Omalizumab for the treatment of patients with severe allergic asthma with immunoglobulin E levels above >1500 IU/mL.

Immunoglobulin E (IgE) plays a critical role in the allergen-initiated inflammatory pathway and thus serves as a viable therapeutic target in allergic or IgE-mediated diseases such as asthma. Omalizumab, an anti-IgE biologic, has been approved in the United States (US, 2003) and in the European Union (EU, 2005) as an add-on therapy in patients with moderate-to-severe persistent asthma and severe allergic asthma (SAA) aged 6 years and older. The dose and frequency of omalizumab are adjusted based on the patient's body weight and baseline IgE levels, as recommended by its dosing tables. Currently, these dosing recommendations are limited to patients with baseline IgE levels of up to 1500 IU/mL in the European Union and 700 IU/mL in the United States. However, many patients with SAA have IgE levels >1500 IU/mL, highlighting an unmet need. This review presents the current evidence on the treatment benefits of omalizumab in patients with IgE levels >1500 IU/mL. The findings from the reviewed studies which included >3000 patients support the efficacy and effectiveness of omalizumab in reducing exacerbations, and improving asthma control, lung function, and quality of life in patients with severe asthma having IgE levels beyond the current dosing range. Omalizumab was well-tolerated in these patients, with no new safety signals. In addition, high IgE levels (>1500 IU/mL) are also reported in several comorbidities of asthma (allergic rhinitis, atopic dermatitis, allergic bronchopulmonary aspergillosis [ABPA], food allergy, and nasal polyposis) and omalizumab has demonstrated efficacy and safety in these indications. These data suggest that omalizumab may be considered for administration in SAA patients, with high IgE levels outside the current dosing tables. A detailed assessment of patients with high IgE levels is needed before deciding on the optimal treatment approach. A management algorithm for SAA patients with IgE >1500 IU/mL is proposed in this review and a suggestion to follow the Delphi consensus is advised.

Socio-economic burden and resource utilisation in Italian patients with chronic urticaria: 2-year data from the AWARE study.

INTRODUCTION: In Italy, the real-world evidence on the extent of adherence to guidelines and the benefits of recommended therapeutic medications and their impact on the quality of life (QoL) of H1-antihistamines (H1-AH) refractory chronic urticaria (CU) patients is limited. METHODS: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) was a global prospective, non-interventional study of CU in real-world setting which included patients aged ≥18 years with a medically confirmed diagnosed of CU present for more than 2 months. In this study, the disease characteristics, pharmacological treatments and patient-reported outcomes (PROs) are reported. RESULTS: In total, 159 patients from 24 study centres in Italy completed the study. At baseline, 221 (89.5%) and 8 (3.2%) patients had chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), respectively, while 18 (7.3%) patients had concomitant CSU and CIndU. For CSU patients, mean dermatology life quality index and CU quality of life questionnaire scores reduced to 3.0 ± 4.9 and 14.6 ± 18.6 at Month 24 from baseline scores of 7.5 ± 6.6 and 33.2 ± 19.5, respectively, indicating an improvement in QoL. This was reflected in their work-life as work productivity impairment reduced considerably after 2 years. Only 71.9% CSU patients had a prior treatment, while during the study, 96.8% of the patients were treated with a medication. At baseline, only 52.9% CSU patients reported nonsedating H1-antihistamines as first-line of treatment in prior medication, this increased to 89.6% during current medication. CONCLUSION: This study shows that CSU has a considerable socio-economic burden and an improvement in QoL can be achieved in CSU patients if an appropriate therapeutic path is followed.

Effectiveness of omalizumab in patients with severe allergic asthma with and without chronic rhinosinusitis with nasal polyps: a PROXIMA study post hoc analysis.

BACKGROUND: A significant proportion of patients with severe asthma may also suffer from nasal polyposis, which is commonly defined as chronic rhinosinusitis with nasal polyps (CRSwNP), the presence of which may adversely affect asthma treatment outcomes. The biologic agent omalizumab is effective as add-on therapy in patients with severe allergic asthma. The aim of this post hoc analysis of the PROXIMA study was to compare the efficacy of omalizumab between patients with severe allergic asthma, with and without comorbid CRSwNP. METHODS: PROXIMA was a prospective observational 2-part study conducted in Italy in adult patients with severe allergic asthma, where, in the second part, patients eligible for add-on omalizumab initiated treatment for 12 months. Patient baseline data such as comorbidities and history of exacerbations were collected. Outcomes were asthma control (Asthma Control Questionnaire [ACQ]), lung function (forced expiratory volume in 1 s [FEV1]) and exacerbation rate. The post hoc analysis compared these outcomes between the cohort with comorbid CRSwNP and the cohort without CRSwNP. RESULTS: Of 123 patients included in this analysis, 17 (13.8%) were in the CRSwNP cohort. There was no significant difference between cohorts in baseline clinical characteristics or in change from baseline at 12 months in ACQ values,  % of predicted FEV1 or annual asthma exacerbation rate, although results were numerically in favor of the CRSwNP cohort versus the non-CRSwNP cohort. The proportion of patients who achieved an improvement in all three outcomes was numerically greater in the CRSwNP cohort (35.7% vs 23.0%). CONCLUSIONS: In an observational real-world setting, add-on omalizumab for severe allergic asthma was effective in improving asthma control, lung function and in reducing exacerbations, including in those patients with CRSwNP.

