PET/MRI for staging patients with Hodgkin lymphoma: equivalent results with PET/CT in a prospective trial.

To compare FDG-PET/unenhanced MRI and FDG-PET/diagnostic CT in detecting infiltration in patients with newly diagnosed Hodgkin lymphoma (HL). The endpoint was equivalence between PET/MRI and PET/CT in correctly defining the revised Ann Arbor staging system. Seventy consecutive patients with classical-HL were prospectively investigated for nodal and extra-nodal involvement during pretreatment staging with same-day PET/CT and PET/MRI. Findings indicative of malignancy with the imaging procedures were regarded as lymphoma infiltration; in case of discrepancy, positive-biopsy and/or response to treatment were evidenced as lymphoma. Sixty of the 70 (86%) patients were evaluable having completed the staging program. Disease staging based on either PET/MRI or PET/CT was correct for 54 of the 60 patients (90% vs. 90%), with difference between proportions of 0.0 (95% CI, -9 to 9%; P=0.034 for the equivalence test). As compared with reference standard, invasion of lymph nodes was identified with PET/MRI in 100% and with PET/CT in 100%, of the spleen with PET/MRI in 66% and PET/CT in 55%, of the lung with PET/MRI in 60% and PET/CT in 100%, of the liver with PET/MRI in 67% and PET/CT in 100%, and of the bone with PET/MRI in 100% and PET/CT in 50%. The only statistically significant difference between PET/MRI and PET/CT was observed in bony infiltration detection rates. For PET/CT, iodinate contrast medium infusions' average was 86 mL, and exposure to ionizing radiation was estimated to be 4-fold higher than PET/MRI. PET/MRI is a promising safe new alternative in the care of patients with HL.

Sensitization to Gibberellin-Regulated Protein (Peamaclein) Among Italian Cypress Pollen-Sensitized Patients.

BACKGROUND AND OBJECTIVES: Peach gibberellin-regulated protein (peamaclein) has recently emerged as a relevant food allergen in cypress pollen-hypersensitive patients. Objective: We investigated monosensitization to peamaclein among Italian cypress pollen-allergic patients. MATERIAL AND METHODS: A total of 835 cypress pollen-hypersensitive patients from 28 Italian allergy centers underwent a thorough work-up to determine food-allergic reactions and performed skin prick testing with a commercial peach extract containing peamaclein. IgE to rPru p 3 was measured in peach reactors, and those with negative results were enrolled as potentially monosensitized to peamaclein. IgE reactivity to rPru p 7 was evaluated using immunoblot and an experimental ImmunoCAP with rPru p 7. RESULTS: Skin prick tests were positive to peach in 163 patients (19.5%); however, 127 (77.9%) were excluded because they reacted to Pru p 3. Twenty-four patients (14.7%) corresponding to 2.8% of the entire study population) were considered potentially monosensitized to peamaclein. No geographic preference was observed. Seventeen of the 24 patients (70.8%) had a history of food allergy, mainly to peach (n=15). Additional offending foods included other Rosaceae, citrus fruits, fig, melon, tree nuts, and kiwi. On peach immunoblot, only 3 of 18 putative peamaclein-allergic patients reacted to a band at about 7 kDa; an additional 4 patients reacted at about 50-60 kDa. Ten of 18 patients (56%) had a positive result for Pru p 7 on ImmunoCAP. CONCLUSION: Allergy and sensitization to peamaclein seem rare in Italy. Most patients react to peach, although other Rosaceae fruits and several citrus fruits may also be offending foods. Peach and cypress pollen probably also share cross-reacting allergens other than peamaclein.

Identification of clusters in multifocal electrophysiology recordings to maximize discriminant capacity (patients vs. control subjects).

PURPOSE: To propose a new method of identifying clusters in multifocal electrophysiology (multifocal electroretinogram: mfERG; multifocal visual-evoked potential: mfVEP) that conserve the maximum capacity to discriminate between patients and control subjects. METHODS: The theoretical framework proposed creates arbitrary N-size clusters of sectors. The capacity to discriminate between patients and control subjects is assessed by analysing the area under the receiver operator characteristic curve (AUC). As proof of concept, the method is validated using mfERG recordings taken from both eyes of control subjects (n = 6) and from patients with multiple sclerosis (n = 15). RESULTS: Considering the amplitude of wave P1 as the analysis parameter, the maximum value of AUC = 0.7042 is obtained with N = 9 sectors. Taking into account the AUC of the amplitudes and latencies of waves N1 and P1, the maximum value of the AUC = 0.6917 with N = 8 clustered sectors. The greatest discriminant capacity is obtained by analysing the latency of wave P1: AUC = 0.8854 with a cluster of N = 12 sectors. CONCLUSION: This paper demonstrates the effectiveness of a method able to determine the arbitrary clustering of multifocal responses that possesses the greatest capacity to discriminate between control subjects and patients when applied to the visual field of mfERG or mfVEP recordings. The method may prove helpful in diagnosing any disease that is identifiable in patients' mfERG or mfVEP recordings and is extensible to other clinical tests, such as optical coherence tomography.

