Coexistence of Eosinophilic Granulomatosis With Polyangiitis and Allergic Bronchopulmonary Aspergillosis: A Fascinating Relationship.

Elevated eosinophil counts are associated with various diseases, including eosinophilic granulomatosis with polyangiitis (EGPA) and allergic bronchopulmonary aspergillosis (ABPA). EGPA is a rare small-vessel vasculitis characterized by asthma, eosinophilia, fleeting pulmonary infiltrates, and systemic manifestations. ABPA, initiated by immune reactions against Aspergillus fumigatus in the airways, presents with poorly controlled asthma, wheezing, hemoptysis, productive cough, and systemic symptoms, which result in characteristic central bronchiectasis. Fleeting pulmonary opacities are common radiologic findings. We present a case of ABPA in a patient with a prior EGPA diagnosis under treatment with mepolizumab 300 mg monthly and review eight similar cases from the literature. In these cases, EGPA and ABPA diagnoses preceded each other or were concurrent. Treatment of the latter improved control of both diseases. IL-5 is pivotal in EGPA pathogenesis, and mepolizumab, targeting IL-5, has been effective in EGPA treatment. Our patient received mepolizumab for EGPA and continued it post-ABPA diagnosis, showing favorable outcomes. This suggests mepolizumab as a therapeutic link between EGPA and ABPA. Mepolizumab therapy holds promise for managing both EGPA and ABPA. Double-blind placebo-controlled studies are warranted to establish its efficacy and safety for ABPA, emphasizing the need for further research in this area.

The role of new staplers in reducing the incidence of air leak.

Surgical staplers play an important role in the contemporary minimally invasive thoracic surgery including resection of lung tissue. However, staple line failure resulting in postoperative air leaks is a common complication after lung surgery, that if persist more than five days are defined as prolonged air leaks (PALs). PALs are associated with increased length of stay, patient morbidity and mortality, and hospital costs. To reduce the incidence of PALs, stapler devices underwent in the last years ongoing development aimed at improving device-to-tissue interaction. This clinical practice review explores the most important aspects of the evolution of surgical staplers, based on the review of the available literature. Modern staple cartridges entail small bumps to engage tissue and minimize tissue movement during compression and firing. Staplers with graduated staple heights are advocated to generate less stress on tissue during compression and clamping, thus affording greater perfusion into the staple line. However, air leaks may occur from an appropriate staple line with complete pleural coverage and perfusion due to enlarged staple canals after lung inflation, particularly in case of emphysema. To buttress staple line, thus prevent air leaks in high-risk patients, several types of tissue coverage (bovine pericardium, polytetrafluoroethylene, knitted calcium alginate, bioabsorbable polyglycolic acid) have been successfully developed in the last years. Finally, the most advanced stapler technology is represented by the new energy powered staplers, able to eliminate the manual firing force, monitor tissue compression during firing, and making automatic adjustments to optimize the staple line.

Using text data instead of SIC codes to tag innovative firms and classify industrial activities.

The paper uses text mining and semantic algorithms to tag innovative firms and offer an alternative perspective to classify industrial activities. Instead of referring to firms' standard industrial classification codes, we gather information from companies' websites and corporate purposes, extract keywords and generate tags concerning firms' activities, specializations, and competences. Evidence is interesting because allows us to understand 'what firms do' in a more penetrating and updated way than referring to standard industrial classification codes. Moreover, through matching firms' keywords, we can explore the degree of closeness between the firms under observation, a measure by which researchers can derive industrial proximity. The analysis can provide policymakers with a detailed and comprehensive picture of the innovative trajectories underlying the industrial structure in a geographic area.

A Delphi Consensus report from the "Prolonged Air Leak: A Survey" study group on prevention and management of postoperative air leaks after minimally invasive anatomical resections.

