The Incredible Adventure of Omalizumab.

The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.

Navigated intraoperative ultrasound in neuro-oncology: volumetric accuracy and correlation with high-field MRI.

OBJECTIVE: The use of intraoperative techniques to detect residual tumors has recently become increasingly important. Intraoperative MRI has long been considered the gold standard; however, it is not widely used because of high equipment costs and long acquisition times. Consequently, real-time intraoperative ultrasound (ioUS), which is much less expensive than MRI, has gained popularity. The aim of the present study was to evaluate the capacity of ioUS to accurately determine the primary tumor volume and detect residual tumors. METHODS: A prospective study of adult patients who underwent surgery for intra-axial brain tumors between November 2017 and October 2020 was performed. Navigated intraoperative ultrasound (nioUS) of the brain was used to guide tumor resection and to detect the presence of residual disease. Both convex (5-8 MHz) and linear array (6-13 MHz) probes were used. Tumor volume and residual disease were measured with nioUS and compared with MR images. A linear regression model based on a machine learning pipeline and a Bland-Altman analysis were used to assess the accuracy of nioUS versus MRI. RESULTS: Eighty patients (35 females and 45 males) were included. The mean age was 58 years (range 25-80 years). A total of 88 lesions were evaluated; there were 64 (73%) gliomas, 19 (21.6%) metastases, and 5 (5.7%) other tumors, mostly located in the frontal (41%) and temporal (27%) lobes. Most of the tumors (75%) were perfectly visible on ioUS (grade 3, Mair grading system), except for those located in the insular lobe (grade 2). The regression model showed a nearly perfect correlation (R2 = 0.97, p < 0.001) between preoperative tumor volumes from both MRI and nioUS. Ultrasonographic visibility significantly influenced this correlation, which was stronger for highly visible (grade 3) tumors (p = 0.01). For residual tumors, the correlation between postoperative MRI and nioUS was weaker (R2 = 0.78, p < 0.001) but statistically significant. The Bland-Altman analysis showed minimal bias between the two techniques for pre- and postoperative scenarios, with statistically significant results for the preoperative concordance. CONCLUSIONS: The authors' findings show that most brain tumors are well delineated by nioUS and almost perfectly correlated with MRI-based measurements both pre- and postoperatively. These data support the hypothesis that nioUS is a reliable intraoperative technique that can be used for real-time monitoring of brain tumor resections and to perform volumetric analysis of residual disease.

Omalizumab in Severe Asthma: Effect on Oral Corticosteroid Exposure and Remodeling. A Randomized Open-Label Parallel Study.

INTRODUCTION: Data on the clinical efficacy and remodeling of omalizumab therapy in patients on oral corticosteroids (OC) are limited. OBJECTIVE: The purpose of the study is to show that in patients with corticosteroid-dependent asthma, omalizumab is a corticosteroid-sparing therapy able to inhibit airway remodeling and to reduce disease burden (lung function impairment, exacerbations). METHODS: This study is a randomised open-label study evaluating the addition of omalizumab to the standard of care in patients with severe asthma receiving oral corticosteroids. The primary endpoint was represented by the change in OC monthly dose by the end of treatment and secondary endpoints included spirometry changes, airway inflammation (FeNO), number of exacerbations and airways remodelling assessed by bronchial biopsies studied by transmission electron microscopy. As a safety variable, adverse effects were recorded. RESULTS: Efficacy was assessed for 16 patients in the omalizumab group and 13 in the control group. The final cumulative mean monthly OC doses were 34.7 mg and 217 mg for the omalizumab and control group, respectively; the mean difference between groups adjusted for baseline was -148.1 [95% confidence interval (CI) -243.6, -52.5; p = 0.004]. OC withdrawal of 75% versus 7.7% (p = 0.001) was observed in the omalizumab and control group, respectively. Omalizumab provided a slowing of forced expiratory volume in one second (FEV1) loss (70 mL versus 260 mL), a significant decrease in FeNO values and a reduction in the annual relative risk of clinically significant exacerbations of 54%. The treatment was well tolerated. The morphological study showed a significant decrease in basement membrane thickness in the omalizumab group (6.7 µm versus 4.6 µm) compared with controls (6.9 µm versus 7 µm) [mean difference between groups adjusted for baseline was -2.4 (95% CI -3.7, -1.2; p < 0.001], as well as a decrease in intercellular spaces (1.18 µm versus 0.62 µm and 1.21 µm versus 1.20 µm, p = 0.011, respectively). A qualitative improvement was also observed in the treated group. CONCLUSIONS: Omalizumab showed a marked OC-sparing capacity and was associated with an improvement in clinical management that correlated with bronchial epithelial repair. In OC-dependent asthma, reversibility of remodelling is possible; the concepts that basement membrane enlargement is detrimental and that chronic airway obstruction is systematically irreversible are outdated (EudraCT: 2009-010914-31).