Electroencephalographic and Neuroimaging Asymmetry Correlation in Patients with Attention-Deficit Hyperactivity Disorder.

The present study explores the correlation between electroencephalographic and neuroimaging asymmetry index from EEG-MRI functional connectome and EEG power analysis in inattention, motion, and mixed profile subgroups of ADHD. Sixty-two subjects from Healthy Brain Network Biobank of the Child Mind Institute dataset were selected basing on the quotient score. From both MRI and EEG asymmetry index, Pearson's correlation, ANOVA, and partial least square analysis were performed matching left and right brain parcels and channels. The asymmetry index significantly correlated across subjects between fMRI and power-EEG in the inattention group in frontal and temporal areas for theta and alpha bands, an anticorrelation in the same areas for delta band was found. Significant patterns of hemispheric asymmetry index have been reported, involving EEG bands that underlie cognitive impairments in ADHD. Alpha and theta bands were altered in the inattention group of patients, reflecting widespread deficiency of basic attentional processing.

The role of allergoids in allergen immunotherapy: from injective to sublingual route.

Summary: Summary Allergen immunotherapy (AIT) is aimed at inducing tolerance to allergens, such as pollens, dust mites or moulds, by administering increasing amounts of the causative allergen through subcutaneous or sublingual route. The evidence of efficacy of AIT is high, but the issue of safety, especially for the subcutaneous route, must be taken into account. The search for safer AIT products aimed at reducing the allergenicity, and thus adverse reactions, while maintaining the immunogenicity, that is essential for effectiveness, gave rise to the introduction of allergoids, which were conceived to fulfill these requirements. In the first allergoids glutaraldehyde or formaldehyde were used as cross-linking agent to polymerize allergens, this resulting in high molecular weight molecules (200,000 to 20,000,000 daltons) which were significantly less allergenic due to a decreased capacity to bridge IgE on its specific receptor, while maintaining the immunogenicity and thus the therapeutic efficacy. In recent years further agents, acting as adjuvants, such as L-tyrosine, monophosphoryl lipid A, aluminium hydroxide, were added to polymerized extracts. Moreover, a carbamylated monomeric allergoid was developed and, once adsorbed on calcium phosphate matrix, used by subcutaneous route. At the same time, in virtue of its peculiarities, such allergoid revealed particularly suitable for sublingual administration. A lot of clinical evidences show that it is well tolerated, largely safer and effective. Importantly, the higher safety of allergoids allows faster treatment schedules that favor patient compliance and, according to pharmaco-economic studies, they might be more cost-effective than other AIT options.

Nasal cytology.

Nasal cytology represents a useful, inexpensive and easy-to-apply diagnostic method to better detail the phenotypic characteristics of rhinitis. In fact, it allows to detect and quantify the cell population within the nasal mucosa at a given time. The technique involves sampling, processing and microscope reading. Sampling requires the collection of cells from the surface of nasal mucosa that is usually done by a sterile disposable curette. Samples should be collected from the middle portion of the inferior turbinate where the ratio ciliate/mucinous cells is expected to be well balanced. This totally painless procedure is performed under anterior rhinoscopy, with an appropriate light source. The sample staining is executed using the common May-Grünwald-Giemsa (MGG). The stained sample is read at optical microscopy with a 1000x objective and with oil detecting the presence of inflammatory elements (eosinophils, mast cells, neutrophils and lymphocytes) in nasal mucosa, as in the case of allergic and non-allergic rhinitis. Nasal cytology is easy to perform, non-invasive, inexpensive and repeatable in the same subject, also at short time intervals. For these reasons it represents an affordable diagnostic technique that can be applied in all age ranges, to better differentiate pathological conditions and also to evaluate the effects of various stimuli (allergens, infectious, irritants) or the effect of treatments.

Role of imaging in allergic rhinology.