OBJECTIVES: This study reports the results of an international expert consensus process evaluating the assessment of intraoperative air leaks (IAL) and treatment of postoperative prolonged air leaks (PAL) utilizing a Delphi process, with the aim of helping standardization and improving practice. METHODS: A panel of 45 questions was developed and submitted to an international working group of experts in minimally invasive lung cancer surgery. Modified Delphi methodology was used to review responses, including 3 rounds of voting. The consensus was defined a priori as >50% agreement among the experts. Clinical practice standards were graded as recommended or highly recommended if 50-74% or >75% of the experts reached an agreement, respectively. RESULTS: A total of 32 experts from 18 countries completed the questionnaires in all 3 rounds. Respondents agreed that PAL are defined as >5 days and that current risk models are rarely used. The consensus was reached in 33/45 issues (73.3%). IAL were classified as mild (<100 ml/min; 81%), moderate (100-400 ml/min; 71%) and severe (>400 ml/min; 74%). If mild IAL are detected, 68% do not treat; if moderate, consensus was not; if severe, 90% favoured treatment. CONCLUSIONS: This expert consensus working group reached an agreement on the majority of issues regarding the detection and management of IAL and PAL. In the absence of prospective, randomized evidence supporting most of these clinical decisions, this document may serve as a guideline to reduce practice variation.

High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma.

Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5'-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08−3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57−1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30−2.08)) and SCC (p = 0.217, HR 0.86 (0.68−1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065).

Peanut allergy in Italy: A unique Italian perspective.

Background: Peanut allergy has not been well characterized in Italy. Objective: Our aim was to better define the clinical features of peanut allergy in Italy and to detect the peanut proteins involved in allergic reactions. Methods: A total of 22 centers participated in a prospective survey of peanut allergy over a 6-month period. Clinical histories were confirmed by in vivo and/or in vitro diagnostic means in all cases. Potential risk factors for peanut allergy occurrence were considered. Levels of IgE to Arachis hypogea (Ara h) 1, 2, 3, 6, 8, and 9 and profilin were measured. Results: A total of 395 patients (aged 2-80 years) were enrolled. Of the participants, 35% reported local reactions, 38.2% reported systemic reactions, and 26.6% experienced anaphylaxis. The sensitization profile was dominated by Ara h 9 (77% of patients were sensitized to it), whereas 35% were sensitized to pathogenesis-related protein 10 (PR-10) and 26% were sensitized to seed storage proteins (SSPs). Sensitization to 2S albumins (Ara h 2 and Ara h 6) or lipid transfer protein (LTP) was associated with the occurrence of more severe symptoms, whereas profilin and PR-10 sensitization were associated with milder symptoms. Cosensitization to profilin reduced the risk of severe reactions in both Ara h 2- and LTP-sensitized patients. SSP sensitization prevailed in younger patients whereas LTP prevailed in older patients (P < .01). SSP sensitization occurred mainly in northern Italy, whereas LTP sensitization prevailed in Italy's center and south. Atopic dermatitis, frequency of peanut ingestion, peanut consumption by other family members, or use of peanut butter did not seem to be risk factors for peanut allergy onset. Conclusions: In Italy, peanut allergy is rare and dominated by LTP in the country's center and south and by SSP in the north. These 2 sensitizations seem mutually exclusive. The picture differs from that in Anglo-Saxon countries.

Systemic allergic reactions induced by labile plant-food allergens: Seeking potential cofactors. A multicenter study.

BACKGROUND: Heat-and-pepsin-sensitive plant food allergens (PR-10 and profilin) sometimes cause systemic reaction. OBJECTIVE: To detect the risk factors for systemic reactions induced by labile food allergens. METHODS: A retrospective multicenter study was performed on patients with a documented history of systemic allergic reaction to labile plant food allergens and on age-matched controls with a history of oral allergy syndrome (OAS) induced by the same foods. Offending foods, their amount, and state (solid or liquid), and potential cofactors (nonsteroidal anti-inflammatory drugs, protonic pump inhibitors, exercise, alcohol, and fasting) were considered. RESULTS: We studied 89 patients and 81 controls. Sensitization to PR-10 or profilin, IgE to Bet v 1 and/or Bet v 2, and foods causing OAS were similar in the two groups. Twenty patients experienced >1 systemic allergic reaction. Tree nuts, Rosaceae, Apiaceae, and soymilk were the main offending foods. Seventeen (19%) patients were taking a PPI when the systemic reaction occurred (vs 5% in controls; P < .025). The ingestion of the offending food in liquid form (soymilk) was frequent among patients (15%) but unusual among controls (2%; P < .025). Soy milk-induced systemic reactions were independent of PPI treatment. Fasting and excess of allergen, but not NSAID and exercise, were other relevant cofactors for systemic reactions. Systemic reactions occurred without any identifiable cofactor in 39 (44%) cases. CONCLUSION: PR-10- and profilin-induced systemic reactions are facilitated by PPI, ingestion of large amounts of unprocessed foods, and fasting. Soybean beverages represent a risk for PR-10 hypersensitive patients and should be avoided.

