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Rheumatologists are increasingly utilizing ultrasound for suspected giant cell arteritis (GCA) or Takayasu arteritis (TAK). This enables direct confirmation of a suspected diagnosis within the examination room without further referrals. Rheumatologists can ask additional questions and explain findings to their patients while performing ultrasound, preferably in fast-track clinics to prevent vision loss. Vascular ultrasound for suspected vasculitis was recently integrated into rheumatology training in Germany. New European Alliance of Associations for Rheumatology recommendations prioritize ultrasound as the first imaging tool for suspected GCA and recommend it as an imaging option for suspected TAK alongside magnetic resonance imaging, positron emission tomography and computed tomography. Ultrasound is integral to the new classification criteria for GCA and TAK. Diagnosis is based on consistent clinical and ultrasound findings. Inconclusive cases require histology or additional imaging tests. Robust evidence establishes high sensitivities and specificities for ultrasound. Reliability is good among experts. Ultrasound reveals a characteristic non-compressible ‘halo sign’ indicating intima-media thickening (IMT) and, in acute disease, artery wall oedema. Ultrasound can further identify stenoses, occlusions and aneurysms, and IMT can be measured. In suspected GCA, ultrasound should include at least the temporal and axillary arteries bilaterally. Nearly all other arteries are accessible except the descending thoracic aorta. TAK mostly involves the common carotid and subclavian arteries. Ultrasound detects subclinical GCA in over 20% of polymyalgia rheumatica (PMR) patients without GCA symptoms. Patients with silent GCA should be treated as GCA because they experience more relapses and require higher glucocorticoid doses than PMR patients without GCA. Scores based on intima-thickness (IMT) of temporal and axillary arteries aid follow-up of GCA, particularly in trials. The IMT decreases more rapidly in temporal than in axillary arteries. Ascending aorta ultrasound helps monitor patients with extracranial GCA for the development of aneurysms. Experienced sonologists can easily identify pitfalls, which will be addressed in this article.

Abstract Background Giant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA. Methods This Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized. Results Of the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n = 6/13) of patients in SAR200 + 26W, 43% (n = 3/7) in SAR150 + 26W, 30% (n = 3/10) in PBO + 52W, and 0 (n = 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n = 6/10) in PBO + 52W and 17% (n = 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n = 6/13, SAR200 + 26W), 43% (n = 3/7, SAR150 + 26W), 60% (n = 6/10, PBO + 52W), and 33% (n = 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80–100%) experienced treatment-emergent adverse events, with similar incidences reported across groups. Conclusions Owing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings. Trial registration ClinicalTrials.gov NCT03600805. Registered on July 26, 2018.

Abstract Background One key pathological finding in giant cell arteritis (GCA) is the presence of interferon-gamma and interleukin (IL)-17 producing T helper (Th) 1 and Th17 cells in affected arteries. There is anecdotal evidence of successful induction and maintenance of remission with the monoclonal anti-IL-17A antibody secukinumab. Inhibition of IL-17A could therefore represent a potential new therapeutic option for the treatment of GCA. Methods This is a randomized, parallel-group, double-blind, placebo-controlled, multi-center, phase II study in which patients, treating physicians, and the associated clinical staff as well as the sponsor clinical team are blinded. It is designed to evaluate efficacy and safety of secukinumab compared to placebo in combination with an open-label prednisolone taper regimen. Patients included are naïve to biological therapy and have newly diagnosed or relapsing GCA. Fifty patients are randomly assigned in a 1:1 ratio to receive either 300 mg secukinumab or placebo subcutaneously at baseline, weeks 1, 2 and 3, and every 4 weeks from week 4. Patients in both treatment arms receive a 26-week prednisolone taper regimen. The study consists of a maximum 6-week screening period, a 52-week treatment period (including the 26-week tapering), and an 8-week safety follow-up, with primary and secondary endpoint assessments at week 28. Patients who do not achieve remission by week 12 experience a flare after remission or cannot adhere to the prednisolone tapering will enter the escape arm and receive prednisolone at a dose determined by the investigator’s clinical judgment. The blinded treatment is continued. Two optional imaging sub-studies are included (ultrasound and contrast-media enhanced magnetic resonance angiography [MRA]) to assess vessel wall inflammation and occlusion before and after treatment. The primary endpoint is the proportion of patients in sustained remission until week 28 in the secukinumab group compared to the proportion of patients in the placebo group. A Bayesian approach is applied. Discussion The trial design allows the first placebo-controlled data collection on the efficacy and safety of secukinumab in patients with GCA. Trial registration ClinicalTrials.gov NCT03765788 . Registration on 5 December 2018, prospective registration, EudraCT number 2018-002610-12; clinical trial protocol number CAIN457ADE11C.

