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To study the relationship between standardized 18F-FDG PET/CT radiomic features and clinicopathological variables and programmed death ligand-1 (PD-L1) expression status in non-small cell lung cancer (NSCLC) patients.58 NSCLC patients with preoperative 18F-FDG PET/CT scans and postoperative results of PD-L1 expression were retrospectively analysed. A standardized, open-source software was used to extract 86 radiomic features from PET and low-dose CT images. Univariate analysis and multivariate logistic regression were used to find independent predictors of PD-L1 expression. The Area Under the Curve (AUC) of receiver operating characteristic (ROC) curve was used to compare the ability of variables and their combination in predicting PD-L1 expression.Multivariate logistic regression resulted in the PET radiomic feature GLRLM_LGRE (Odds Rate (OR): 0.300 vs 0.114, 95% confidence interval (CI): 0.096-0.931 vs 0.021-0.616, in NSCLC and adenocarcinoma respectively) and the CT radiomic feature GLZLM_SZE (OR: 3.338 vs 7.504, 95%CI: 1.074-10.375 vs 1.382-40.755, in NSCLC and adenocarcinoma respectively), being independent predictors of PD-L1 status. In NSCLC group, after adjusting for gender and histology, the PET radiomic feature GLRLM_LGRE (OR: 0.282, 95%CI: 0.085-0.936) remained an independent predictor for PD-L1 status. In the adenocarcinoma group, when adjusting for gender the PET radiomic feature GLRLM_LGRE (OR: 0.115, 95%CI: 0.021-0.631) and the CT radiomic feature GLZLM_SZE (OR: 7.343, 95%CI: 1.285-41.965) remained associated with PD-L1 expression.NSCLC and adenocarcinoma with PD-L1 expression show higher tumour heterogeneity. Heterogeneity-related 18F-FDG PET and CT radiomic features showed good ability to non-invasively predict PD-L1 expression.ZIEL: Untersuchung der Beziehung zwischen standardisierten 18F-FDG-PET/CT-Radiomics-Merkmalen, klinisch-pathologischen Variablen und der Expression des Programmed Death Ligand 1 (PD-L1) bei Patienten mit nichtkleinzelligem Bronchialkarzinom (non-small cell lung cancer, NSCLC).58 NSCLC-Patienten mit präoperativen 18F-FDG-PET/CT-Scans und postoperativen Befunden zur PD-L1-Expression wurden retrospektiv analysiert. Eine standardisierte Open-Source-Software wurde verwendet, um 86 Radiomics-Merkmale aus PET- und Niedrigdosis-CT-Bildern zu extrahieren. Univariate Analyse und multivariate logistische Regression wurden verwendet, um unabhängige Prädiktoren für die PD-L1-Expression zu ermitteln. Die Fläche unter der Kurve (AUC) der Receiver-Operating-Characteristic (ROC) -Kurve wurde verwendet, um die Fähigkeit der Variablen und ihrer Kombination bei der Vorhersage der PD-L1-Expression zu vergleichen.Die multivariate logistische Regression ergab das PET-Radiomics-Merkmal GLRLM_LGRE (Odds Ratio (OR): 0,300 vs. 0,114, 95%-Konfidenzintervall (KI): 0,096–0,931 vs. 0,021–0,616, bei NSCLC bzw. Adenokarzinom) und das CT-Radiomics-Merkmal GLZLM_SZE (OR: 3,338 vs. 7,504, 95%-KI: 1,074–10,375 vs. 1,382–40,755, bei NSCLC bzw. Adenokarzinom), wobei es sich um unabhängige Prädiktoren für den PD-L1-Status handelt.In der NSCLC-Gruppe blieb das PET-Radiomics-Merkmal GLRLM_LGRE (OR: 0,282, 95%-KI: 0,085–0,936) nach Berücksichtigung von Geschlecht und Histologie ein unabhängiger Prädiktor für den PD-L1-Status. In der Adenokarzinom-Gruppe waren nach Berücksichtigung des Geschlechts das PET-Radiomics-Merkmal GLRLM_LGRE (OR: 0,115, 95%-KI: 0,021–0,631) und das CT-Radiomics-Merkmal GLZLM_SZE (OR: 7,343, 95%-KI: 1,285–41,965) mit der PD-L1-Expression assoziiert.NSCLC und Adenokarzinome mit PD-L1-Expression zeigen eine höhere Tumorheterogenität. Heterogenitätsbezogene 18F-FDG-PET- und CT-Radiomics-Merkmale zeigten eine gute Fähigkeit zur nichtinvasiven Vorhersage der PD-L1-Expression.