NOP10 predicts lung cancer prognosis and its associated small nucleolar RNAs drive proliferation and migration.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.

Tumor infiltrating T cells influence prognosis in stage I-III non-small cell lung cancer.

BACKGROUND: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4+ T helper cells (Th), CD8+ cytotoxic (Tc) and FOXP3+ regulatory T (Treg) cells in NSCLC, we performed this analysis. METHODS: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral Th cells, Treg cells and Tc cells in n=294 NSCLC patients with pTNM stage I-III disease. RESULTS: Strong CD4+ infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4+ infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio <1 was associated with high grade NSCLC tumors (P=0.020). High CD8+ T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8+ infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3+ expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). CONCLUSIONS: High proportion of CD8+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC. Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.

Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I-III NSCLC.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer-associated fibroblasts (CAFs) are reported to regulate this process. OBJECTIVES: To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non-small cell lung cancer (NSCLC). METHODS: Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I-III disease. All tissue samples were embedded on tissue microarrays (TMAs). RESULTS: Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I-III NSCLC). Besides, SMA+ expression correlated with higher pTNM-tumor stages and lymphatic spread (pN stage). In turn, SMA-negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage). CONCLUSIONS: CD34 was identified as an independent prognostic marker in pTNM stage I-III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC. KEY POINTS: Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I-III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.

Reptin drives tumour progression and resistance to chemotherapy in nonsmall cell lung cancer.

While targeted nonsmall cell lung cancer (NSCLC) therapies have improved the outcome of defined disease subtypes, prognosis for most patients remains poor. We found the AAA+ ATPase Reptin to be highly expressed in the vast majority of 278 NSCLC tumour samples. Thus, the objective of the study was to assess the role of Reptin in NSCLC.Survival analyses of 1145 NSCLC patients revealed that high RNA expression levels of Reptin are associated with adverse outcome. Knockdown of Reptin in human NSCLC cells impaired growth ex vivo and eliminated engraftment in a xenograft model. Reptin directly interacted with histone deacetylase 1 (HDAC1) as the critical mechanism driving NSCLC tumour progression. Pharmacological disruption of the Reptin/HDAC1 complex resulted in a substantial decrease in NSCLC cell proliferation and induced significant sensitisation to cisplatin.Our results identify Reptin as a novel independent prognostic factor and as a key regulator mediating proliferation and clonal growth of human NSCLC cells ex vivo and in vivo We unveil a Reptin/HDAC1 protein complex whose pharmacological disruption sensitises NSCLC cells to cisplatin, suggesting this approach for application in clinical trials.

[Modern Management of Pancoast Tumour]. / Modernes Management des Pancoast-Tumors.

Pancoast or superior pulmonary sulcus tumour is a subset of lung carcinoma that invades the structures of the thoracic inlet - first ribs, distal roots of the brachial plexus, stellate ganglion, vertebrae, and subclavian vessels. The first symptom is usually shoulder pain; consequently, most patients are initially treated for osteoarthritis. Late diagnosis is common. Success of therapy depends on an accurate staging: standard imaging with CT scan of the chest, PET-CT scan, brain MRI are needed to rule out distant metastases, endobronchial ultrasound-guided needle biopsy (EBUS-TBNA) or mediastinoscopy are mandatory for reliable nodal staging. An MRI of the thoracic inlet allows to clearly define the boundaries of local invasion. Modern management of Pancoast tumour includes induction concurrent chemoradiotherapy followed by surgical resection. As compared with historical series treated by preoperative radiation, a trimodally approach did enhance complete resection rates and perhaps long-term survival - from about 30% 5-year survival rate to 60% in R0-resected patients. In patients who have unresectable but non-metastatic Pancoast tumours and appropriate performance status, definitive concurrent chemoradiotherapy and radiotherapy are recommended options.

Outbreak of febrile gastroenteritis caused by Listeria monocytogenes 1/2a in sliced cold beef ham, Italy, May 2016.

