spondylodiscitis: a systematic review and meta-analysis of seventy two studies.

OBJECTIVES: Knowledge of Candida spondylodiscitis is limited to case reports and smaller case series. Controversy remains on the most effective diagnostical and therapeutical steps once Candida is suspected. This systematic review summarized all cases of Candida spondylodiscitis reported to date concerning baseline demographics, symptoms, treatment, and prognostic factors. METHODS: A PRISMA-based search of PubMed, Web of Science, Embase, Scopus, and OVID Medline was performed from database inception to November 30, 2022. Reported cases of Candida spondylodiscitis were included regardless of Candida strain or spinal levels involved. Based on these criteria, 656 studies were analyzed and 72 included for analysis. Kaplan-Meier curves, Fisher's exact, and Wilcoxon's rank sum tests were performed. RESULTS: In total, 89 patients (67% males) treated for Candida spondylodiscitis were included. Median age was 61 years, 23% were immunocompromised, and 15% IV drug users. Median length of antifungal treatment was six months, and fluconazole (68%) most commonly used. Thirteen percent underwent debridement, 34% discectomy with and 21% without additional instrumentation. Median follow-up was 12 months. The two year survivorship free of death was 80%. The two year survivorship free of revision was 94%. Younger age (p = 0.042) and longer length of antifungal treatment (p = 0.061) were predictive of survival. CONCLUSION: Most patients affected by Candida spondylodiscitis were males in their sixties, with one in four being immunocompromised. While one in five patients died within two years of diagnosis, younger age and prolonged antifungal treatment might play a protective role.

Ten-step minimally invasive slalom unilateral laminotomy for bilateral decompression (sULBD) with navigation.

BACKGROUND: Unilateral laminotomy for bilateral decompression (ULBD) is a MIS surgical technique that offers safe and effective decompression of lumbar spinal stenosis (LSS) with a long-term resolution of symptoms. Advantages over conventional open laminectomy include reduced expected blood loss, muscle damage, mechanical instability, and less postoperative pain. The slalom technique combined with navigation is used in multi-segmental LSS to improve the workflow and effectiveness of the procedure. METHODS: We outline ten technical steps to achieve a slalom unilateral laminotomy for bilateral decompression (sULBD) with navigation. In a retrospective case series, we included patients with multi-segmental LSS operated in our institution using the sULBD between 2020 and 2022. The primary outcome was a reduction in pain measured by Visual Analogue Scale (VAS) for back pain and leg pain and Oswestry Disability Index (ODI). RESULTS: In our case series (N = 7), all patients reported resolution of initial symptoms on an average follow-up of 20.71 ± 9 months. The average operative time and length of hospital stay were 196.14 min and 1.67 days, respectively. On average, VAS (back pain) was 4.71 pre-operatively and 1.50 on long-term follow-up of an average of 19.05 months. VAS (leg pain) decreased from 4.33 to 1.21. ODI was reported as 33% pre-operatively and 12% on long-term follow-up. CONCLUSION: The sULBD with navigation is a safe and effective MIS surgical procedure and achieves the resolution of symptoms in patients presenting with multi-segmental LSS. Herein, we demonstrate the ten key steps required to perform the sULBD technique. Compared to the standard sULBD technique, the incorporation of navigation provides anatomic localization without exposure to radiation to staff for a higher safety profile along with a fast and efficient workflow.

NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function.

Nuclear factor-κB (NF-κB) is generally believed to be pro-tumorigenic. Here we report a tumor-suppressive function for NF-κB1, the prototypical member of NF-κB. While NF-κB1 downregulation is associated with high lung cancer risk in humans and poor patient survival, NF-κB1-deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor-suppressive function of NF-κB1 is independent of its classical role as an NF-κB factor, but instead through stabilization of the Tpl2 kinase. NF-κB1-deficient tumors exhibit 'normal' NF-κB activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-κB1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-κB1-deficient lung tumor cells. Remarkably, Tpl2-knockout mice resemble NF-κB1 knockouts in urethane-induced lung tumorigenesis. Mechanistic studies indicate that p105/Tpl2 signaling is required for suppressing urethane-induced lung damage and inflammation, and activating mutations of the K-Ras oncogene. These studies reveal an unexpected, NF-κB-independent but Tpl2-depenednt role of NF-κB1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis.