Background and Objectives: Interstitial lung diseases have always been an issue for pulmonary and rheumatology physicians. Computed tomography scans with a high-resolution protocol and bronchoalveolar lavage have been used along with biochemical blood tests to reach a diagnosis. Materials and Methods: We included 80 patients in total. First, all patients had their diagnosis with computed tomography of the thorax, serological/ immunological blood tests and bronchoalveolar lavage. However; after 3 months, all were divided into 2 groups: those who had bronchoalveolar lavage again and those who had cryobiopsy instead of bronchoalveolar lavage (40/40). Positron emission-computed tomography was also performed upon the first and second diagnosis. The patients’ follow-up was 4 years from diagnosis. Results: Patients suffered most from chronic obstructive pulmonary disease (56, 70%), while lung cancer was rarely encountered in the sample (7, 9.75%). Age distribution ranged between 53 and 68 years with a mean value of 60 years. The computed tomography findings revealed 25 patients with typical diagnosis (35.2%), 17 with interstitial pulmonary fibrosis (23.9%) and 11 with probable diagnosis (11%). The cryobiopsy technique led to a new diagnosis in 28 patients (35% of the total sample). Patients who had a new diagnosis with cryobiopsy had a mean survival time of 710 days (

Supplementary Figure S7. Coding variants detected in MPM cell cultures and their relation to TERT promoter status.

Supplementary Material and Methods

Supplementary Table S6

Purpose:Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.Experimental Design:TERT promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for in vitro immortalization. The respective MPM cell models (N = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.Results:TERT promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. TERT promoter–mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While BAP1 mutations/deletions were exclusive with TERT promoter mutations, homozygous deletions at the RBFOX1 and the GSTT1 loci were clearly enriched in mutated cases.Conclusions:TERT promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.

Supplementary Tables S1 to S9 with the exception of Supplementary Table S6

Supplementary Table 1 from Genome-Wide Transcriptional Response to 5-Aza-2′-Deoxycytidine and Trichostatin A in Multiple Myeloma Cells

Supplementary Figure 1 from Genome-Wide Transcriptional Response to 5-Aza-2′-Deoxycytidine and Trichostatin A in Multiple Myeloma Cells

To identify epigenetically silenced cancer-related genes and to determine molecular effects of 5-aza-2′-deoxycytidine (Aza-dC) and/or trichostatin A (TSA) in multiple myeloma (MM), we analyzed global changes in gene expression profiles of three MM cell lines by microarray analysis. We identified up-regulation of several genes whose epigenetic silencing in MM is well known. However, much more importantly, we identified a large number of epigenetically inactivated cancer-related genes that are involved in various physiologic processes and whose epigenetic regulation in MM was unknown thus far. In addition, drug treatment of MM cell lines resulted in down-regulation of several MM proliferation-associated factors (i.e., MAF, CCND1/2, MYC, FGFR3, MMSET). Ten Aza-dC and/or TSA up-regulated genes (CPEB1, CD9, GJA1, BCL7c, GADD45G, AKAP12, TFPI2, CCNA1, SPARC, and BNIP3) were selected for methylation analysis in six MM cell lines, 24 samples from patients with monoclonal gammopathy of undetermined significance (MGUS), and 111 samples from patients with MM. Methylation frequencies of these genes ranged between 0% and 17% in MGUS samples and between 5% and 50% in MM samples. Interestingly, methylation of SPARC and BNIP3 was statistically significantly associated with a poor overall survival of MM patients (P = 0.003 and P = 0.017, respectively). Moreover, SPARC methylation was associated with loss of SPARC protein expression by immunostaining in a subset of MM patients. In conclusion, we identified new targets for aberrant methylation in monoclonal gammopathies, and our results suggest that DNA methyltransferase and histone deacetylase inhibition might play an important role in the future treatment of patients with MM. [Cancer Res 2008;68(1):44–54]

Supplementary Table 3 from Genome-Wide Transcriptional Response to 5-Aza-2′-Deoxycytidine and Trichostatin A in Multiple Myeloma Cells

Supplementary Table 2 from Genome-Wide Transcriptional Response to 5-Aza-2′-Deoxycytidine and Trichostatin A in Multiple Myeloma Cells