Plasma Galectin-3 and urine proteomics predict FEV1 improvement in omalizumab-treated patients with severe allergic asthma: Results from the PROXIMA sub-study.

BACKGROUND: Patients with severe allergic asthma (SAA) when treated with omalizumab may exhibit different extent of response. Identifying biomarkers that can predict the extent of treatment effectiveness in patients can be useful in personalizing omalizumab treatment. METHODS: Patients from the longitudinal phase of the PROXIMA study were selected for this ancillary study. After 12 months of omalizumab treatment, patients were categorized according to their response to treatment as: "clinical responder" (Asthma Control Questionnaire [ACQ] total score <1 at Month 12 and/or with a reduction in number of exacerbation versus the previous year); "functional responder" (an increment of ≥0.1 L in forced expiratory volume in 1 s [FEV1] at Month 12 versus baseline); and "super responder" (among clinical responders group, who also showed a functional response). Plasma galectin-3 (GAL-3) levels were quantified using a micro titer plate-based enzyme linked immunosorbent assay kit. RESULTS: The Majority of patients (86.36%) in sub-study population were identified as clinical responders. Of the total patients identified as clinical responders, 64.86% were identified as super responders. A statistically significant difference in the baseline plasma GAL-3 levels between responders and non-responders was observed only in the functional responders group (P = 0.0446). Patients with plasma GAL-3 level of ≥11 ng/mL had a greater probability of being a super responder (P = 0.0118) or a functional responder (P = 0.0032). CONCLUSION: Our findings support the use of plasma GAL-3 as a predictive marker to stratify responders and identify super responders and functional responders to omalizumab treatment in patients with severe allergic asthma using less invasive sample like plasma.

Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth.

The microbiota has been shown to promote intestinal tumourigenesis, but a possible anti-tumourigenic effect has also been postulated. Here, we demonstrate that changes in the microbiota and mucus composition are concomitant with tumourigenesis. We identified two anti-tumourigenic strains of the microbiota-Faecalibaculum rodentium and its human homologue, Holdemanella biformis-that are strongly under-represented during tumourigenesis. Reconstitution of ApcMin/+ or azoxymethane- and dextran sulfate sodium-treated mice with an isolate of F. rodentium (F. PB1) or its metabolic products reduced tumour growth. Both F. PB1 and H. biformis produced short-chain fatty acids that contributed to control protein acetylation and tumour cell proliferation by inhibiting calcineurin and NFATc3 activation in mouse and human settings. We have thus identified endogenous anti-tumourigenic bacterial strains with strong diagnostic, therapeutic and translational potential.

Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors.

Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.

Lymph node hyperplasia: clonal chromosomal and genomic rearrangements. Report of two new cases and literature review.

Cytogenetic analysis is not routinely performed on lymph node hyperplasia (LH). We describe clonal chromosomal rearrangements in two unrelated cases of LH. Lymph nodes of both patients showed typical morphologic features of benign follicular hyperplasia. Cytogenetic analysis revealed clonal chromosomal rearrangements in both cases. Patient 1 showed interstitial 14q and 6q mosaic deletions, whereas patient 2 showed a terminal 14q mosaic deletion. Fluorescence in situ hybridization with IGH break-apart probes identified a partial deletion of IGH in both cases, but the loss of the LSI IGH in patient 2 and loss of the LSI IGHV in patient 1 were observed on the morphologically normal chromosome 14. In the latter case, the finding of two morphologically normal chromosomes 14 with the IGHV deletion in one of the chromosomes suggested that the first mutational event was the IGH deletion and the second event was the interstitial deletion of chromosome 14 with the IGH intact. Array comparative genomic hybridization performed on both biopsies confirmed the IGH deletion at mosaic, but not the chromosomal deletion. Patient 1 was re-biopsied after 9 months and a marginal zone lymphoma was diagnosed. The finding of clonal cytogenetic abnormalities in LH highlighted the difficulties in interpretation of results and clinical follow-up.

The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

Investigating the role of X chromosome breakpoints in premature ovarian failure.