Abstract Introduction To evaluate the efficacy and safety of sirukumab in giant cell arteritis (GCA). Methods In this multicentre, randomised, double-blind, placebo-controlled, two-part phase 3 trial (NCT02531633; Part A [52-week double-blind treatment]; Part B [104-week follow-up]), patients with GCA were randomised (3:3:2:2:2) to sirukumab 100 mg every 2 weeks plus 6-month or 3-month prednisone taper, sirukumab 50 mg every 4 weeks plus 6-month prednisone taper, or placebo every 2 weeks plus 6-month or 12-month prednisone taper. The primary endpoint was the proportion of patients in sustained remission at week 52. Secondary endpoints included disease flare and safety. The study was terminated early (October 2017; sponsor decision). Results Of 161 patients randomised (sirukumab: n = 107; placebo: n = 54), 28 (17.4%) completed week 52 (median treatment duration: 24–30 weeks). In a revised intent-to-treat (ITT) subgroup (completed week 52 or discontinued before study termination [n = 55]); six patients (all receiving sirukumab) achieved the primary endpoint. In the ITT population (n = 161), the proportion of patients with flares (week 2–52) was lower with sirukumab (18.4–30.8%) than placebo (37.0–40.0%). The proportion of patients with flares (week 2–12) was highest with sirukumab 100 mg every 2 weeks plus 3-month prednisone taper (23.1%). In Part A, 94.4% of patients reported ≥ 1 treatment-emergent adverse event (TEAE); 19.3% reported serious TEAEs. The proportions of patients with TEAEs were generally similar across treatment arms. No deaths occurred. Conclusions Although data were limited due to early termination and shortened treatment duration, sirukumab treatment resulted in numerically lower proportions of patients with flare by week 52 versus placebo, with no unexpected safety findings. Trial Registration Clinicaltrials.gov: NCT02531633.

Aims: To assess intima-media thickness (IMT) changes measured by ultrasound in axillary arteries of giant cell arteritis (GCA) patients over time and to calculate an ultrasound cut-off value for the diagnosis of chronic axillary artery involvement in patients with longstanding GCA. Methods: Ultrasound of both axillary arteries was performed in 109 GCA patients at time of diagnosis and at several follow-up visits and in 40 healthy controls (HCs). IMT determined at the prospective follow-up visit was compared between GCA patients with (axGCA) and without (non-axGCA) vasculitis of axillary arteries at baseline, as well as with HCs. Changes in IMT were depicted. Receiver operating characteristics were performed for cut-off calculations. Inter-/intra-rater agreement was evaluated using stored images and intraclass correlation coefficient (ICC). Results: Seventy-three patients were in the axGCA and 36 in the non-axGCA group. Pathological IMT of axillary arteries (axGCA) declined in the first 18 months of treatment by −0.5 mm, (range −2.77 to 0.50), independent of age and gender. Median IMT, after median disease duration of 48 months (16–137), was 0.90 mm (0.46–2.20) in axGCA and 0.60 mm (0.42–1.0) in the non-axGCA group pooled with HCs. An IMT of 0.87 mm was highly specific (specificity 96%, sensitivity 61%) for diagnosis of chronic axGCA. Intra-rater and inter-reader agreement of ultrasound images were good [ICC 0.96–1.0 (three readers) and 0.87, respectively]. Conclusion: Pathological IMT of the axillary artery declined under treatment. An IMT of 0.87 mm is highly specific for diagnosis of chronic vasculitis of axillary arteries in long-standing GCA patients.