From the Allergic Cascade to the Epithelium-Driven Disease: The Long Road of Bronchial Asthma.

In medicine, much of the progress made is due to the emergence of new drugs [...].

Intracavernous Branches of the Internal Carotid Artery Through an Endoscopic Endonasal Approach: Anatomical Study and Review of the Literature.

OBJECTIVE: The endoscopic endonasal transcavernous (EET) approach is an increasingly popular approach for the cavernous sinus and surrounding structure lesions as well as a surgical corridor to pre-mesencephalic cisterns. This endoscopic study describes the main intracavernous branches of the internal carotid artery, providing nuances to improve the safety of this approach. MATERIAL AND METHODS: Forty-six fresh cavernous sinus (23 heads) were injected with colored silicon and studied via an EET approach; 6 were excluded due to insufficient injection. The internal carotid artery, the meningohyphophyseal trunk (MHT) and its branches, and the inferolateral trunk were dissected, and branching patterns identified and classified. RESULTS: The MHT was identified in 82.5% of cases. Two main MHT types were identified: complete, with 3 main branches, and incomplete, with fewer than 3. The main branches encountered were the inferior hypophyseal artery, present in 92.5% of cases, the dorsal meningeal artery (DMA), present in 87.5%, and the tentorial artery, present in 87.5%. The DMA was classified as prominent medial (48.6%), prominent lateral (20%), or bifurcation type (25.7%). Complete and incomplete MHT were further classified as complete MHT (A, B, and C) and incomplete MHT (A, B, C, and D) according to the combination of the different DMA types with other branches. The inferolateral trunk was a branch of the MHT in 7% of cases. CONCLUSIONS: The MHT is a highly prevalent intracavernous branch, with 7 identifiable patterns based on DMA morphology and branch combination. This knowledge could guide surgeons in performing a safer EET approach.

Description and relationships of the parotid gland levels proposed by the European Salivary Gland Society staging system: an anatomical study.

OBJECTIVES: To perform an anatomical study to analyze the size, weight, and the relationships of the parotid levels proposed by the European Salivary Gland Society (ESGS). MATERIALS AND METHODS: Anatomical dissections of the parotid region in 19 human specimens were performed. All dissections were systematically carried out to study the dimensions and weight of each level. We also studied the facial nerve distribution between the different levels and the relative position of the facial nerve main trunk and parotid duct in regard to the Frankfort line plane. RESULTS: The facial nerve trunk and the parotid duct were identified in all the 19 specimens, which made it feasible to define the 4 principal levels of the parotid gland body (levels I-IV). Level V was identified in 9 out of 19 dissections (47.5%). For the whole gland, the mean for the height and width dimensions were 66.37 mm and 46.84 mm, respectively, and it weighted 18.13 g. In terms of relative weight regarding the whole gland, level II was always the heaviest, representing from 41 to 47% of the gland's weight, depending on the presence of level V. Levels I and III represent almost the same amount of relative weight as they range from 20 to 22% for each one. Level IV was the lightest body level representing 8-10% of the whole, and when present, level V represented less than 5% of the whole parotid weight. The temporal and zygomatic terminal branches were always found between the cranial levels, whereas the cervical and marginal nerves lie in all cases between the caudal levels. The buccal branches had multiple ramifications that lie between both cranial and caudal levels in 47% of the cases, being found exclusively between cranial levels in 21% and between the caudal levels in the remaining 32%. CONCLUSION: As traditionally reported, the caudal superficial portion of the gland represents the most voluminous portion of the gland, being labeled in our classification as level II. Levels I and III represent similar amounts of gland, though presenting a significantly different morphological disposition. Level IV is the smallest portion of the body gland and level V, when present represents a scarce 5% of the whole body gland weight. The ESGS levels have a clear anatomical basis and the basic references needed to define them are always present.