The importance of the genetic factor in the aetiology of premature ovarian failure (POF) is emphasized by the high percentage of familial cases and X chromosome abnormalities account for 10% of chromosomal aberrations. In this study, we report the detailed analysis of 4 chromosomal abnormalities involving the X chromosome and associated with POF that were detected during a screening of 269 affected women. Conventional and molecular cytogenetics were valuable tools for locating the breakpoint regions and thus the following karyotypes were defined: 46,X,der(X)t(X;19)(p21.1;q13.42)mat, 46,X,t(X;2)(q21.33;q14.3)dn, 46,X,der(X)t(X;Y)(q26.2;q11.223)mat and 46,X,t(X;13)(q13.3;q31)dn. A bioinformatic analysis of the breakpoint regions identified putative candidate genes for ovarian failure near the breakpoint regions on the X chromosome or on autosomes that were involved in the translocation event. HS6ST1, HS6ST2 and MATER genes were identified and their functions and a literature review revealed an interesting connection to the POF phenotype. Moreover, the 19q13.32 locus is associated with the age of onset of the natural menopause. These results support the position effect of the breakpoint on flanking genes, and cytogenetic techniques, in combination with bioinformatic analysis, may help to improve what is known about this puzzling disorder and its diagnostic potential.

Cytogenetics of premature ovarian failure: an investigation on 269 affected women.

The importance of X chromosome in the aetiology of premature ovarian failure (POF) is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause.

Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity.

Antigen-presenting dendritic cells (DCs) trigger the activation of cytotoxic CD8 T cells that target and eliminate cells with the antigen on their surface. Although DCs usually pick up and process antigens themselves, they can also receive peptide antigens from other cells via gap junctions. We demonstrate here that infection with Salmonella can induce, in both human and murine melanoma cells, the up-regulation of connexin 43 (Cx43), a ubiquitous protein that forms gap junctions and that is normally lost during melanoma progression. Bacteria-treated melanoma cells can establish functional gap junctions with adjacent DCs. After bacterial infection, these gap junctions transferred preprocessed antigenic peptides from the tumor cells to the DCs, which then presented those peptides on their surface. These peptides activated cytotoxic T cells against the tumor antigen, which could control the growth of distant uninfected tumors. Melanoma cells in which Cx43 had been silenced, when infected in vivo with bacteria, failed to elicit a cytotoxic antitumor response, indicating that this Cx43 mechanism is the principal one used in vivo for the generation of antitumor responses. The Cx43-dependent cross-presentation pathway is more effective than standard protocols of DC loading (peptide, tumor lysates, or apoptotic bodies) for generating DC-based tumor vaccines that both inhibit existing tumors and prevent tumor establishment. In conclusion, we exploited an antimicrobial response present in tumor cells to activate cytotoxic CD8 T cells specific for tumor-generated peptides that could directly recognize and kill tumor cells.

TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells.

Skin cancers are the most commonly diagnosed cancers. Understanding what are the factors contributing to skin tumour development can be instrumental to identify preventive therapies. The myeloid differentiation primary response gene (MyD)88, the downstream adaptor protein of most Toll-like receptors (TLR), has been shown to be involved in several mouse tumourigenesis models. We show here that TLR4, but not TLR2 or TLR9, is upstream of MyD88 in skin tumourigenesis. TLR4 triggering is not dependent on lipopolysaccharide associated to skin-colonizing bacteria, but on the high mobility group box-1 protein (HMGB1), an endogenous ligand of TLR4. HMGB1 is released by necrotic keratinocytes and is required for the recruitment of inflammatory cells and for the initiation of inflammation. The expression of TLR4 on both bone marrow-derived and radioresistant cells is necessary for carcinogenesis. Consistently, a human tissue microarray analysis showed that melanoma and colon cancer display an over-expression of TLR4 and its downstream adaptor protein MyD88 within tumours. Together, our results suggest that the initial release of HMGB1 triggers a TLR4-dependent inflammatory response that leads to tumour development.

Intra-tumoral Salmonella typhimurium induces a systemic anti-tumor immune response that is directed by low-dose radiation to treat distal disease.

Salmonella typhimurium is a facultative anaerobic bacterium able to multiply preferentially in tumors and inhibit their growth. The mechanisms through which Salmonella exerts its anti-cancer properties are not fully understood. We recently showed that intra-tumoral Salmonella injection results not only in the regression of even bulky tumor masses, but also impacts on the growth of distant untreated lesions. Here we describe how Salmonella exerts its systemic anti-cancer effects and means to potentiate them. The outburst of an early inflammatory reaction in the treated tumor promotes the development of an immunostimulatory cytokine environment both locally and in the draining lymph node. Within the next 10 days, an efficient cross-presentation of endogenous tumor antigens by dendritic cells at the tumor-draining lymph node leads to the priming of effective anti-tumor CD8+ T cell responses. This potentially broadly reactive T cell repertoire can be directed to other pre-established melanomas by low-dose radiotherapy enhancing the Salmonella anti-cancer effect. We demonstrate that Salmonella-based therapy coupled to low-dose radiotherapy dampens tumor immune escape mechanisms at different levels and allows controlling systemic disease in a CD8+ T cell-dependent manner.