Rhinitis is an underestimated clinical condition, which has a considerable impact on the quality of life of the affected patients. The subject of this review focuses on three fundamental aspects: the development of knowledge concerning anatomic landmarks, the development of radiological imaging technology, and developments that can make a difference in the treatment of allergic rhinitis. The anatomical study of paranasal sinuses has been conducted since the time of the ancient Egyptians. Development of radiological equipment from the early 1900s has helped to improve information on the morphology of paranasal sinuses, sufficient to be considered valuable information regarding frontal anatomy and its variability. Imaging has become increasingly important in the diagnosis and treatment of inflammatory diseases of the paranasal sinuses. In recent decades, radiology has helped to study this region as we have progressed from plain radiography to high-resolution Computed Tomography (HRCT). Subsequently, from radiologic imaging, digital volume tomography (DVT) has been developed, in high resolution and narrow section width. Currently, experience with third generation Cone-Beam Computed Tomography (CBCT) technologies provides useful information about bones, and it is now possible to highlight anatomical variants that involve bone structures. We still lack the ability to make a qualitative evaluation of soft tissues, as there are no Hounsfield levels in CBCT. However, this is a new area of research, and its application is evolving in an interesting manner, especially for soft-tissue allergic-inflammatory diseases.

Omalizumab a new prospective: a nasal polyposis.

Omalizumab, a monoclonal antibody against IgE, may be effective on nasal polyps, but its use is not currently authorized to treat that disease. We report the cases of three patients who were given omalizumab for asthma after undergoing nasal surgical polypectomy. Although such procedure is frequently followed by polyp recurrence, none of the three patients developed this complication, and in one subject the regression of initial polyp return was registered after starting omalizumab. Our data support the hypothesis that omalizumab may be useful to treat nasal polyposis.

New scientific synergies to manage patients with severe Rhinitis: allergy diagnosis and treatment for ENT specialists.

INTRODUCTION: Allergic rhinitis (AR) is a global health problem because of its steadily increasing incidence and prevalence that currently concerns about 30% of the world’s population. Although AR is not a disease that reduces the life expectancy, it is a disorder with a major impact on the quality of life of patients, resulting from an impaired social life, school performance and work productivity. Furthermore, AR produces significant costs for its treatment.

Human nasal immune system: a special site for immune response establishment.

The mucosal immune system located in correspondence to the olfactory organs in adult humans is not well identifiable but has proven important in establishing an effective immune response against inhaled antigens, including the generation of Helper 1 (TH1)- and TH2-cells, cytotoxic T lymphocytes (CTLs), plasma cells (PCs) and memory B cells. It is constituted by a diffused network of cells of epithelial and immune origin, as well as organized lymphoid tissue, where each component has a role in the initiation and maintenance of a long-lasting immune response, which is evoked not only in the oral and nasal cavities but also in the respiratory, intestinal and genito-urinary tracts. These peculiarities, in association to the easy anatomical accessibility of such immunological site, render the nasal mucosa a good candidate for the development of vaccine, even if a better understanding of the mechanism of the immune response induction as well as finding a safe adjuvant are necessary.

Laboratory tests for allergy diagnosis.

The introduction of highly purified natural and recombinant single allergenic molecules represented an important improvement in the diagnosis of IgE sensitization. The identification of specific IgE against cross-reacting molecules such as profilin, lipid transfer proteins, calcium binding proteins or against “genuine molecules”, represents an added value and allows to distinguish between true and false polysensitization. In vitro tests add information to recognize patients with sensitization to genuine molecules that cause allergic diseases and to evaluate in childhood the spreading of sensitization for each molecule in order to choose the best treatment and to identify the ideal patient for allergen immunotherapy. Also, in order to detect patients with sensitization to pan-allergens it is important to manage the risk of anaphylaxis for patients allergic to latex and to identify IgE to particular molecules involved in occupational allergy. In patients with negative skin prick tests (SPT), that results in a lower sensitivity compared with in vitro tests, the negative test may be caused by the lack of some important allergenic molecules in the extract used for SPT.

Pollens causing allergy and their monitoring by aerobiology and phenology.

Allergies caused by inhalant allergens, particularly pollens, are steadily increasing in urban centers. It is known that atmospheric pollution is strongly related to the inflammatory disease of the upper and lower airways but it is equally important in the development of sensitization towards pollens. Particulate Matter (PM), sulfur dioxide (SO2) and nitrogen dioxide (NO2) have an enhancement function on the persistence of pollens in the air, increasing the concentration and duration of pollinosis. It is therefore essential to use air quality control methods in urban centers to monitor the presence of pollen and fine dust that can drive the doctor and the patient to improve prevention, a step of primary importance in the treatment of allergies. Aerobiology and phenology are essential tools to monitor pollen production. The opportunity for the patients to use social media as information sources, including teletext, sms, mail and social networks, as well as a wide range of apps, allows to have reliable information on the air we breathe and therefore to better manage the methods of prevention at our disposal.