Anatomic Landmarks in Transoral Oropharyngeal Surgery.

INTRODUCTION: Minimally invasive transoral surgery for oropharyngeal cancer is a challenge for head and neck surgeons because of the inside-out anatomic presentation and the confined workspace. This study was performed to describe the main neurovascular and muscular landmarks in a transoral approach. The authors propose an anatomic stratification for this surgery. MATERIALS AND METHODS: Lateral wall of the oropharynx and base of the tongue of 15 formalin-fixed heads (30 sides) and 5 fresh cadaveric heads (10 sides) sagittal sectioned were dissected from the inside outwards. Dissection of 7 fresh cadaveric heads via an endoscopic transoral approach was also performed. RESULTS: The lateral oropharyngeal wall was divided into 3 layers from medial to lateral, based in the styloid muscle diaphragm. The first layer, medial to styloid muscles, includes the tonsillar vascularization and the lingual branch of the glossopharyngeal nerve. The second layer, lateral to constrictor muscles, includes the pharyngeal venous plexus, the glossopharyngeal nerve, and the lingual artery. The third layer, lateral to styloid diaphragm, includes the parapharyngeal and submandibular spaces, the carotid vessels and lingual, vagus, glossopharyngeal and hypoglossal nerves. The base of the tongue was divided into central and lateral parts, which contain the lingual artery and lingual branches of the glossopharyngeal nerve. The main landmarks to find the neurovascular structures in each layer are described. CONCLUSION: The authors propose an anatomic division, which helps to plan oropharynx and base of the tongue surgery. This anatomic stratification is useful to surgeons when performing a reconstruction of the oropharynx with a transoral approach.

A step-down protocol for omalizumab treatment in oral corticosteroid-dependent allergic asthma patients.

AIMS: There are no specific criteria for a step-down or withdrawal dose of omalizumab (OMA). Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA). METHODS: The study population included 35 SAA patients treated during a minimum period of 1 year with oral corticosteroids (OC) equivalent to a mean daily dose of 4 mg of methyl-prednisolone. To qualify for the protocol, the patients had to have received treatment with OMA for at least one and a half years, OC dose had to have reached the lowest tolerated dose and spirometry had to be greater than or equal to that at entry. The interventions were (a) OMA dose was reduced by half; (b) if patients were clinically stable after 6 months, the dose was halved again; (c) if repeated OC boosters were needed and/or spirometry worsened by more than 10%, OMA dose was raised to the previous figure until stabilization. RESULTS: Mean age was 52.5 (17) years, median monthly OC dose was 120 (IQR: 225) mg. Pulmonary function: FVC: 79.7 (20.2)%; FEV1 : 64.8 (21.7)%; FEV1 / FVC: 61.7(13.8)%. OMA could be withdrawn in 34.3% of the patients; 22.9% tolerated a reduction, and in 42.9% the dose could not be modified. Follow-up time after reduction or withdrawal ranged from 12 to 30 months. There were no severe exacerbations requiring emergency assistance or admission. CONCLUSIONS: The OMADORE study found that in more than 50% of SAA patients on OC, OMA dose can be safely reduced or withdrawn based on a progressive dose reduction protocol.

Omalizumab Is Equally Effective in Persistent Allergic Oral Corticosteroid-Dependent Asthma Caused by Either Seasonal or Perennial Allergens: A Pilot Study.