Patients with systemic autoimmune rheumatic diseases (SARD) often receive abdominal ultrasound examinations to screen for organ involvement; yet, the spectrum of findings and their clinical relevance are poorly understood. We conducted a retrospective chart review of inpatients from a rheumatological referral centre with an abdominal ultrasound between 1 January2006 and 31 December 2015, examining 1092 SARD patients with a total of 1695 inpatient stays. The mean age was 55.1 years (range: 17–90 years, SD: 15.8), and the mean disease duration was 6.4 years (range: 0.0–52.8 years, SD: 9.1). A total of 87.5% of the patients were female. The most frequent ultrasound findings were hepatic steatosis (in 26.8% of all patients), splenomegaly (15.2% of all patients), pancreatic lipomatosis (14.3% of all patients) and aortic sclerosis (13.9% of all patients). Based on glucocorticoid and disease-modifying antirheumatic drug use, we identified cases where immuno-modulatory medication was escalated; there was an association between therapy escalation and the findings of hepatomegaly and pleural effusion (as tested via Fisher’s exact test). In patients with several examinations during the defined time span (n = 318), we found ultrasound findings to change, especially findings of hepatomegaly, pleural effusion and splenomegaly. When justifying decisions regarding the further treatment of a patient in the discharge letter, abdominal ultrasound results were rarely discussed. Abdominal ultrasound rarely yielded disease-specific or treatment-changing results.

Objective. A study supported by the EULAR and the ACR being conducted to establish classification criteria for polymyalgia rheumatica (PMR) will include ultrasound examination of the shoulders and hips. Ultrasound (US) depicts glenohumeral joint effusion, biceps tenosynovitis, subdeltoid bursitis, hip joint synovitis, and trochanteric bursitis in PMR. These findings may aid in distinguishing PMR from other diseases. The purpose of this study was to assess standards and US interreader agreement of participants in the PMR classification criteria study. Methods. Sixteen physicians in four groups examined shoulders and hips of 4 patients and 4 healthy adults with ultrasound. Overall agreement and interobserver agreement were calculated. Results. The overall agreement (OA) between groups was 87%. The OA for healthy shoulders was 88.8%, for healthy hips 100%, for shoulders with pathology 85.2%, and 74.3% for hips with pathology, respectively. Conclusion. There was a high degree of agreement found for the examination of healthy shoulders and pathologic hips. Agreement was moderate for pathologic shoulders and perfect for healthy hips. US of shoulder and hips performed by different examiners is a reliable and feasible tool for assessment of PMR related disease pathology and can be incorporated into a classification criteria study.

Introduction: Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases. Methods: 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. Discussion: This article presents all locally administered treatment options and provides useful insights for future local endoscopically applied treatments.

Introduction: 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. Materials and methods: 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. Results: 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. Conclusions: These two drugs can be easily administered as aerosol and an vivo clinical study will prove the safety for the airways.

Background: To evaluate the benefit of second-line chemotherapy with platinum-based treatment in patients with recurrent small cell lung cancer (SCLC). Patients and methods: A total of 535 patients continued with follow-up or best supportive care if needed, and 229 patients who progressed after the completion of first-line chemotherapy were treated with second-line chemotherapy at the time of progression. In total, 103/229 patients received paclitaxel 190 mg/m² and carboplatin 5.5 area under the curve while 126/229 patients received etoposide 200 mg/m² and carboplatin 5.5 area under the curve every 28 days. Results: Patients administered second-line chemotherapy lived significantly longer, with a median survival of 422 days compared to 228 days in patients with best supportive care alone (P<0.001). Patients who received paclitaxel as second-line chemotherapy lived for an average of 462 days (95% confidence interval: 409-514), versus 405 days in the etoposide group (95% confidence interval: 371-438), which was not statistically significant (P=0.086). The overall response rate was 8% for the paclitaxel group and 6% for the etoposide group. Patients with progression of the disease in more than 3 months had significantly better survival compared with those that progressed in less than 3 months (P<0.001). Conclusion: Continuation with carboplatin/paclitaxel or carboplatin/etoposide as second-line chemotherapy has no significant survival impact, and it did not improve response rates. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a marker of airway inflammation and indirectly a general indicator of inflammation and oxidative stress. NO is a contributing factor in lung cancer at an early stage and also after chemotherapy treatment of lung cancer. We studied whether exhaled NO levels were altered by three cycles of chemotherapy at diagnosis and after chemotherapy, and whether, directly or indirectly, these changes were related to the course of disease. Also, a correlation of NO levels with other markers of inflammation was performed. We studied 42 patients diagnosed early: 26 men and 16 women with lung cancer. We analyzed blood tests for control of inflammatory markers, functional pulmonary tests, and alveolar exhaled NO. We recorded a decrease in exhaled NO after three cycles of chemotherapy in all patients, regardless of histological type and stage: there were 42 patients with mean 9.8 NO after three cycles (average 7.7). Also, a strong correlation appeared between NO measurements before and after chemotherapy and C-reactive protein (P < 0.05, r = 0.42, before) and (P < 0.045, r = 0.64, after). NO alveolar measurement as an indicator of airway inflammation indicates response to chemotherapy in lung cancer. Also, the inflammatory process in lung cancer was confirmed and indicated response to chemotherapy through an index that is sensitive to inflammatory disease of the airways. [ABSTRACT FROM AUTHOR]