Supplementary Table 4 from Genome-Wide Transcriptional Response to 5-Aza-2′-Deoxycytidine and Trichostatin A in Multiple Myeloma Cells

Introdução: Os sarcomas primários do pulmão são tumores malignos raros com incidência estimada em torno de 0,5% de todas as neoplasias pulmonares. De suas tipificações descritas na literatura, duas especialmente, os leiomiossarcomas e os rabdomiossarcomas, apresentam semelhanças em seu perfil genético, morfológico e imuno-histoquímico, o que os levou a receberem uma mesma classificação: tumor rabdomioblástico inflamatório. Esse tipo de tumor costuma acometer tecidos moles em extremidades e tronco, e predomina em meio a homens jovens e de meia-idade. Em razão do pequeno número de casos de tumores rabdomioblásticos relatados na literatura, tanto seu diagnóstico quanto seu tratamento são pouco descritos. Relato de caso: Paciente, sexo feminino, 19 anos, apresentou três episódios de infecção respiratória no lobo inferior do pulmão direito em um período de 18 meses. A tomografia computadorizada do tórax evidenciou obstrução do brônquio intermediário e áreas de bronquiectasias no lobo inferior direito. Diante disso, realizou-se bilobectomia inferior-média, conduzida por cirurgia robótica. A paciente recebeu alta hospitalar três dias depois do pós-operatório. A imuno-histoquímica revelou tumor rabdomioblástico inflamatório de baixo grau. Conclusão: Este relato apresentou um caso de tumor pulmonar raro, abordado por uma técnica cirúrgica ainda não relatada para esse tipo de patologia.

Background The contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. More importantly, the risk of fomite-based transmission has not been systematically addressed. Therefore, the aim of this study was to evaluate whether confirmed hospitalized coronavirus disease 2019 (COVID-19) patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. Methods We initiated a single-center observational study including 15 COVID-19 patients with a high baseline viral load (cycle threshold value ≤25). We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative polymerase chain reaction, and virus sequencing. Results Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral ribonucleic acid on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2%). After coughing, no infectious virus could be recovered, however, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5%). Conclusions Transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but it is unlikely to occur in real-life scenarios and from droplet-contaminated fomites.

Whipple's disease (WD) is a rare and infectious condition leading to multi-organ impairment caused by Tropheryma whipplei (TW), a ubiquitously occurring bacterium. TW can be detected in tissues by histological detection of PAS ("periodic acid-ship reaction")-positive macrophages and by polymerase-chain-reaction (PCR). Clinically, WD is often characterized by diarrhea, abdominal pain, and weight loss. These symptoms are also typical for a flare in Crohn's disease (CD) and, therefore, can lead to fatal misdiagnosis and wrong treatment by using biologics (e.g., anti-TNF-α).We here report a young male patient with pre-existing CD. The patient's symptoms were misinterpreted as a flare of CD and illustrate the multifaceted nature of WD. After intensifying immunosuppressive therapy, the patient developed therapy-refractory diarrhea with several opportunistic infections with a final, fatal outcome.Patients with inflammatory bowel disease (IBD) are not only at risk from infectious complications known with clostridium difficile or cytomegalovirus (CMV); infection with WD should also be ruled out by endoscopy and biopsy before the escalation of the immunosuppressive regime.Der Morbus Whipple (WD) ist eine seltene und infektiöse Erkrankung, die zu Multi-Organbefall führen kann, ausgelöst durch Tropheryma whipplei (TW), ein allgegenwärtig vorkommendes Bakterium. TW kann im Gewebe durch histologischen Nachweis von PAS (“Periodic Acid-Ship Reaction”)-positiven Makrophagen und durch Polymerasekettenreaktion (PCR) nachgewiesen werden. Klinisch ist WD häufig durch Durchfall, Bauchschmerzen und Gewichtsverlust gekennzeichnet. Diese Symptome sind aber auch typisch für einen Schub bei Morbus Crohn und können daher zur Fehldiagnose und falscher Behandlung unter Verwendung von Biologika (z.B. anti-TNF-α) führen.Unser Fallbericht beschreibt einen jungen männlichen Patienten mit bereits bestehendem Morbus Crohn (CD). Die Symptome des Patienten wurden als Schub des M. Crohn falsch interpretiert und veranschaulichen die vielfältige Natur der WD-Infektion. Der Patient entwickelte nach Intensivierung der immunsuppressiven Therapie einen Therapie-refraktären Durchfall sowie zahlreiche opportunistische Infektionen mit tödlichem Ausgang.Patienten mit chronisch-entzündlicher Darmerkrankung (CED) sind nicht nur durch bekannte Infektionen mit Clostridium difficile oder Cytomegalovirus (CMV) gefährdet; eine Infektion mit T. whipplei sollte auch vor Eskalation der immunsuppressiven Therapie mittels Endoskopie und Biopsie ausgeschlossen werden.