In May 2016, two separate clusters of febrile gastroenteritis caused by Listeria monocytogenes were detected by the local health authority in Piedmont, in northern Italy. We carried out epidemiological, microbiological and traceback investigations to identify the source. The people affected were students and staff members from two different schools in two different villages located in the Province of Turin; five of them were hospitalised. The epidemiological investigation identified a cooked beef ham served at the school canteens as the source of the food-borne outbreak. L. monocytogenes was isolated from the food, the stools of the hospitalised pupils and the environment of the factory producing the cooked beef ham. All isolates except one were serotype 1/2a, shared an indistinguishable PFGE pattern and were 100% identical by whole genome sequencing (WGS). By combining a classical epidemiological approach with both molecular subtyping and WGS techniques, we were able to identify and confirm a Listeria gastroenteritis outbreak associated with consumption of sliced cold beef ham.

Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer.

OBJECTIVES: PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated. RESULTS: PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases. CONCLUSION: Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.

Correction: Potential therapeutic impact of CD13 expression in non-small cell lung cancer.

[This corrects the article DOI: 10.1371/journal.pone.0177146.].

Potential therapeutic impact of CD13 expression in non-small cell lung cancer.

BACKGROUND: Aminopeptidase N (CD13) is a zinc-binding protease that has functional effects on both cancerogenesis and tumor angiogenesis. Since CD13 is an antigen suitable for molecular targeted therapies (e.g. tTF-NGR induced tumor vascular infarction), we evaluated its impact in NSCLC patients, and tested the effects of the CD13-targeted fusion protein tTF-NGR (truncated tissue factor (tTF) containing the NGR motif: asparagine-glycine-arginine) in vivo in nude mice. METHODS: Expression of both CD13 and CD31 was studied in 270 NSCLC patients by immunohistochemistry. Clinical correlations and prognostic effects of the expression profiles were analyzed using univariate and multivariate analyses. In addition, a microarray-based analysis on the basis of the KM plotter database was performed. The in vivo effects of the CD13-targeted fusion protein tTF-NGR on tumor growth were tested in CD1 nude mice carrying A549 lung carcinoma xenotransplants. RESULTS: CD13 expression in tumor endothelial and vessel associated stromal cells was found in 15% of the investigated samples, while expression in tumor cells was observed in 7%. Although no significant prognostic impact was observed in the full NSCLC study cohort, both univariate and multivariate models identified vascular CD13 protein expression to correlate with poor overall survival in stage III and pN2+ NSCLC patients. Microarray-based mRNA analysis for either adenocarcinomas or squamous cell carcinomas did not reveal any significant effect. However, the analysis of CD13 mRNA expression for all lung cancer histologies demonstrated a positive prognostic effect. In vivo, systemic application of CD13-targeted tissue factor tTF-NGR significantly reduced CD13+ A549 tumor growth in nude mice. CONCLUSIONS: Our results contribute a data basis for prioritizing clinical testing of tTF-NGR and other antitumor molecules targeted by NGR-peptides in NSCLC. Because CD13 expression in NSCLC tissues was found only in a specific subset of NSCLC patients, rigorous pre-therapeutic testing will help to select patients for these studies.

In systemic sclerosis skin perfusion of hands is reduced and may predict the occurrence of new digital ulcers.

Systemic sclerosis (SSc) patients are at high risk for the development of ischemic digital ulcers (DUs). The aim of this study was to assess in SSc patients a correlation between skin perfusion evaluated by LDPI and DUs and to evaluate the prognostic value of skin perfusion to predict the new DUs occurrence. Fifty eight (47 female, 11 male) SSc patients were enrolled. Skin perfusion of hands and region of interest (ROIs) was measured by Laser Doppler perfusion Imager (LDPI). The proximal-distal gradient (PDG) was present when the perfusion mean difference between ROI1 and ROI2 was >30 pU. The skin perfusion of hands is lower in SSc patients than in healthy controls. The skin perfusion decreased with severity of capillaroscopic damage. Both mean perfusion of hand and PDG are significantly (p<0.01 and p<0.0001, respectively) lower in SSc patients with new DUs than in SSc patients without DUs. Only 2 of 11 SSc patients (18.2%) with PDG developed new digital ulcers, conversely 36 of 47 (76.6%) SSc patients without PDG developed new digital ulcers (p<0.001). The ROC curves demonstrated a good accuracy of new DUs prediction for PDG (0.78, p<0.0001). Using this cut-off value of 30 pU, RR for new DUs development in SSc patients without PDG is 4,2 (p<0.001). LDPI indices could be used in association to the capillaroscopic and clinical findings or serological tests in the identification of patients at high risk of developing DUs.