Abstract.  Given a finite subset of an additive group such as or , we are interested in efficient covering of by translates of , and efficient packing of translates of in . A set provides a covering if the translates with cover (i.e., their union is ), and the covering will be efficient if has small density in . On the other hand, a set will provide a packing if the translated sets with are mutually disjoint, and the packing is efficient if has large density. In the present part (I) we will derive some facts on these concepts when , and give estimates for the minimal covering densities and maximal packing densities of finite sets . In part (II) we will again deal with , and study the behaviour of such densities under linear transformations. In part (III) we will turn to . [ABSTRACT FROM AUTHOR]

Abstract. Subsets [script A], [script S] of an additive group G are complementary if [script A] + [script S] = G. When [script A] is of finite cardinality ∣[script A]∣, and G is ℤ or ℝ, we give sufficient conditions for the existence of a complementary set [script S] with "density" not much larger than 1/∣[script A]∣. [ABSTRACT FROM AUTHOR]

Let $f$ be a polynomial in one variable with integer coefficients, and $p$ a prime. A solution of the congruence $f(x) \equiv 0 (\text{mod} p)$ may branch out into several solutions modulo $p^{2}$, or it may be extended to just one solution, or it may not extend to any solution. Again, a solution modulo $p^{2}$ may or may not be extendable to solutions modulo $p^{3}$, etc. In this way one obtains the ``solution tree'' $T = T(f)$ of congruences modulo $p^{\lambda }$ for $\lambda = 1,2,\ldots $. We will deal with the following questions: What is the structure of such solution trees? How many ``isomorphism classes'' are there of trees $T(f)$ when $f$ ranges through polynomials of bounded degree and height? We will also give bounds for the number of solutions of congruences $f(x) \equiv 0 (\text{mod} p^{\lambda })$ in terms of $p, \lambda $ and the degree of $f$. [ABSTRACT FROM AUTHOR]

Abstract Background Glucocorticoids (GC) are the standard treatment for giant cell arteritis (GCA), even though they are associated with adverse side effects and high relapse rates. Tocilizumab (TCZ), an interleukin-6 receptor antagonist, has shown promise in sustaining remission and reducing the cumulative GC dosage, but it increases the risk of infections and is expensive. After discontinuation of TCZ, only about half of patients remain in remission. Additionally, only few studies have been conducted looking at remission maintenance, highlighting the need for alternative strategies to maintain remission in GCA. Methotrexate (MTX) has been shown to significantly decrease the risk of relapse in new-onset GCA and is already a proven safe drug in many rheumatologic diseases. Methods This study aims to evaluate the efficacy and safety of MTX in maintaining remission in patients with GCA who have previously been treated with GC and at least 6 months with TCZ. We hypothesize that MTX can maintain remission in GCA patients, who have achieved stable remission after treatment with GC and TCZ, and prevent the occurrence of relapses. The study design is a monocentric, randomized, double-blind, placebo-controlled, parallel-group phase II trial randomizing 40 GCA patients 1:1 into a MTX or placebo arm. Patients will receive 17.5 mg MTX/matching placebo weekly by subcutaneous injection for 12 months, with the possibility of dose reduction if clinically needed. A 6-month follow-up will take place. The primary endpoint is the time to first relapse in the MTX group versus placebo during the 12-month treatment period. Secondary outcomes include patient- and investigator-reported outcomes and laboratory findings, as well as the prevalence of aortitis, number of vasculitic vessels, and change in intima-media thickness during the study. Discussion This is the first clinical trial evaluating remission maintenance of GCA with MTX after a previous treatment cycle with TCZ. Following the discontinuation of TCZ in GCA, MTX could be a safe and inexpensive drug. Trial registration ClinicalTrials.gov, NCT05623592. Registered on 21 November 2022. EU Clinical Trials Register, 2022-501058-12-00. German Clinical Trials Register DRKS00030571.