How to stay on mummy's back: Morphological and functional changes of the pretarsus in arachnid postembryonic stages.

A specific type of maternal care occurs in several groups of Arachnida: mothers carry their offspring on their back (pulli-carrying behaviour). In scorpions, whip scorpions and whip spiders it is the prenymphal stage that settles on the mother. The prenymph is not yet fully developed for a free life and very limited in its mobility, but its feet are equipped with special adhesive organs (arolia) that become lost at the nymphal stage. Here we study the morphology, ultrastructure and mechanical function of the arolia. In scorpions (Scorpiones) the contact area between arolia and substrate and thus adhesion of the pad is controlled by the antagonistic work of hydrostatic pressure and muscular retraction. Arolia of whip scorpions (Thelyphonida) do not require muscular action for strong attachment. Arrays of long, branching fibres in the mesocuticle lead to high compliancy of the pad. In whip spiders (Amblypygi) the prenymphal pretarsus is already equipped with sclerites and claws. Its arolium is retained in nymphs and adults in some taxa, but acquires a more complex structure. These results contribute to our knowledge on the postembryonic development of arachnids and to the understanding of attachment pad evolution among arthropods. Some of the described developmental, structural, and mechanical phenomena are not known from other animals and might be of potential interest for further biomimetic developments.

Excellent biochemical response to polychemotherapy with nab-paclitaxel/gemcitabine in an 82-year-old female with metastatic breast cancer.

We report the case of an 82-year-old female diagnosed with HER2-negative, hormone receptor (HR)-positive metastatic breast cancer. Upon biochemical disease progression of the initially HR-receptor positive disease under anti-hormonal treatment with tamoxifen and letrozole, she received combination chemotherapy with paclitaxel/gemcitabine. Due to her suffering from severe toxicity, therapy was switched to nab-paclitaxel/gemcitabine. From April 22, 2013, to July 15, 2013, the patient received 5 cycles of nab-paclitaxel/gemcitabine as a 30-min infusion every 3 weeks, with excellent biochemical responses to treatment. Tumor marker levels as well as bilirubin were reduced to baseline levels. Chemotherapy with nab-paclitaxel/gemcitabine was well tolerated. At a follow-up visit immediately after the end of chemotherapy, the patient reported well-being and presented with a Karnofsky performance status (KPS) of 100%. At the last follow-up in October 2013, she was alive with multiple metastatic sites in the liver and bone metastases in the spine without risk of fracture and a KPS of 90%. She has received palliative single agent chemotherapy with capecitabine (14/7 regimen, 1,500 mg b.i.d.) since August 2013 and continued to show a good biochemical treatment response at the last follow-up in October 2013. Since August 2013, the patient has also received denosumab (120 mg sc, q4w) for her metastatic bone disease. As of July 2014, treatment has not been changed and the patient reports her well-being.

Dosing to rash: a phase II trial of the first-line erlotinib for patients with advanced non-small-cell lung cancer an Eastern Cooperative Oncology Group Study (E3503).