Objective By loading transfer RNAs with their cognate amino acids, aminoacyl-tRNA synthetases (ARS) are essential for protein translation. Both cytosolic ARS1-deficiencies and mitochondrial ARS2 deficiencies can cause severe diseases. Amino acid supplementation has shown to positively influence the clinical course of four individuals with cytosolic ARS1 deficiencies. We hypothesize that this intervention could also benefit individuals with mitochondrial ARS2 deficiencies. Methods This study was designed as a N-of-1 trial. Daily oral L-phenylalanine supplementation was used in a 3-year-old girl with FARS2 deficiency. A period without supplementation was implemented to discriminate the effects of treatment from age-related developments and continuing physiotherapy. Treatment effects were measured through a physiotherapeutic testing battery, including movement assessment battery for children, dynamic gait index, gross motor function measure 66, and quality of life questionnaires. Results The individual showed clear improvement in all areas tested, especially in gross motor skills, movement abilities, and postural stability. In the period without supplementation, she lost newly acquired motor skills but regained these upon restarting supplementation. No adverse effects and good tolerance of treatment were observed. Interpretation and Conclusion Our positive results encourage further studies both on L-phenylalanine for other individuals with FARS2 deficiency and the exploration of this treatment rationale for other ARS2 deficiencies. Additionally, treatment costs were relatively low at 1.10 €/day.

Summary For years, clinicians and researchers working on giant cell arteritis have been battling with the conundrum of a disease that displays a short-term steroid responsiveness but is burdened by a remarkable risk of flares and chronic damage in the long term. This issue should be addressed by a change in the direction of research and clinical practice. Evidence suggests that giant cell arteritis is not a monolithic disease; it varies in extent and severity. Hence, treatment should be guided by disease stratification. The current one-size-fits-all strategy leads to overreliance on glucocorticoids and progression of glucocorticoid-related and disease-related complications. A new approach requires disease stratification using clinical, laboratory, histology, and imaging parameters. A giant cell arteritis registry might offer opportunities to scrutinise disease course and prognostic variables early; however, more studies that directly incorporate disease stratification through the above parameters are required. This Series paper also suggests that future clinical trials should be targeted at patients with different disease strata of giant cell arteritis and should incorporate ultrasound, PET-CT scanning, and other imaging modalities as key outcomes.

With the emergence of novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs), vaccination studies that elucidate the efficiency and effectiveness of a vaccination campaign are critical to assess the durability and the protective immunity provided by vaccines. SARS-CoV-2 vaccines have been found to induce robust humoral and cell-mediated immunity in individuals vaccinated with homologous vaccination regimens. Recent studies also suggest improved immune response against SARS-CoV-2 when heterologous vaccination strategies are employed. Yet, few data exist on the extent to which heterologous prime-boost-boost vaccinations with two different vaccine platforms have an impact on the T cell-mediated immune responses with a special emphasis on the currently dominantly circulating Omicron strain. In this study, we collected serum and peripheral blood mononuclear cells (PBMCs) from 57 study participants of median 35-year old’s working in the health care field, who have received different vaccination regimens. Neutralization assays revealed robust but decreased neutralization of Omicron VOC, including BA.1 and BA.4/5, compared to WT SARS-CoV-2 in all vaccine groups and increased WT SARS-CoV-2 binding and neutralizing antibodies titers in homologous mRNA prime-boost-boost study participants. By investigating cytokine production, we found that homologous and heterologous prime-boost-boost-vaccination induces a robust cytokine response of CD4+ and CD8+ T cells. Collectively, our results indicate robust humoral and T cell mediated immunity against Omicron in homologous and heterologous prime-boost-boost vaccinated study participants, which might serve as a guide for policy decisions.