Abstract The leading first‐in‐class ruthenium‐complex BOLD‐100 currently undergoes clinical phase‐II anticancer evaluation. Recently, BOLD‐100 is identified as anti‐Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD‐100‐resistant colon and pancreatic carcinoma cells. Acute BOLD‐100 treatment reduces lipid droplet contents of BOLD‐100‐sensitive but not ‐resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD‐100‐resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame‐shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl‐coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell‐free BOLD‐100‐CoA adduct formation suggesting acetyl‐CoA depletion as mechanism bridging BOLD‐100‐induced lipid metabolism alterations and histone acetylation‐mediated gene expression deregulation. Indeed, BOLD‐100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de‐acetylation as central mode‐of‐action of BOLD‐100 and metabolic programs stabilizing histone acetylation as relevant Achilles’ heel of acquired BOLD‐100‐resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD‐100 responsiveness. Summarizing, BOLD‐100 is identified as epigenetically active substance acting via targeting several onco‐metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD‐100 resistance opens novel strategies to tackle therapy failure.

Objectives To update the evidence on imaging for diagnosis, monitoring and outcome prediction in large vessel vasculitis (LVV) to inform the 2023 update of the European Alliance of Associations for Rheumatology recommendations on imaging in LVV.Methods Systematic literature review (SLR) (2017–2022) including prospective cohort and cross-sectional studies (>20 participants) on diagnostic, monitoring, outcome prediction and technical aspects of LVV imaging. Diagnostic accuracy data were meta-analysed in combination with data from an earlier (2017) SLR.Results The update retrieved 38 studies, giving a total of 81 studies when combined with the 2017 SLR. For giant cell arteritis (GCA), and taking clinical diagnosis as a reference standard, low risk of bias (RoB) studies yielded pooled sensitivities and specificities (95% CI) of 88% (82% to 92%) and 96% (95% CI 86% to 99%) for ultrasound (n=8 studies), 81% (95% CI 71% to 89%) and 98% (95% CI 89% to 100%) for MRI (n=3) and 76% (95% CI 67% to 83%) and 95% (95% CI 71% to 99%) for fluorodeoxyglucose positron emission tomography (FDG-PET, n=4), respectively. Compared with studies assessing cranial arteries only, low RoB studies with ultrasound assessing both cranial and extracranial arteries revealed a higher sensitivity (93% (95% CI 88% to 96%) vs 80% (95% CI 71% to 87%)) with comparable specificity (94% (95% CI 83% to 98%) vs 97% (95% CI 71% to 100%)). No new studies on diagnostic imaging for Takayasu arteritis (TAK) were found. Some monitoring studies in GCA or TAK reported associations of imaging with clinical signs of inflammation. No evidence was found to determine whether imaging severity might predict worse clinical outcomes.Conclusion Ultrasound, MRI and FDG-PET revealed a good performance for the diagnosis of GCA. Cranial and extracranial vascular ultrasound had a higher pooled sensitivity with similar specificity compared with limited cranial ultrasound.

Bronchial atresia corresponds to a congenital anomaly of the airways, in which a bronchial segment presents a focal obstruction. As a result, there are mucoid impactions with or without bronchocele, resulting in air trapping and distention of the lung parenchyma. In the present study, we report the case of a patient incidentally diagnosed with bronchial atresia when undergoing chest computed tomography after performing thoracic sympathectomy as a treatment for palmoplantar hyperhidrosis. Classically, the diagnosis is made incidentally with an asymptomatic patient, but cough, shortness of breath, wheezing, hemoptysis, chest pain, or pneumothorax may be present. There is still no established consensus on the treatment of this pathology, but in asymptomatic patients, the usual approach is conservative, with outpatient follow-up.