BACKGROUND: The development of a rash has been retrospectively associated with increased response and improved survival when treated with erlotinib at the standard dose of 150 mg per day. The objective of this trial was to evaluate the association of the activity of erlotinib in the first-line setting in patients with advanced non-small-cell lung cancer (NSCLC) with the development of a tolerable rash via dose escalation of erlotinib or tumour characteristics. METHODS: Patients, with advanced NSCLC without prior systemic therapy, were treated with erlotinib 150 mg orally per day. The dose was increased by 25mg every two weeks until the development of grade 2/tolerable rash or other dose limiting toxicity. Tumour biopsy specimens were required for inclusion. RESULTS: The study enrolled 137 patients, 135 were evaluable for safety and 124 were eligible and evaluable for response. Only 73 tumour samples were available for analysis. Erlotinib dose escalation occurred in 69/124 patients. Erlotinib was well tolerated with 70% of patients developing a grade 1/2 rash and 10% developing grade 3 rash. Response rate and disease control rate were 6.5% and 41.1% respectively. Median overall survival was 7.7 months. Toxicity and tumour markers were not associated with response. Grade 2 or greater skin rash and low phosphorylated mitogen-activated protein kinase (pMAPK) were associated with improved survival. CONCLUSIONS: Overall survival was similar in this trial compared to first-line chemotherapy in this unselected patient population. Dose escalation to the development of grade 2 skin rash was associated with improved survival in this patient population.

SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15.

The heparan sulfate 6-O-endosulfatase (SULF2) promotes growth and metastasis of solid tumors. We recently identified that cytosine methylation of the SULF2 promoter is associated with better survival of resected lung adenocarcinoma patients, and now also demonstrates a marginal improvement in survival of advanced non-small cell lung cancer (NSCLC) patients receiving standard chemotherapy (hazard ratio=0.63, P=0.07). Subsequent studies focused on investigating the effect of methylation on SULF2 expression and its genome-wide impact. The genes and pathways modulated by epigenetic inactivation of SULF2 and the effects on sensitivity to chemotherapy were characterized in vitro and in vivo. Silencing SULF2 through small interfering RNA or methylation primarily increased expression of interferon-inducible genes including ISG15, a marker for increased sensitivity to topoisomerase-1 inhibitors such as camptothecin (CPT). NSCLC cell lines with methylated SULF2 (SULF2M) express 60-fold higher ISG15 compared with SULF2 unmethylated (SULF2U) NSCLC cell lines and normal human bronchial epithelial cells. In vitro, SULF2M and high ISG15 (ISG15H)-expressing NSCLC cell lines were 134-fold more sensitive to CPT than SULF2U and low ISG15 (ISG15L)-expressing cell lines. Topotecan, a soluble analog of CPT and FDA-approved anticancer drug, dramatically arrested the growth of SULF2M-ISG15H, but not SULF2U-ISG15L lung tumors in nude mice (P<0.002). Similarly, high ISG15 expression that is comparable to the topotecan (TPT)-sensitive NSCLC cell lines was found in tumors from 25% of NSCLC patients compared with normal lung, indicating a potential to identify and target the most sensitive NSCLC subpopulation for personalized TPT therapy.

HGF-independent potentiation of EGFR action by c-Met.

The c-Met receptor is a potential therapeutic target for non-small cell lung cancer (NSCLC). Signaling interactions between c-Met and the mutant epidermal growth factor receptor (EGFR) have been studied extensively, but signaling intermediates and biological consequences of lateral signaling to c-Met in EGFR wild-type tumors are minimally understood. Our observations indicate that delayed c-Met activation in NSCLC cell lines is initiated by wild-type EGFR, the receptor most often found in NSCLC tumors. EGFR ligands induce accumulation of activated c-Met, which begins at 8 h and continues for 48 h. This effect is accompanied by an increase in c-Met expression and phosphorylation of critical c-Met tyrosine residues without activation of mitogen-activated protein kinase (MAPK) or Akt. Gene transcription is required for delayed c-Met activation; however, phosphorylation of c-Met by EGFR occurs without production of hepatocyte growth factor (HGF) or another secreted factor, supporting a ligand-independent mechanism. Lateral signaling is blocked by two selective c-Met tyrosine kinase inhibitors (TKIs), PF2341066 and SU11274, or with gefitinib, an EGFR TKI, suggesting kinase activity of both receptors is required for this effect. Prolonged c-Src phosphorylation is observed, and c-Src pathway is essential for EGFR to c-Met communication. Pretreatment with pan-Src family kinase inhibitors, PP2 and dasatinib, abolishes delayed c-Met phosphorylation. A c-Src dominant-negative construct reduces EGF-induced c-Met phosphorylation compared with control, further confirming a c-Src requirement. Inhibition of c-Met with PF2341066 and siRNA decreases EGF-induced phenotypes of invasion by ~86% and motility by ~81%, suggesting that a novel form of c-Met activation is utilized by EGFR to maximize these biological effects. Combined targeting of c-Met and EGFR leads to increased xenograft antitumor activity, demonstrating that inhibition of downstream and lateral signaling from the EGFR-c-Src-c-Met axis might be effective in treatment of NSCLC.