BackgroundThe contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. Importantly, the risk of fomite-based transmission has not been systematically addressed.MethodsWe initiated this single-center observational study to evaluate whether hospitalized COVID-19 patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. Fifteen hospitalized patients with a high baseline viral load (CT value ≤ 25) shortly after admission were included. We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR and virus sequencing.ResultsNasopharyngeal and oropharyngeal swabs of all patients were positive for viral RNA on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2 %). While after coughing, no infectious virus could be recovered, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5 %).ConclusionsTransmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but unlikely to occur in real-life scenarios and from droplet-contaminated fomites.

Introduction: Diagnosis of lung nodules is still under investigation. We use computed tomography scans and positron emission tomography in order to identify their origin. Patients and Methods: In our retrospective study, we included 248 patients with a single lung nodule or multiple lung nodules of size ≥1 cm. We used a radial-endobronchial ultrasound and a C-Arm. We used a 1.1 mm cryoprobe versus a 22G needle vs. forceps/brush. We compared the sample size of each biopsy method with the number of cell-block slices. Results: Central lesions indifferent to the method provided the same mean number of cell-block slices (0.04933–0.02410). Cryobiopsies provide less sample size for peripheral lesions due to the higher incidence of pneumothorax (0.04700–0.02296). Conclusion: The larger the lesion ≥2 cm, and central, more cell-blocks are produced indifferent to the biopsy method (0.13386–0.02939). The time of the procedure was observed to be less when the C-Arm was used as an additional navigation tool (0.14854–0.00089).

Aberrant expression of dystrophin, utrophin, dysferlin, or calpain-3 was originally identified in muscular dystrophies (MDs). Increasing evidence now indicates that these proteins might act as tumor suppressors in myogenic and non-myogenic cancers. As DNA damage and somatic aneuploidy, hallmarks of cancer, are early pathological signs in MDs, we hypothesized that a common pathway might involve the centrosome. Here, we show that dystrophin, utrophin, dysferlin, and calpain-3 are functional constituents of the centrosome. In myoblasts, lack of any of these proteins caused excess centrosomes, centrosome misorientation, nuclear abnormalities, and impaired microtubule nucleation. In dystrophin double-mutants, these defects were significantly aggravated. Moreover, we demonstrate that also in non-myogenic cells, all four MD-related proteins localize to the centrosome, including the muscle-specific full-length dystrophin isoform. Therefore, MD-related proteins might share a convergent function at the centrosome in addition to their diverse, well-established muscle-specific functions. Thus, our findings support the notion that cancer-like centrosome-related defects underlie MDs and establish a novel concept linking MDs to cancer.

ObjectivesTo develop an Outcome Measures in Rheumatology (OMERACT) ultrasonography score for monitoring disease activity in giant cell arteritis (GCA) and evaluate its metric properties.MethodsThe OMERACT Instrument Selection Algorithm was followed. Forty-nine members of the OMERACT ultrasonography large vessel vasculitis working group were invited to seven Delphi rounds. An online reliability exercise was conducted using images of bilateral common temporal arteries, parietal and frontal branches as well as axillary arteries from 16 patients with GCA and 7 controls. Sensitivity to change and convergent construct validity were tested using data from a prospective cohort of patients with new GCA in which ultrasound-based intima–media thickness (IMT) measurements were conducted at weeks 1, 3, 6, 12 and 24.ResultsAgreement was obtained (92.7%) for the OMERACT GCA Ultrasonography Score (OGUS), calculated as follows: sum of IMT measured in every segment divided by the rounded cut-off values of IMTs in each segment. The resulting value is then divided by the number of segments available. Thirty-five members conducted the reliability exercise, the interrater intraclass correlation coefficient (ICC) for the OGUS was 0.72–0.84 and the median intrareader ICC was 0.91. The prospective cohort consisted of 52 patients. Sensitivity to change between baseline and each follow-up visit up to week 24 yielded standardised mean differences from −1.19 to −2.16, corresponding to large and very large magnitudes of change, respectively. OGUS correlated moderately with erythrocyte sedimentation rate, C reactive protein and Birmingham Vasculitis Activity Score (corrcoeff0.37–0.48).ConclusionWe developed a provisional OGUS for potential use in clinical trials.