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular insufficiency syndrome presenting with an ejection fraction (EF) of greater than 50% along with different proinflammatory and metabolic co-morbidities. Despite previous work provided key insights into our understanding of HFpEF, effective treatments are still limited. In the current study we attempted to unravel the molecular basis of sex-dependent differences in HFpEF pathology. We analyzed left ventricular samples from 1-year-old female and male transgenic (TG) rats homozygous for the rat Ren-2 renin gene (mRen2) characterized with hypertension and diastolic dysfunction and compared it to age-matched female and male wild type rats (WT) served as control. Cardiomyocytes from female and male TG rats exhibited an elevated titin-based stiffness (Fpassive), which was corrected to control level upon treatment with reduced glutathione indicating titin oxidation. This was accompanied with high levels of oxidative stress in TG rats with more prominent effects in female group. In vitro supplementation with heat shock proteins (HSPs) reversed the elevated Fpassive indicating restoration of their cytoprotective function. Furthermore, the TG group exhibited high levels of proinflammatory cytokines with significant alterations in apoptotic and autophagy pathways in both sexes. Distinct alterations in the expression of several proteins between both sexes suggest their differential impact on disease development and necessitate distinct treatment options. Hence, our data suggested that oxidative stress and inflammation distinctly drive diastolic dysfunction and remodeling in female and male rats with HFpEF and that the sex-dependent mechanisms contribute to HF pathology.

Objective. Ophthalmic complications are common in acute GCA. Do temporal artery ultrasound and clinical parameters correlate with the occurrence and severity of ophthalmic complications? Methods. The results of temporal artery ultrasound examinations are compared with the occurrence of anterior ischaemic optic neuropathy (AION), central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), diplopia and amaurosis fugax in 222 consecutive patients with newly diagnosed, active GCA. Results. Temporal artery ultrasound displayed vasculitic wall swelling (halo), stenoses and/or acute occlusions in 84% (58% in 67 large-vessel GCA patients and 95% in 155 patients without proximal arm vasculitis). Ophthalmic complications occurred in 64 (29%), AION in 30 (14%), CRAO in 7 (3%), BRAO in 2 (1%), amaurosis fugax in 16 (7%) and diplopia in 9 patients (4%). Ophthalmic complications were insignificantly more common if temporal artery ultrasound was positive (31 vs 17%; P = 0.11) as a greater number of patients without arm vasculitis showed eye involvement (34 vs 18%; P = 0.02). The number of pathological temporal artery segments, presence of stenoses or bilateral findings did not correlate with ophthalmic complications. Age  72 yrs at diagnosis correlated with a higher incidence of ophthalmic complications. Conclusion. Ophthalmic complications occurred less frequently if proximal arm vasculitis was present. Findings of temporal artery ultrasound did not correlate with eye complications. [ABSTRACT FROM AUTHOR]

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.

BackgroundSingle pulmonary nodules are a common issue in everyday clinical practice. Currently, there are navigation systems with radial-endobronchial ultrasound and electromagnetic navigation for obtaining biopsies. Moreover, rapid on-site evaluation can be used for a quick assessment. These small lesions, even when they do not have any clinically significant information with positron emission tomography, are important to investigate.Case descriptionRadiofrequency and microwave ablation have been evaluated as local treatment techniques. These techniques can be used as therapy for a patient population that cannot be operated on. Currently, one verified operating system is used for endoscopic radiofrequency ablation through the working channel of a bronchoscope.ConclusionIn our case, a new system was used to perform radiofrequency ablation with long-term follow-up.

Objective: Considering the essential role of KRAS mutation in NSCLC and the limited experience of PET radiomic features in KRAS mutation, a prediction model was built in our current analysis. Our model aims to evaluate the status of KRAS mutants in lung adenocarcinoma by combining PET radiomics and machine learning. Method: Patients were retrospectively selected from our database and screened from the NSCLC radiogenomic dataset from TCIA. The dataset was randomly divided into three subgroups. Two open-source software programs, 3D Slicer and Python, were used to segment lung tumours and extract radiomic features from 18F-FDG-PET images. Feature selection was performed by the Mann–Whitney U test, Spearman’s rank correlation coefficient, and RFE. Logistic regression was used to build the prediction models. AUCs from ROCs were used to compare the predictive abilities of the models. Calibration plots were obtained to examine the agreements of observed and predictive values in the validation and testing groups. DCA curves were performed to check the clinical impact of the best model. Finally, a nomogram was obtained to present the selected model. Results: One hundred and nineteen patients with lung adenocarcinoma were included in our study. The whole group was divided into three datasets: a training set (n = 96), a validation set (n = 11), and a testing set (n = 12). In total, 1781 radiomic features were extracted from PET images. One hundred sixty-three predictive models were established according to each original feature group and their combinations. After model comparison and selection, one model, including wHLH_fo_IR, wHLH_glrlm_SRHGLE, wHLH_glszm_SAHGLE, and smoking habits, was validated with the highest predictive value. The model obtained AUCs of 0.731 (95% CI: 0.619~0.843), 0.750 (95% CI: 0.248~1.000), and 0.750 (95% CI: 0.448~1.000) in the training set, the validation set and the testing set, respectively. Results from calibration plots in validation and testing groups indicated that there was no departure between observed and predictive values in the two datasets (p = 0.377 and 0.861, respectively). Conclusions: Our model combining 18F-FDG-PET radiomics and machine learning indicated a good predictive ability of KRAS status in lung adenocarcinoma. It may be a helpful non-invasive method to screen the KRAS mutation status of heterogenous lung adenocarcinoma before selected biopsy sampling.