Omalizumab is marketed for chronic severe asthma patients who are allergic to perennial allergens. Our purpose was to investigate whether omalizumab is also effective in persistent severe asthma due to seasonal allergens. Thirty patients with oral corticosteroid-dependent asthma were treated with Omalizumab according to the dosing table. For each patient with asthma due to seasonal allergens, we recruited the next two consecutive patients with asthma due to perennial allergens. The dose of oral methyl prednisolone was tapered at a rate of 2 mg every two weeks after the start of treatment with omalizumab depending on tolerance. At each monthly visit, a forced spirometry and fractional exhaled nitric oxide (FeNO) measurement were performed and the accumulated monthly methyl prednisolone dose was calculated. At entry, there were no differences between groups in terms of gender, body mass index or obesity, year exacerbation rate, monthly dose of methyl-prednisolone (MP), FeNO and blood immunoglobuline E (IgE) MP, FeNO and IgE values, or spirometry (perennial: FVC: 76%; FEV1: 62%; seasonal: FVC: 79%; FEV1: 70%). The follow-up lasted 76 weeks. One patient in each group was considered a non-responder. Spirometry did not worsen in either group. There was a significant intragroup reduction in annual exacerbation rate and methyl prednisolone consumption but no differences were detected in the intergroup comparison. Omalizumab offered the same clinical benefits in the two cohorts regardless of whether the asthma was caused by a seasonal or a perennial allergen. These results strongly suggest that allergens are the trigger in chronic asthma but that it is the persistent exposure to IgE that causes the chronicity.

Prevalence of bronchiectasis in asthma according to oral steroid requirement: influence of immunoglobulin levels.

PURPOSE: To establish the prevalence of bronchiectasis in asthma in relation to patients' oral corticosteroid requirements and to explore whether the increased risk is due to blood immunoglobulin (Ig) concentration. METHODS: Case-control cross-sectional study, including 100 sex- and age-matched patients, 50 with non-steroid-dependent asthma (NSDA) and 50 with steroid-dependent asthma (SDA). STUDY PROTOCOL: (a) measurement of Ig and gG subclass concentration; (b) forced spirometry; and (c) high-resolution thoracic computed tomography. When bronchiectasis was detected, a specific etiological protocol was applied to establish its etiology. RESULTS: The overall prevalence of bronchiectasis was 12/50 in the SDA group and 6/50 in the NSDA group (p = ns). The etiology was documented in six patients (four NSDA and two SDA). After excluding these patients, the prevalence of bronchiectasis was 20% (10/50) in the SDA group and 2/50 (4%) in the NSDA group (P < 0.05). Patients with asthma-associated bronchiectasis presented lower FEV1 values than patients without bronchiectasis, but the levels of Ig and subclasses of IgG did not present differences. CONCLUSIONS: Steroid-dependent asthma seems to be associated with a greater risk of developing bronchiectasis than non-steroid-dependent asthma. This is probably due to the disease itself rather than to other influencing factors such as immunoglobulin levels.

Oropharyngeal examination to predict sleep apnea severity.

OBJECTIVE: To evaluate the usefulness of the examination of the upper airway, paying special attention to the Friedman tongue position (FTP), to confirm obstructive sleep apnea syndrome (OSAS) and its severity. DESIGN: Prospective, single-center, cross-sectional study. SETTING: Sleep disorders unit of a community hospital. PATIENTS: A total of 301 consecutive patients admitted to the sleep disorders unit due to suspicion of OSAS. Assessments included body mass index calculated as weight in kilograms divided by height in meters squared (BMI); neck perimeter measurement; oropharyngeal examination; fiberendoscopy; rhinomanometry; and a sleep study. MAIN OUTCOME MEASURES: Apnea-hypopnoea index (AHI), FTP, the uvula size, and certain complementary examinations (sex, age, BMI, cervical perimeter, nasal flow) whose importance has not been clearly established, and to explore their potential value as predictors of the AHI. RESULTS: Findings included the following: the mean (SD) age of the patients was 51 (12) years; 71.1% were male; the mean (SD) BMI was 29.8 (4.6); and the mean (SD) cervical perimeter, 40.5 (3.7) cm. In 94.0% of the patients the AHI value was at least 5.0/hour. Patients with FTP scores of 2 and 3 accounted for 74.1% of the whole cohort: 14.3% had an FTP score of 1, and only 11.6% had a score of 4. Of the 6.0% of cases with a normal AHI, 16 patients were classified as having FTP scores of 1, and 2 as having a score of 2. Tonsil size score (P = .005), uvula score (P = .003), BMI (P < .001), cervical perimeter (P < .001), nasal flow at 150 Pa (P = .02), and age (P = .007) were related to OSAS severity. Curiously, AHI in patients who had undergone tonsillectomy was higher than in the TS1 group (tonsils inside the tonsillar fossa) and quite similar to the TS 2 group (tonsils that extend beyond the tonsillar pillars). In the multiple regression model, only the FTP score showed a relevant relationship to OSAS severity. CONCLUSIONS: First, since the FTP score is almost the only parameter related to OSAS severity, a simple oropharyngeal examination can provide key information on this issue. Second, tonsillectomy does not seem to protect against development of OSAS.