Aim: We aimed to observe the clinical practicing value of radial endobronchial ultrasonography evaluating airway wall thickness before and after bronchial thermoplasty. Methods: We selected two patients who received bronchial thermoplasty in our hospital. We measured the thickness of each segmental airway wall of each patient by radial endobronchial ultrasonography, and observed the difference before and after the therapy. All the treatments and measurement were performed by a designated bronchoscopist and the locations and depths of the ultrasound probe were relatively fixed, to reduce the operational error. Results: In both two patients, the mean thicknesses of all segmental airway walls was 4.9 ± 0.7 mm before the first session of BT; the mean thickness was 4.13 ± 0.92 mm before the second session; the mean thickness was 2.69 ± 0.68 mm before the third session; the mean thickness was 2.7 ± 0.5 mm in the follow-up measurement at six months after the BT treatment; all thicknesses of airway wall were significantly reduced comparing with those before treatment; all the thicknesses of the airway walls were stable without any tendency of thickening after six months. Although the airways in the right middle lobe of both two patients were not received BT, their thicknesses were also decreased comparing with those before the treatment; both upper lobes bronchus of both two patients were not activated in the first and second sessions, but their thicknesses were also decreased at the third measurement. Conclusion: Radial endobronchial ultrasonography is a simple and practical method to measure the thickness of patient's airway wall. Bronchial thermoplasty can effectively reduce the thickness of airway wall. It can reduce airway smooth muscle by direct activation and other possible more complicated mechanism, which need further research.

ObjectivesTo develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR).MethodsA systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously.ResultsFive overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment.ConclusionThese are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.

X-linked lymphoproliferative disease (XLP1) is a combined immunodeficiency characterized by severe immune dysregulation caused by mutations in the SH2D1A/SAP gene. Loss or dysfunction of SH2D1A is associated with the inability in clearing Epstein-Barr-Virus (EBV) infections. Clinical manifestation is diverse and ranges from life-threatening hemophagocytic lymphohistiocytosis (HLH) and fulminant infectious mononucleosis (FIM) to lymphoma and antibody deficiency. Rare manifestations include aplastic anemia, chronic gastritis and vasculitis. Herein, we describe the case of a previously healthy eight-year old boy diagnosed with XLP1 presenting with acute non-EBV acute meningoencephalitis with thrombotic occlusive vasculopathy. The patient developed multiple cerebral aneurysms leading to repeated intracerebral hemorrhage and severe cerebral damage. Immunological examination was initiated after development of a susceptibility to infections with recurrent bronchitis and one episode of severe pneumonia and showed antibody deficiency with pronounced IgG1-3-4 subclass deficiency. We could identify a novel hemizygous SH2D1A point mutation affecting the start codon. Basal levels of SAP protein seemed to be detectable in CD8+ and CD4+ T- and CD56+ NK-cells of the patient what indicated an incomplete absence of SAP. In conclusion, we could demonstrate a novel SH2D1A mutation leading to deficient SAP protein expression and a rare clinical phenotype of non-EBV associated acute meningoencephalitis with thrombotic occlusive vasculopathy.

Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse.To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment. This is achieved through the combination of Dasatinib and Epacadostat integrated into biodegradable nanosomes which can inhibit and reverse Treg-supporting immunosuppression. Flow cytometry and immunofluorescence analysis, PET/CT scan, PTT/PA imaging and the Balb/c tumor model were used to explore the anti-tumor effect of Treg-targeted NCs both in vitro and in vivo.Findings reveal that NC treatment triggered substantial tumor cell apoptosis and drastically decreased tumor volume followed by downregulation of Ki-67 antigen expression, respectively. Drug circulation time was also increased as shown by biodistribution analysis accompanied by greater accumulation in lung and peripheral tissues. Intratumoral Th1 cytokines' expression was also increased, especially TNF-A, IL-12 by 42%, and IL-6 by 18% compared to PBS treatment. In addition, the presence of mature CD80Overall, our findings present a novel nano-enabled platform for the inhibition of Treg-dependent immunosuppression in NSCLC and provide a novel nanotherapeutic strategy for the treatment of metastatic neoplasia.

Objectives To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. Methods Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0–2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2–3, and at weeks 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. Results Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8. Conclusion Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA. Trial registration ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.