Atheroprotective effects of dietary L-arginine increase with age in cholesterol-fed rabbits.

NO has several putative atheroprotective properties but its precursor, L-arginine, and inhibitors of its synthesis have had inconsistent effects on the extent of experimental atherosclerosis in rabbits. The location and character of experimental atherosclerosis differ between immature and mature rabbits; both phenomena have been attributed to changes with age in the NO pathway. We investigated whether the influence of dietary L-arginine on experimental atherosclerosis is also age-related. The frequency of lesions was mapped in the descending thoracic and upper abdominal aorta of immature and mature rabbits fed 1 % cholesterol, with or without supplementary L-arginine, for 8 weeks. Consistent with earlier data, the distribution of lesions around the branch points changed with age in control rabbits. The mean frequency of lesions was essentially the same at both ages. L-Arginine supplements had no effect on the distribution of lesions at either age. They significantly reduced the mean frequency of lesions in mature animals but not in immature animals. Thus, the atheroprotective effect of dietary L-arginine in cholesterol-fed rabbits increases with age.

Geophysical and atmospheric evolution of habitable planets.

The evolution of Earth-like habitable planets is a complex process that depends on the geodynamical and geophysical environments. In particular, it is necessary that plate tectonics remain active over billions of years. These geophysically active environments are strongly coupled to a planet's host star parameters, such as mass, luminosity and activity, orbit location of the habitable zone, and the planet's initial water inventory. Depending on the host star's radiation and particle flux evolution, the composition in the thermosphere, and the availability of an active magnetic dynamo, the atmospheres of Earth-like planets within their habitable zones are differently affected due to thermal and nonthermal escape processes. For some planets, strong atmospheric escape could even effect the stability of the atmosphere.

Prospective study of breast MRI in BRCA1 and BRCA2 mutation carriers: effect of mutation status on cancer incidence.

Annual MRI screening is recommended as an adjunct to mammography for BRCA1 and BRCA2 mutation carriers. Prophylactic oophorectomy has been shown to decrease breast cancer risk in BRCA1/2 mutation carriers. Here, we aimed to examine the combined effects of MRI and oophorectomy. For this purpose, 93 BRCA1/2 mutation carriers were screened with yearly mammograms and yearly MRI scans. Study endpoints were defined as date of breast cancer diagnosis, date of prophylactic mastectomy, or date of most recent contact. Of 93 women, with a median age of 47, 80 (86%) had prophylactic oophorectomy. Fifty-one women (55%) had BRCA1 mutations. A total of 283 MRI scans were performed. Eleven breast cancers (9 invasive, 2 ductal carcinoma in situ) were detected in 93 women (12%) with a median follow-up of 3.2 years (incidence 40 per 1,000 person-years). Six cancers were first detected on MRI, three were first detected by mammogram, and two were "interval cancers." All breast cancers occurred in BRCA1 mutation carriers (incidence 67 per 1,000 person-years). Apart from BRCA1 vs. BRCA2 mutation status, there were no other significant predictors of breast cancer incidence. Most invasive breast cancers were estrogen receptor negative (7 of 9) and lymph node negative (7 of 9). There have been no systemic recurrences with a median follow-up of 19 months after cancer diagnosis. Finally, it was concluded that all breast cancers occurred in BRCA1 mutation carriers, in most cases despite oophorectomy. These data suggest that surveillance and prevention strategies may have different outcomes in BRCA1 and BRCA2 mutation carriers.