Relevance of human anatomy in daily clinical practice.

AIM: the aim of this study has been to evaluate the relevance of gross human anatomy in daily clinical practice and to compare it to that of other basic sciences (biochemistry, bioethics, cytohistology, microbiology, pharmacology, physiology, psychology). MATERIALS AND METHODS: a total of 1250 questionnaires were distributed among 38 different medical speciality professionals. Answers were analyzed taking into account speciality (medical, surgery and others), professional status (training physician or staff member) and professional experience. RESULTS: the response rate was 42.9% (n=536). Gross human anatomy was considered the most relevant basic discipline for surgical specialists, while pharmacology and physiology were most relevant for medical specialists. Knowledge of anatomy was also considered fundamental for understanding neurological or musculoskeletal disorders. In undergraduate programmes, the most important focuses in teaching anatomy were radiological, topographical and functional anatomy followed by systematic anatomy. In daily medical practice anatomy was considered basic for physical examination, symptom interpretation and interpretation of radiological images. When professional status or professional experience was considered, small variations were shown and there were no significant differences related to gender or community. CONCLUSION: our results underline the relevance of basic sciences (gross anatomy, physiology, and pharmacology) in daily professional activity. Evidence-based studies such as ours, lend greater credibility and objectivity to the role of gross anatomy in the undergraduate training of health professionals and should help to establish a more appropriate curriculum for future professionals.

Late-onset congenital cystic adenomatoid malformation of the lung. Embryology, clinical symptomatology, diagnostic procedures, therapeutic approach and clinical follow-up.

BACKGROUND: Congenital cystic adenomatoid malformation of the lung (CCAM) is an embryonic developmental anomaly of an unknown etiology usually diagnosed antenatally by imaging techniques. A minority of cases may not be identified by prenatal imaging techniques and may go unnoticed for the first 6 months of their extrauterine life. Due to its rarity, physicians are unlikely to suspect the condition. OBJECTIVES: To highlight the embryology, clinical symptomatology, diagnostic procedures, therapeutic approach and clinical follow-up of a series of 12 patients with late-onset CCAM. METHODS: An observational study which offers the description of the clinical presentation, diagnostic methods, treatment and follow-up of 12 patients with late-onset CCAM. SETTING: A 600-bed teaching hospital in a reference area of 350,000 inhabitants. PATIENTS: 12 patients from 1983 to 1999. RESULTS: Twelve diagnosed cases of late-onset CCAM. Mean age at diagnosis: 6.7 years (range: 6 months to 23 years). CLINICAL PRESENTATION: 9 out of 12 (75%) with repeated lung infections, 2 out of 12 (16%) chance finding, and 1 case (8%) with pneumothorax. On pathological examination, 7 were found to be CCAM type I and 4 CCAM type II according to Stocker's classification; 1 patient is currently awaiting surgery. The diagnostic method of choice nowadays is a computed tomography (CT) scan performed in the 7 more recent cases; in the former 5 cases an isotopic lung scan was done (and in 2 of them a bronchography was also performed). TREATMENT: 11 patients were operated: 8 lobectomies, 2 segmentectomies and 1 localized resection. Mean follow-up: 8 years (range: 6 months to 16 years). COMPLICATIONS: One reintervention due to a reappearance of the lesion in the patient who underwent localized resection of the CCAM. No cases of malignancy were found. CONCLUSIONS: Late-onset CCAM is an infrequent illness which requires a high level of clinical suspicion. It usually presents in the form of repeated infections. The most frequent pathological forms are type I and II (Stocker). The diagnostic method of choice is the CT scan. The recommended treatment is radical surgery of the lesion once diagnosis has been established. Malignancy and relapses are very infrequent when radical surgery is not postponed.