ENT tests for assessing the allergic patient.

Allergic rhinitis (AR) is a disease that afflicts a large percentage of the world population. It concerns both allergists and otolaryngologists, therefore it is important for both specialists to be aware of the characteristics of a patient who suffers from AR. Often, patients complain of nasal breathing difficulty only, initially not reporting any other symptoms typical of AR. In this brief review, the most important investigations, physical examination, nasal endoscopy, nasal peak flow and rhinomanometry, are described. All these investigations allow us not only to make the correct diagnosis, but also to monitor the course of the disease and the effects of therapy.

Allergic rhinitis.

Allergic rhinitis (AR) was long considered a quite trivial disease, but the advance in epidemiological and clinical knowledge, with a major role for Allergic rhinitis and its Impact on Asthma (ARIA) initiative, substantially changed the scene. Now we know that AR has significant effects on patients’ quality of life and also has a relevant economic burden. The ARIA phenotypes related to the duration of symptoms and to the severity of AR are very useful in establishing the optimal strategy in each patient with AR, also according to the kind of allergens that cause rhinitis. When traditional allergy testing, including skin prick tests and in vitro of specific IgE antibodies are not sufficient for the diagnosis, modern techniques such as molecular diagnostics may be used. Also the management of AR may be tailored to single patients according to the clinical expression of AR, that may vary from mild to moderate-severe stage, with the aim of achieving the best possible control of the disease.

Should omalizumab be used in severe asthma/COPD overlap?

A large number of patients suffering from asthma or chronic obstructive pulmonary disease (COPD) can show overlapping features of both diseases. Several subjects affected by asthma-COPD overlap (ACO) may be at a severe stage, poorly responsive to triple therapy including inhaled corticosteroids, long-acting ß2 agonists and muscarinic antagonists. This review tries to explore whether omalizumab can be used in poorly controlled severe ACO patients. According to the few studies available, omalizumab may improve asthma outcomes in ACO, although the magnitude of improvements may be lower in comparison to those obtained in subjects affected only by severe asthma. Omalizumab, by acting on IgE, might improve the eosinophilic pattern which is characteristic of the ACO asthma inflammation component. It can be hypothesized that a prevalence of Th1/Th17 airway inflammation pathways can modulate a lower response to anti-IgE while a Th2 pattern can lead to a higher effectiveness to omalizumab in ACO. High levels of IgE, FeNO and blood eosinophil count may be markers of a better response to omalizumab. In conclusion, on the basis of the few studies available, omalizumab could be effective in poorly-controlled severe ACO, although to a reduced extent in comparison to patients affected only by asthma.

Allergic conjunctivitis: current concepts on pathogenesis and management.

Allergic conjunctivitis (AC) includes a wide spectrum of clinical entities characterized by different incidence, age of onset, natural course, clinical outcome and response to treatment. Taken together, they represent one of the most frequent ocular surface diseases affecting more than 30% of the young-adult population and show an increasing incidence over the years. Moreover, comorbidities with other systemic atopic conditions such as asthma, atopic dermatitis and rhinitis require a multidisciplinary approach. Recent advances in the knowledge of the pathogenic mechanism overcome the classic role of type I hyper-sensitivity and mast cells’ activation, demonstrating an involvement of innate immunity and neuroinflammation in the pathogenesis of the most severe forms such as atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). Ocular itching, swelling and tearing are the most frequent symptoms complained by patients with all forms of AC, while photophobia and pain are typical of the most severe forms, such as VKC and AKC, due to the frequent corneal involvement. Upper tarsal papillary reaction represents the main clinical sign of AC associated with conjunctival hyperemia and mucous secretion. Diagnosis is based on clinical history and eye evaluation and can be confirmed through allergological tests. Additional ocular exams include specific allergen conjunctival provocation tests and the presence of eosinophils in the conjunctival scraping. Current treatments of AC include the use of antiallergic eye drops for mild forms, while recurrences of ocular surface inflammations with corneal involvement in severe forms require the use of topical steroids to avoid visual impairment. Novel steroid sparing therapies such as Cyclosporine A eye drops or topical Tacrolimus have been proposed to improve VKC and AKC management.

Asthma associated to rhinitis.