Artificial neural network-based classification to screen for dysphonia using psychoacoustic scaling of acoustic voice features.

SUMMARY: For diagnosis and classification of dysphonia, voice specialists can choose from an array of diagnostic tools like perceptual tests or acoustic voice analysis. These methods have in common that they require a high level of specialized training and experience, and therefore are mostly reserved to specialized centers. We aimed at developing an acoustic voice analysis system that could be used as a screening device to monitor, document, and diagnose voice problems that are also encountered by non-voice specialists, such as anesthesiologists, head and neck surgeons, and general surgeons before surgery of the thyroid gland and the upper thoracic aperture. An acoustical feature extraction paradigm that focused on jitter, shimmer, standard deviation of fundamental frequency, and the glottal-to-noise excitation ratio was used to reanalyse 120 voice samples previously analyzed by Schönweiler et al (A Novel Approach to Acoustical Voice Analysis Using Artificial Neural Networks. JARO. 2000:1;270-282). An improved artificial neural network (ANN) was used for classification. Building on this preliminary work, we modified the mathematical algorithm to further improve classification accuracy. Eighty percent of all voice samples could be classified correctly as either healthy or hoarse (sensitivity: 63.0%; specificity: 93.9%; area under the curve: 0.854). The adaptation of the ANN-voice analysis system for mobile use may facilitate its use and acceptance by non-voice specialists for the discovery and documentation of preexisting voice disorders, and may thereby lead to a timely initiation of further diagnosis and therapy by voice specialists.

Biomedical vocabularies--the demand for differentiation.

The need of biomedical vocabularies is well known for various tasks, e.g., supporting structured data entry, decision support and electronic data exchange as well as retrieval and statistical evaluation of the data. Due to a considerable diversity of artifacts like interface terminologies, classifications and thesauri it seems to be reasonable to demand for a massive reduction and, finally, to end up with just one unique "multi-purpose world terminology". Concept-based reference terminologies like SNOMED CT might be candidates for that idea. Unfortunately, the above mentioned kinds of vocabularies cannot be replaced because of their specific purpose-dependent nature. Their mutual distinctive characteristics are outlined and compared with inherent purpose-less concept systems that are based on formal approaches like description logics. For supporting interoperability the different kinds of purpose-dependent vocabularies can and should be improved by mappings to machine-processible reference terminologies. As a side-effect, this paper may contribute to the meta-terminology in this field of medical terminology.

Multianalyte profiling of serum cytokines for detection of pancreatic cancer.

Early detection of pancreatic cancer might improve clinical outcome. Significant alterations in the levels of individual serum cytokines have been reported in pancreatic cancer. We hypothesized that a multicytokine panel could serve as biomarkers for pancreatic cancer. To evaluate the diagnostic utility of such a panel, we have utilized a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple markers. In this study, a panel of 31 serological markers including cytokines, chemokines, growth and angiogenic factors in combination with CA 19-9 was analyzed in sera of pancreatic cancer patients, patients with chronic pancreatitis, and matched control healthy subjects. Statistical analysis identified a multicytokine panel that was able to distinguish pancreatic cancer from healthy controls with a sensitivity of 85.7% and specificity of 92.3%, which was superior to performance of CA 19-9 alone. Importantly, a multicytokine panel allowed the discrimination of pancreatic cancer from chronic pancreatitis with high sensitivity of 98% and specificity of 96.4%. In conclusion, we demonstrated that analysis of multiple serum cytokines using a novel LabMAP technology is a promising approach for development of a diagnostic assay for pancreatic cancer.

The 'subsequent artificial neural network' (SANN) approach might bring more classificatory power to ANN-based DNA microarray analyses.