Background: Inhaled drugs have been available in the market for several years and for several diseases. Drugs for chronic obstructive pulmonary disease, cystic fibrosis, and diabetes have been used for several years. In the field of drug modification, these drugs range from tablets to aerosol. Methods: Milling as used to break down the tablets to powder and nebulisers are used to produce aerosol droplets. A mastersizer was used to measure the mass median aerodynamic diameter of the aerosol droplets. Results: Apremilast produced mmad diameters (2.43 μm) without any statistical difference between the different jet-nebulizers. The residual cup B contributed to greater mmad diameters as the 95% interval of mean values, based on those the ANOVA mean square clearly indicated, followed by cups C and F. The previous interval plot is much better clarified when the interaction means between drug and residual cap are plotted. The residual cups B, C and F produce mmad between (2.0–3.2). Conclusion: In the current research study we demonstrated our methodology to create apremilast powder and produce apremilast aerosol droplets with different nebulisers and residual cups.

e18603 Background: Cancer patients (pts) were among the first to receive vaccination against SARS-CoV-2 (vac). However, their attitude towards as well as experience with vac remain unclear. Methods: Between 04-11/2021 cancer pts at our university cancer center completed a baseline (BL) and follow-up (FU) questionnaire (Q) containing multiple choice questions and ten eleven-level Likert items ranging from 1 (“totally disagree”) to 11 (“totally agree”). Data was analyzed using Student’s t-test or Chi-square test. Results: 219 pts (43% female) completed BLQ (110 FUQ). Mean age was 64 (24-87) years. 82% had solid tumors, 93% were on active therapy (80% chemotherapy). 4% had history of COVID-19. 78% had already received at least one vac at BL, mainly BNT162b2 (91%) or ChAdOx1-S (8%). Only 1% refused vac. Most pts completely agreed to “definitely get vaccinated” (82%) and completely disagreed with “vac is dispensable due to COVID-19 being no serious threat” (82%; more dissent among men, p = 0.037) or “being against vaccination in general” (81%). Self-assessment as member of a risk group (p = 0.03) and fear of COVID-19 (p = 0.002) were more common among women. Every third patient (31%) completely agreed to “being afraid of COVID-19”, every second thinks “SARS-CoV-2 infection would be very dangerous” (56%). Only 41% expressed “complete confidence in the vaccine being safe” and 37% “not being afraid of side effects”. Fear of side effects (SE) was more common among women (p = 0.0016), pts with solid tumors (p = 0.05), with GI tumors (p < 0.0001) and below mean age (p = 0.006). The latter expressed less “confidence in the vaccine being safe” (p = 0.0029). At FUQ, most pts (91%) reported their vac to be well tolerated, 44% reported no SE, especially men (p = 0.001) and pts above age average (p = 0.002). Most common SE was local pain at injection site (36%), which was more frequent among women (p = 0.002), younger pts (p = 0.024) and pts with solid tumors (p = 0.04). Other common SE included fatigue (18%) and myalgia (8%). No thromboembolic events occurred. Only 3 pts had their therapy postponed due to SE. Almost all pts felt retrospectively sufficiently informed about vac and possible SE (94%), would have it again (88%) and agree to get it yearly, if recommended (78%). After vac, pts felt safe meeting friends or family (91%) or shopping (62%). Vacation (32%), work (22%), public transport (21%) or sports (19%) were considered less safe (less frequent among men, p < 0.05). Most pts (70%) did not feel that the COVID-19 pandemic negatively influenced their treatment and regarded the hospitals protective measures as adequate (91%). Conclusions: Willingness to get vac is high among cancer pts and vac is well tolerated in this sensitive cohort. However, concerns about vac safety remain an issue. Those as well as gender differences need to be addressed to increase vac rates and tolerability. The present results may help identify pts that benefit from more detailed pre-vac consultation.

Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases.A variety of endoscopic tools for local treatment exist, especially for treating malignancies. Using these endoscopic tools, one can administer drugs specifically designed for the airways.This article presents all locally administered treatment options and provides useful insights for future local endoscopically applied treatments.

Aerosolised drugs have been approved for several diseases such as cystic fibrosis and diabetes. Moreover; there are already drugs for pulmonary hypertension in aerosol form already on the market.Two drugs for pulmonary hypertension (Tadalafil and Macitentan) were milled and transformed from tablets to powder. Three different jet-nebulizers with seven different residual cups were combined. Moreover, we used 3 different ultrasound nebulizers with two different release methods.The drug and residual cup designs produce alone or jointly different MMAD diameters. The three large (10 mls) residual cups with the jet-nebulisers produced the smallest aerosol droplets. Both ultrasound nebulisers are capable of producing optimal size aerosol droplets ≤5 μm mmad.These two drugs can be easily administered as aerosol and an vivo clinical study will prove the safety for the airways.