A large amount of data show that AR and asthma are associated both epidemiologically and clinically, introducing the definition of “united airway disease”. The mechanisms underlying such association were initially suggested to start from the nose, including the loss of the protective and homeostatic effects of nasal function, the activation of a naso-bronchial reflex and the spread of allergic inflammation from the nose to the lower airways. Later, other factors such as microbial stimuli and systemic inflammatory mechanisms, involving bloodstream and bone marrow, were advocated. The advance in knowledge made it clear that the link between asthma and AR is multifactorial, with particular importance for inflammatory cells and especially eosinophils. By the model of nasal challenge, important immunological responses were revealed, with particular importance for the increased expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and of cytokines such as interleukin (IL)-13, that was accompanied by a rise of eosinophils in blood and developement of bronchial hyper-responsiveness. The occurrence in AR of a concomitant sinusitis is frequently associated with worse asthma outcomes, as assessed by a lower pulmonary function, increased asthma symptoms and poorer quality-of-life compared to patients with asthma alone.

The skin prick test.

The skin prick test (SPT) is the most common test for the diagnosis of allergy. SPT is performed by pricking the skin, usually in the volar surface of the forearm, with a lancet through a drop of an allergen extract and is usually the first choice test in the diagnostic workup for allergic diseases because of its reliability, safety, convenience and low cost. SPT is minimally invasive and has the advantage of testing multiple allergens in 15 to 20 min. In children, SPT is far less disturbing than venipuncture and is used to obtain a sample of serum to measure specific IgE through in vitro tests. There is a good correlation (about 85-95%) between SPT and in vitro tests. Globally, SPT is an excellent diagnostic tool, with a positive predictive value ranging from 95-100%. SPTs can identify sensitivity to inhalants, foods, some drugs, occupational allergens, hymenoptera venom and latex. However, the relevance of such sensitivity to allergens should always be carefully interpreted in the light of the clinical history, because sensitization and clinical allergy may not coincide. In regards to safety, though the reports of systemic reactions, and particularly anaphylaxis, are very rare, in vitro IgE tests should be preferred if previous severe reactions emerge from the patient’s clinical history.

Biophysics and protein corona analysis of Janus cyclodextrin-DNA nanocomplexes. Efficient cellular transfection on cancer cells.

The self-assembling processes underlining the capabilities of facially differentiated ("Janus") polycationic amphiphilic cyclodextrins (paCDs) as non-viral gene nanocarriers have been investigated by a pluridisciplinary approach. Three representative Janus paCDs bearing a common tetradecahexanoyl multitail domain at the secondary face and differing in the topology of the cluster of amino groups at the primary side were selected for this study. All of them compact pEGFP-C3 plasmid DNA and promote transfection in HeLa and MCF-7 cells, both in absence and in presence of human serum. The electrochemical and structural characteristics of the paCD-pDNA complexes (CDplexes) have been studied by using zeta potential, DLS, SAXS, and cryo-TEM. paCDs and pDNA, when assembled in CDplexes, render effective charges that are lower than the nominal ones. The CDplexes show a self-assembling pattern corresponding to multilamellar lyotropic liquid crystal phases, characterized by a lamellar stacking of bilayers of the CD-based vectors with anionic pDNA sandwiched among them. When exposed to human serum, either in the absence or in the presence of pDNA, the surface of the cationic CD-based vector becomes coated by a protein corona (PC) whose composition has been analyzed by nanoLC-MS/MS. Some of the CDplexes herein studied showed moderate-to-high transfection levels in HeLa and MCF-7 cancer cells combined with moderate-to-high cell viabilities, as determined by FACS and MTT reduction assays. The ensemble of data provides a detail picture of the paCD-pDNA-PC association processes and a rational base to exploit the protein corona for targeted gene delivery on future in vivo applications.

Is lingual tonsil a preferential target for processing sublingually administered materials?

The oral cavity is a site of pivotal importance in the immune response to foreign antigens, ensuring tolerance induction to harmless agents but reactivity to potentially noxious antigens. Tolerance or reactivity are driven by a number of secondary lymphoid organs, all belonging to the Waldeyer ring, that include adenoids, tubal, palatine and lingual tonsils. Waldeyer's ring tissues were acknowledged as implicated not only in the adaptive immune system but also in the innate immune system modulation, involving the toll-like receptors. In particular, findings from animal studies suggested that the lingual tonsil can be considered as an inductive site sampling and processing antigens to stimulate naïve T and B lymphocytes. According to a recent study showing that immunologically active or inactive materials placed under the tongue of allergic subjects rapidly reach the lingual tonsil, such a role seems likely also in humans, and warrants to be investigated in-depth for possible applications in medical treatments.