MOTIVATION: Human decisions often proceed in two steps. Initially those most preferred are chosen followed by a subsequent choice of these preferences. Applying one artificial neural network (ANN), a classification is limited to the preselection process. The final categorization is only possible by a subsequent ANN that distinguishes the pre-chosen classes. Existing strategies using coupled ANNs are discussed and a new approach particularly suited for multiclass classification problems is introduced ('Subsequent ANN', SANN). RESULTS: Evaluating a simulated data base comprising 3 classes, classification results of SANN were obviously superior to those achieved by ANN. To evaluate a real-world data base the microarray benchmark GCM (14 classes) was chosen. The ANN results reached 72%, comparable to previous results. Using SANN, up to 81% of the tumors were correctly classified. AVAILABILITY: Programs used in this work and numerical results are available upon request.

Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy.

c-Met is a receptor tyrosine kinase whose activation by hepatocyte growth factor (HGF) can lead to transformation and tumorigenicity in a variety of tumors. We investigated the effects of suppressing c-Met protein expression in human non-small cell lung tumors. Expression plasmids containing either sense or antisense sequences of the human c-met gene were constructed under control of the U6 snRNA promoter. A U6 control plasmid was also constructed that did not contain any c-met sequence. These constructs have been examined both in vitro and in an in vivo tumor xenograft model. The c-Met protein was downregulated by 50-60% in two lung cancer cell lines that were transiently transfected with the c-Met antisense versus U6 control. Tumor cells treated with the c-Met antisense construct also show decreased phosphorylation of c-Met and MAP kinase when exposed to exogenous HGF. Lung cancer cells were grown as xenografts in mice and treated by intratumoral liposome-mediated transfer of the c-Met sense, antisense or U6 control plasmids. The treatment of lung tumors with c-Met antisense versus U6 control plasmid resulted in the downregulation of the c-Met protein expression, a 50% decrease in tumor growth over a 5-week treatment period and an increased rate of apoptosis. These results suggest that targeting the HGF/c-Met pathway may be an effective novel strategy to treat lung cancer patients.

A novel method for diagnosing chronic rhinosinusitis based on an electronic nose.

The nasal out-breath of persons with chronic nasal and/or paranasal infections may have characteristic strange odors, which in our experience are in most cases related to bacterial and/or fungal infections of the sinuses. The objective of the present study was to examine nasal out-breath samples from patients with chronic rhinosinusitis (CRS) (with or without polyposis) and healthy control volunteers using the electronic-nose (EN) technology. We developed a simple technique for collecting samples of nasal out-breath in disposable sterile plastic sacks with a tight closing seal. The principal component analysis correctly classified all individual EN patterns for CRS patients and misclassified 2 samples from the healthy controls (80.0% successful classification rate). The artificial neural network analysis correctly classified 60.0% of the patterns of both groups. We believe that the use of methodologies based on EN technology, combined with conventional clinical examinations, may improve the diagnosis of chronic rhinosinusitis.

Un nuevo método para el diagnóstico de la rinosinusitis crónica basado en una nariz electrónica / A novel method for diagnosing chronic rhinosinusitis based on an electronic nose

El aire nasal respirado por las personas con infecciones crónicas nasales y/o paranasales puede tener extraños olores característicos, que según nuestra experiencia, en muchos casos está relacionado a infecciones micóticas y/o bacteriológicas de los senos paranasales. El objetivo del presente estudio consistió en examinar muestras del aire nasal respirado de pacientes con rinosinusitis crónica (CRS) (con o sin poliposis) y controles voluntarios sanos usando la tecnología electrónica nasal (EN). Desarrollamos una técnica simple para recoger las muestras del aire nasal respirado en bolsas estériles de plástico con un cierre hérmético. El análisis de los componentes principales clasificó correctamente todos los patrones EN individuales de los pacientes con CRS y subclasificó 2 muestras de los controles sanos (tasa de clasificación correcta 80,0 por ciento). El análisis de red neural artificial clasificó correctamente el 60,6 por ciento de los patrones de los dos grupos. Creemos que el uso de las metodologías basadas en la tecnología EN, combinada con los exámenes clínicos convencionales puede mejorar el diagnóstico de la rinosinusitis crónica (AU)

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