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.

Abstract Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

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 (Conclusions: Cryobiopsy is a safe tool for patients with interstitial lung disease and can assist in the diagnosis of interstitial lung diseases. The survival of patients was increased in the cryobiopsy group versus only bronchoalveolar lavage for disease diagnosis.

Abstract The knowledge of airway length is the theoretical basis in the diagnosis and management of airway disease. The objective of this study is to measure the length of trachea and left and right main bronchus in Chinese Shanghai population. A total of 153 consecutive adult patients with minor pulmonary disease in Xinhua hospital were enrolled for bronchoscopy examination. Measurements were conducted on head and neck neutral position and height, weight and age for each patient were recorded either. Student t test and multiple linear regression was used to compare means between males and females and to analyze correlation among height, weight, sexual dimorphism and the lengths of the trachea and bronchus. The lengths of the trachea and left main bronchus are significantly different between male and female patients (P

Abstract Background There has been a shift in recent years to using ultrasound (US) and magnetic resonance imaging (MRI) as first-line investigations for suspected cranial large vessel vasculitis (LVV) and is a new recommendation by the EULAR 2018 guidelines for imaging in LVV. This cross-sectional study compares the performance of US and MRI and contrast-enhanced magnetic resonance angiography (MRA) for detecting vasculitis in patients with giant cell arteritis (GCA). Methods Patients with new-onset or already diagnosed GCA were recruited. The common temporal arteries and supra-aortic large vessels were evaluated by US and MRI/MRA. Blinded experts read the images and applied a dichotomous score (vasculitis: yes/no) in each vessel. Results Thirty-seven patients with giant cell arteritis (GCA) were recruited. Two patients were excluded. Of the remaining patients, nine had new-onset disease and 26 had established disease. Mean age was 71 years, and median C-reactive protein (CRP) was 7.5 mg/L. The median time between US and MRI was 1 day. Overall, US revealed vasculitic changes more frequently than MRI (p

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.

Nowadays immunotherapy is considered the tip of the arrow as treatment for non-small cell lung cancer for inoperable patients. Programmed death-ligand 1 is considered a valuable marker for the success of immunotherapy. The higher the score ≥50% the more successful the treatment will be. However; previous studies have presented favorable data even for those patients where the programmed death-ligand 1 was ≤50% or even 0%, therefore it can be administered as first line treatment in these patients with the addition of chemotherapy or radiotherapy. Other treatment modalities are tested as surrogates like gene therapy with immunotherapy to improve the results in patients with programmed death-ligand 1 was ≤50% or even 0%. The main issue for these patients is an adverse effect pneumonitis, in case we will present the valuable method of lung parenchyma sampling with cryobiopsy for early diagnosis of immunotherapy induced pneumonitis.

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.

Cholangitis in patients with ulcerative colitis (UC) can lead to misdiagnosis of primary sclerosing cholangitis (PSC). Furthermore, it can mimic cholangiocellular carcinoma, which also can lead to inappropriate and potentially harmful treatment of the patient. An 18-year-old male patient with known UC presented with pain in his right upper abdomen and elevation of the cholestatic liver enzymes (alkaline phosphatase: 197 U/L, γ-glutamyltransferase: 229 U/L) and increased inflammatory parameters (leukocytosis and CrP of 13.6 mg/L). Magnetic resonance cholangiopancreatography revealed unclear stenosis in the bifurcation of the main hepatic bile duct as well as in the prepapillary bile duct. Ultrasound (US) examination and endoscopic retrograde cholangiopancreatography showed dilatation of the intra -and extrahepatic bile ducts, which raised the suspicion of PSC. US image with dilated intra- and extrahepatic dilatation of the bile duct was also suggestive for autoimmune cholangitis. However, serum analysis revealed an elevated soluble interleukin-II receptor (1,305 U/mL), while immunoglobulin G4 was within normal ranges. Liver biopsy demonstrated hepatic inflammation and presence of granulomatous cells within the portal fields – convenient to sarcoidosis. After starting treatment with steroids, we observed a rapid clinical response with improvement of the dilated bile ducts and decrease of the initially elevated cholestatic liver enzymes. Sarcoidosis within the bile duct is a rare condition. Steroids are the treatment of choice and – along with the histology – are furthermore helpful to differentiate between several potential differential diagnoses like IgG4 cholangitis, primary biliary cholangitis, or PSC.

Bronchogenic cysts are rare congenital malformations which derive from primitive ventral foregut. They are usually observed in intrathoracically. A fifty year old male was admitted for the investigation of a three month chest pain. Computed tomography scan of the thorax revealed a lesion around the esophagus and left stem bronchus. Endobronchial ultrasound with convex probe and a 19G needle biopsy revealed a bronchogenic cystic which was removed with video assisted thoracic surgery. Initial radiologic assessment although was thought to be lung cancer because of the smoking habit it turned out to be benignancy. EBUS-TBNAB with 10G needle is safe and absolutely necessary for these lesions, as they take large samples.

A fifty year old male was diagnosed with bronchial HPV. He was treated with local interventional treatment argon plasma coagulation and subcutaneous injections bevacizumab. Spraying of the regions followed with a specially designed catheter with interferon-α (2b). Systematic treatment of esomeprazole was also administered. After six months the patient is disease free and on close follow-up.

A report a case of a 63 year old male diagnosed with lung cancer adenocarcinoma. The patient had a right paratracheal mass diagnosed with EBUS-TBNA 22G. The patient had surgery, however 7 days after the billau catheter was removed pneumothorax was diagnosed which did not resolved. Bronchoscopy reveled two minor fistulas in the interior wall of the trachea. An additional surgery was performed in order to add muscle patches on the exterior part of the trachea. Unfortunately additional stent placement was placed after a silicon stent since the muscle patches failed. We chose a metallic auto expandable stent since after three months of follow up a small metastatic lesion was observed in the liver. Stent placement is an option for these patients and the right stent has to be placed for each case.

Objective: To evaluate the contribution that unilateral thoracic sympathectomy in dominant side or two-stage bilateral thoracic sympathectomy can have as strategies to reduce the incidence of compensatory sweating after sympathectomy for palmar hyperhidrosis. Methods: This is a prospective, controlled, randomized multicenter trial of 200 participants with palmar hyperhidrosis, which will be randomized into two arms: (a) one-stage bilateral thoracic sympathectomy (control arm); or (b) unilateral thoracic sympathectomy in dominant side (intervention arm). At six months the participants submitted to unilateral procedure can make the contralateral surgery if they wanted it, creating a third group called two-stage bilateral sympathectomy. Participants will be evaluated for the degree of sweating by the Hyperhidrosis Disease Severity Scale (HDSS) and of quality of life questionnaires. Results: 96 participants out of the 200 proposed have been included so far, with 48 participants randomized to each arm. From the sample 61 (63.5%) are female, with a mean age of 24 (20–32) years. There were exclusive palmar hiperhydrosis in 14 cases (14.5%), palmar and plantar hyperhidrosis in 36 (37.5%) cases, palmar and axillar hyperhidrosis in 12 (12,5%) cases and palmar-axillary-plantar hyperhidrosis in 34 (35,4%) cases. The age at the beginning of the disease was childhood (78%), with mean of time of disease 15 (11–22) years. Conclusions: If one or both hypothesis: (a) unilateral sympathectomy in dominant hand is a satisfactory treatment; b) two-stage bilateral sympathectomy causes less compensatory sweating than in one stage are confirmed there is a chance that surgical therapy for palmar hyperhidrosis can be changed for better.

Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

Nowadays we have novel therapies for advanced stage non-small cell lung cancer. Immunotherapy has been introduced in the market for several years and until now its administration is mostly based on the programmed death-ligand 1. First line treatment with immunotherapy can be administered alone if programmed death-ligand 1 expression is ≥ 50%. All therapies for advanced stage disease have advantages and disadvantages, immunotherapy until now has presented mild adverse effects when compared to chemotherapy. However; it is known to induce inflammatory response to different tissues within the body. In our case acute pneumothorax was induced after immunotherapy administration.